Androgen Deprivation Therapy In Men Research Articles

Selective Estrogen Receptor Alpha Agonist GTx-758 Decreases Testosterone with Reduced Side Effects of Androgen Deprivation Therapy in Men with Advanced Prostate Cancer

BackgroundA need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course. ObjectiveTo assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency–related side effects of androgen-deprivation therapy. Design, setting, and participantsHormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000mg/d, 2000mg/d, or leuprolide depot. InterventionGTx-758 and leuprolide. Outcome measurements and statistical analysisThe primary end point was the proportion of patients achieving total testosterone ≤50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels. Results and limitationsOf 159 randomized patients, leuprolide reduced total testosterone to ≤50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000mg [p<0.001], GTx-758 2000mg [p=0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%). ConclusionsAlthough leuprolide reduced total testosterone to ≤50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs. Patient summaryThis paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events. Trial registrationClinicaltrials.gov identifier NCT01615120.

Intermittent versus continuous androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been the standard of care for metastatic prostate cancer for decades; however, the choice of continuous or intermittent administration is a matter of debate. Two large phase III trials have reported results comparing these 2 forms of ADT administration. The National Cancer Institute of Canada (NCIC) PR-7 trial studied men with an increasing prostate-specific antigen (PSA) level and no evidence of metastatic disease after definitive or salvage radiation therapy and radical prostatectomy. The Southwest Oncology Group 9346 trial studied men with newly diagnosed hormone-sensitive metastatic disease. The primary end point in both trials was overall survival with a noninferiority design. The NCIC trial showed that the overall survival in men treated with intermittent ADT was not inferior to that of men treated with continuous ADT, but the SWOG trial was inconclusive regarding noninferiority. Certain domains of quality of life were better in the intermittent arms of both trials. If using ADT in the setting of biochemical relapse, intermittent ADT should be strongly considered over continuous ADT, except perhaps in patients with Gleason score of 8 or higher. In men with metastatic disease, continuous ADT remains the standard of care, because the SWOG trial did not establish noninferiority of intermittent ADT with respect to survival. However, for those with significant side effects from ADT, establishing the risk group, as determined by PSA value after 7 months of ADT or the presence of pain at diagnosis, may help guide the choice of intermittent versus continuous ADT in men with metastatic disease.

Prostate progenitor cells proliferate in response to castration

Androgen-deprivation is a mainstay of therapy for advanced prostate cancer but tumor regression is usually incomplete and temporary because of androgen-independent cells in the tumor. It has been speculated that these tumor cells resemble the stem/progenitor cells of the normal prostate. The purpose of this study was to examine the response of slow-cycling progenitor cells in the adult mouse prostate to castration. Proliferating cells in the E16 urogenital sinus were pulse labeled by BrdU administration or by doxycycline-controlled labeling of the histone-H2B GFP mouse. A small population of labeled epithelial cells in the adult prostate localized at the junction of the prostatic ducts and urethra. Fluorescence-activated cell sorting (FACS) showed that GFP label-retaining cells were enriched for cells co-expressing stem cell markers Sca-1, CD133, CD44 and CD117 (4- marker cells; 60-fold enrichment). FACS showed, additionally, that 4-marker cells were androgen receptor positive. Castration induced proliferation and dispersal of E16 labeled cells into more distal ductal segments. When naïve adult mice were administered BrdU daily for 2weeks after castration, 16% of 4-marker cells exhibited BrdU label in contrast to only 6% of all epithelial cells (P<0.01). In sham-castrated controls less than 4% of 4-marker cells were BrdU labeled (P<0.01). The unexpected and admittedly counter-intuitive finding that castration induced progenitor cell proliferation suggests that androgen deprivation therapy in men with advanced prostate cancer could not only exert pleiotrophic effects on tumor sub-populations but may induce inadvertent expansion of tumor stem cells.

Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).

54 Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m2) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (&gt; 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA &lt;0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]

Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer

Aging skeletal muscle is associated with not only a reduction in muscle size and strength but also in muscle quality which reflects an increase in fatty infiltration of muscle. In men with prostate cancer, androgen deprivation therapy (ADT) accelerates this loss of muscle size and strength, but it is unknown if muscle quality is also adversely affected. Therefore, we examined the effects of ADT on muscle attenuation, an indirect measure of intramuscular lipid content, as well as the muscle cross-sectional area (CSA) in men with prostate cancer. Pre- and post-CT scans of the pelvis in 39 men aged 49-78 years receiving leuprorelin were examined. The time between baseline and follow-up scans was 14.6-20 weeks after the commencement of ADT. Changes in skeletal muscle attenuation in Hounsfield units of the rectus femoris and the CSA of the rectus femoris, sartorius and quadricep muscles were assessed. Muscle attenuation of the rectus femoris muscle was significantly reduced following the initiation of ADT by 18.9% (P < 0.001). In addition, there was a significant decrease (P < 0.001) in the CSA for the sartorius, quadriceps and rectus femoris muscles. There was no effect of Zometa on muscle attenuation or muscle CSA. Our results indicate that not only muscle size but also muscle quality may be adversely affected by the undertaking of ADT in men with prostate cancer. Consequently, interventions to counteract deteriorations to both muscle mass and possibly muscle quality should be considered in men receiving ADT.

Intermittent Versus Continuous Androgen Deprivation Therapy in Advanced Prostate Cancer

Intermittent androgen deprivation is increasingly employed as an alternative to continuous life long androgen deprivation therapy for men with advanced or recurrent prostate cancer. Two recent phase III trials have clarified the benefits of intermittent therapy. In men with non-metastatic disease with PSA recurrence after definitive local therapy, intermittent therapy showed equivalent survival to continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experience improved bone health, less metabolic and hematologic disturbances, fewer hot flashes, as well as improved sexual function. In men with metastatic disease, the data is less clear. The long-awaited results of SWOG 9324 comparing intermittent to continuous therapy in metastatic disease showed a trend to worse outcome in the patients with 'minimal' metastatic disease, and no difference in those with widespread bone mets. The significance of this observation is in dispute. This review also addresses practical issues in the use intermittent therapy, including patient selection, follow-up and cycling of therapy. The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care for most patients with non-metastatic prostate cancer requiring hormonal therapy.

A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.

5016 Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P&lt;.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.

Androgen-deprivation therapy in men with metastatic prostate cancer: less may not necessarily be more

In a pivotal phase 3 randomized controlled trial, Hussain et al. tested the hypothesis that, with respect to survival, intermittent androgen deprivation therapy (ADT) is non-inferior to continuous in men with newly diagnosed metastatic prostate cancer. While the trial findings were statistically inconclusive, the study suggests, but does not prove, that intermittent may do more harm than good, although findings are not definitive. While outcomes of ongoing trials are awaited, the trial by Hussain et al., in conjunction with an earlier trial in men with non-metastatic prostate cancer by Crook et al., does provide important new guidance regarding the choice of ADT in men with androgen-sensitive prostate cancer.

Bone health in the prostate cancer patient receiving androgen deprivation therapy: a review of present and future management options

Osteoporosis and bone fractures are frequently overlooked complications of androgen deprivation therapy in men with nonmetastatic prostate cancer. All such patients should have their bone mineral density (BMD) monitored and be offered preventive measures, such as calcium and vitamin D supplementation; patients with low BMD should be offered treatment. Several agents, including bisphosphonates, are available (although this use is currently off-label), and upcoming treatments, such as denosumab and toremifene, have shown promise in reducing fracture risk in these patients.

Changes in blood glucose and cholesterol levels due to androgen deprivation therapy in men with non-metastatic prostate cancer

Objective: To investigate the effects of androgen deprivation therapy(ADT) on blood glucose and cholesterol over 12 months in aprospective matched cohort study.Methods: English-speaking patients with non-metastatic prostatecancer attending the Princess Margaret Hospital were invited toparticipate in this study. Patients were divided into two cohorts:ADT users and controls. Androgen deprivation therapy users werefrequency matched to controls on age, education and body massindex (BMI). The study consisted of two visits. Sociodemographicand clinical information, medication use, physical fitness, heightand weight were collected before initiation of ADT. Twelve monthslater, fasting morning blood work was obtained to measure plasmaglucose, total cholesterol, high-density lipoprotein (HDL), low-densitylipoprotein (LDL) and triglycerides. Statistical analyses includedunivariate and multivariable linear regression.Results: We recruited 75 patients (mean age 68.9), 38 of whomwere undergoing ADT. Twelve patients with prior diabetes and 29patients taking cholesterol-lowering medication at baseline wereexcluded from the glucose and cholesterol analysis, respectively.In adjusted analyses, ADT users had a significantly higher glucoselevel compared to controls (5.88 vs. 5.52 mmol/L, p = 0.024).Overall, ADT users had higher levels of total cholesterol, HDL,LDL, and triglycerides than controls, although none of the differencesreached statistical significance.Conclusion: One year of ADT use is associated with elevated fastingglucose levels and may increase all lipid fractions in men withprostate cancer.

Androgen Deprivation Therapy in Advanced Prostate Cancer: Is Intermittent Therapy the New Standard of Care?

Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer. Two recent phase iii trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with "minimal" metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling. The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease. Level i evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure.Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects.Patient selection for intermittent therapy is important to maintain good oncologic results.Monitoring of prostate-specific androgen response and duration of off-treatment intervals allow for stratification of patients by risk of progression.

Vertebral fractures and trabecular microstructure in men with prostate cancer on androgen deprivation therapy

Androgen deprivation therapy (ADT), a treatment for prostate cancer, is associated with bone loss and fractures. Dual-energy X-ray absorptiometry (DXA)-measured bone mineral density does not assess vertebral fractures (VF). High-resolution micro-magnetic resonance imaging (HR-MRI) assesses bone microarchitecture and provides structural information. To determine if VF identification increased the diagnosis of osteoporosis beyond DXA and if HR-MRI demonstrated skeletal deterioration in men with VF, we cross-sectionally studied 137 men aged ≥ 60 years with nonmetastatic prostate cancer on ADT for ≥ 6 months. Vertebral fracture assessment (VFA) by DXA was confirmed with X-rays. HR-MRI of the wrist included bone volume to total volume (BV/TV), surface density (trabecular plates), surface/curve ratio (plates/rods), and erosion index (higher depicts deterioration). VF were found in 37% of men; the majority were unknown. Seven percent of participants were classified as osteoporotic by hip or spine DXA. Thirty-seven percent of men without osteoporosis by DXA had VF identified, suggesting that 90% of patients with clinical osteoporosis would have been misclassified by DXA alone. By ANOVA comparison across VF grades, the BV/TV, surface density, and spine, hip, and wrist DXA were lower, and erosion index was higher in men with moderate-severe VF compared with lesser grades (all p < 0.05). By unadjusted ROC analysis, the addition of HR-MRI to DXA at the spine, hip, and femoral neck added substantially (AUC increased 0.831 to 0.902, p < 0.05) to prediction of moderate-severe vertebral fracture. HR-MRI indices were associated with spine, hip, and wrist DXA measures (p < 0.01). Longer duration of ADT was associated with lower BV/TV, surface density, and surface/curve ratio (p < 0.05). ADT for men with prostate cancer is associated with silent VF. DXA alone leads to misclassifications of osteoporosis, which can be avoided by VF assessment. HR-MRI provides a novel technique to assess deterioration of structural integrity in men with VF and adds micro-structural information.

923P - GTX-758, An Oral ERa Agonist, Increases Sex Hormone Binding Globulin, Reduces Free T and Decreases PSA in Patients with Castration Resistant Prostate Cancer

ABSTRACT Introduction & objective GTx-758 is an oral, selective estrogen receptor α agonist, which induces sex hormone binding globulin (SHBG) and subsequently reduces free testosterone (FT) to levels below that achieved with LHRH agonists. Such agonists represent a distinct class of agents with the potential to impact men with advanced prostate cancer. Herein we report the results of a proof of concept trial of GTx-758 in patients who developed castration resistant prostate cancer (CRPC) while on androgen deprivation therapy (ADT). Methods Men (n = 9) receiving ADT and developed CRPC, were enrolled in a Phase II open label study to 2000 mg GTx-758 daily. Primary endpoint was the proportion of subjects with a ≥ 50% reduction in prostate specific antigen (PSA) from Day 1. Secondary endpoints included serum FT and SHBG. SHBG, FT, and PSA were assessed at, Days 1, 15, 30, 60, and 90 days. Results At enrollment (Day 1) values (n = 9) observed for PSA (38.7 ng/mL ± 52.8), FT (0.89 pg/mL ± 0.70), and SHBG (53.4± 28.6 nmol/L). Data were available from 7 subjects with at least one on-study assessment for FT and SHBG. By Day 15, 75% (3/7) and by Day 60, 100% (4/4) of patients had a ≥50% reduction in PSA. Mean change in FT, at last observation, was -70.4% ± 16.7%. All subjects demonstrated significant increases in SHBG at day 15 (251 ± 63.1 pmol/L) and end of study (266 ± 73.0 pmol/L), with a mean change at last observation of 429% ± 158%. Although there were no venous thromboembolic events (VTEs) in this study, a separate study of GTx-758 for primary ADT in men with advanced prostate cancer was stopped prematurely due to an increased risk of VTEs, and consequently, this study was halted as well. Conclusions GTx-758 is an oral selective ERα agonist that has demonstrated ability to increase SHBG more than 4-fold and decrease FT in men with CRPC. Coupled with the observation that 4/4 patients respond with a ≥50% reduction in PSA at day 30, these results suggest that progression of disease, and the need for increasingly toxic therapies, may be delayed in this population. Significantly lower doses of GTx-758 (100 – 600mg) have also been shown to increase SHBG with a more favorable safety profile in previous Phase I and II GTx-758 studies. Lower doses of GTx-758 are being evaluated in an ongoing Phase II trial in men with CRPC. Disclosure M.S. Steiner: CEO of GTx and own stock, R.P. Taylor: employee of GTx, Inc. and own stock in GTx, Inc., R.H. Getzenberg: employee of GTx, Inc., M.A. Johnston: employee of GTx and own stock, M. Hancock: employee of GTx, Inc. and own stock in GTx, Inc., J.T. Dalton: employee of GTx, Inc. and own stock in GTx, Inc.

Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

BackgroundProstate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT) has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT.MethodsA 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale.DiscussionThe significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT.Trial registrationNCT00856102

Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: a critical review.

Loss of bone mineral density is an unintended consequence of androgen deprivation therapy in men with prostate cancer. Supplementation with calcium and/or vitamin D in these men seems logical and is advocated by many lay and professional groups. We reviewed guidelines for calcium and vitamin D supplementation and the results of clinical trials of calcium and vitamin D supplementation on bone mineral density in men with prostate cancer undergoing androgen deprivation therapy. Whether supplementation of men undergoing androgen deprivation therapy with calcium and/or vitamin D results in higher bone mineral density than no supplementation has not been tested. The results of 12 clinical trials show that, at the doses commonly recommended, 500-1,000 mg calcium and 200-500 IU vitamin D per day, men undergoing androgen deprivation lose bone mineral density. The doses of calcium and vitamin D that have been tested are inadequate to prevent loss of bone mineral density in men undergoing androgen deprivation therapy. In light of evidence that high levels of dietary calcium and calcium supplement use are associated with higher risks for cardiovascular disease and advanced prostate cancer, intervention studies should evaluate the safety as well as the efficacy of calcium and vitamin D supplementation in these men.

Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer

ObjectiveThis study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT. DesignBMD and samples of blood and urine were studied before and after 6months of ADT in 70 patients with localized prostate cancer. ResultsBefore ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs=0.344, p=0.004; rs=0.264, p=0.027; rs=0.329, p=0.005; rs=0.300, p=0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p=0.001). These relationships disappeared after ADT (p=0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3μmol/L and 5.6 to 2.9nmol/L, respectively) (p<0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3nmol/L, p<0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: +2.2, ranged between −7.1 and +15.3) were inversely correlated with the pretreatment (rs=−0.333 p=0.005) and post-treatment (rs=−0.408, p=0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs=0.328, p=0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs=0.388, p=0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs=−0.302, p=0.024) among the bone formation/resorption markers including serum/urine N-telopeptide. ConclusionsSerum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.

Effective communication of study results to older participants with prostate cancer: Results of a survey

Abstract Objectives We examined attitudes towards, satisfaction with, and costs associated with providing end of study feedback in a group presentation format to older men participating in an observational prostate cancer study. We also aimed to capture the resources required for such a presentation. Methods We invited all 186 participants of a longitudinal matched cohort study examining health effects of androgen deprivation therapy in men with prostate cancer who were attending an end-of-study presentation to complete a survey exploring attitudes towards and prior experience with end-of-study results. We also explored the burden communicating end-of-study results might place on study investigators and clinicians. Results Usable surveys were returned by 59 of 70 presentation attendees (84%). Thirty-nine of 59 respondents were study participants while the rest were spouses or guests. Eighty-five percent of respondents agreed/strongly agreed that they had a right to know end-of-study results. Forty-six percent wanted to receive results via email while 45% wanted a group presentation. One-third of respondents had participated in clinical research before; of these, 84% never received study results. Ninety percent of respondents indicated that they were more likely to participate in a study if they knew results would be provided to them. Total resources were under 40 hours and $670 CAD. Conclusions End-of-study results are expected by most study participants. Presentation of aggregate results in a group format may be an effective and efficient way to communicate study results. Including a commitment to an end-of-study presentation may enhance recruitment. Attitudes of non-attendees should be examined in future research.

Degarelix: a guide to its use in advanced prostate cancer

Degarelix (Firmagon®), a gonadotropin-releasing hormone (GnRH) receptor antagonist, is indicated as an androgen-deprivation therapy in men with advanced hormone-dependent prostate cancer. It effectively induces and maintains suppression of serum testosterone to castration levels and has an acceptable tolerability profile. Relative to leuprolide, degarelix is associated with more rapid induction of testosterone and prostate-specific antigen (PSA) suppression without the testosterone surges associated with GnRH receptor agonists, and a potentially lower risk of the combined endpoint of PSA progression and death.

Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications.

Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.

Sekundäre Osteoporose – praxisrelevante Besonderheiten bei der Diagnostik und Therapie

Osteoporosis is a systemic skeletal disease causing increased fracture risk. According to pathogenesis, primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) are distinguished. Secondary osteoporosis comprises all entities in which osteoporosis is predominantly and causally associated with certain diseases or conditions. The aim of this review article is to put attention to special features in diagnosis, prophylaxis and treatment of secondary osteoporosis in general and to demonstrate some forms of secondary osteoporosis which seem particularly important during clinical practice. The manuscript refers to the guidelines of the DVO 2009 for prevention, diagnosis and therapy of osteoporosis and selective original papers considering the special types of secondary osteoporosis. History, clinical examination and basic laboratory tests are indicative for the diagnosis of secondary osteoporosis. Its clinical presentation is frequently characterized by rapid development and multiple fractures. Therefore, early diagnosis, prophylaxis and causal treatment is decisive. If causal treatment is impossible, risk adaption of bone mineral density (BMD) for osteoporosis specific treatment is essential. Common causes are medications, endocrine, gastrointestinal and hematologic diseases. Glucocorticoid induced osteoporosis, antihormonal therapy (aromatase inhibitor in women with breast cancer, androgen deprivation therapy in men with prostate cancer) and vitamin D deficiency causing secondary hyperparathyroidism are presented in detail. History and basic laboratory testing are decisive to identify possible causes for secondary osteoporosis and to initiate early diagnostic procedures. The risk of severe osteoporosis can be reduced by early and causal treatment or by risk stratified early bone specific medication if causal therapy is impossible.