Androgen Deprivation Therapy Treatment Research Articles

Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis

The current study is a retrospective analysis of 49 patients with bone metastatic prostate cancer: 26 receiving androgen deprivation therapy (ADT) alone versus 23 receiving cytoreductive cryosurgery of the primary tumor plus ADT treatment. Progression-free survival (PFS) was the primary outcome variable, and Cox proportional hazards regression analysis was used to identify predictors for PFS. The baseline characteristics were generally comparable between the 2 groups. Median follow-up time was 41 months (range 24–56) and 37 months (range 19–53) in ADT alone group and cryosurgery groups, respectively. Patients receiving cryosurgery had significantly longer PFS (35 vs 25 months, P = 0.0027) and time to castration resistance (36 vs 25 months, P = 0.0011). Cox multivariate analysis associated longer PFS with the following factors: cryosurgery (HR0.207, 95% CI 0.094–0.456), lower prostate specific antigen at diagnosis (≤100 ng/ml, HR0.235, 95% CI 0.072–0.763) and lower Gleason score (≤7, HR0.195, 95% CI 0.077–0.496). Cryosurgery reduced the risk of progression by 79.3%. In conclusion, cytoreductive cryosurgery of the primary tumor in patients with bone metastatic prostate cancer could reduce the risk of progression and delay time to castration-resistant prostate cancer.

THE EFFECT OF ANDROGEN DEPRIVATION THERAPY ON THE LIPID PROFILE AND BLOOD GLUCOSE LEVEL IN PROSTATE CANCER PATIENTS IN ADAM MALIK GENERAL HOSPITAL MEDAN

Objective: The aim of this study is to observe the effect of Androgen Deprivation Therapy (ADT) on patients with advanced stage of prostate cancer on the lipid profile and blood glucose level. Material & Methods: This is a descriptive cross-sectional study and include the prostate cancer patients which were admitted to Urology Policlinic in Haji Adam Malik General Hospital, Medan from June 2014 – June 2015 and also received ADT. Results: From June 2014 – June 2015, a total of 25 prostate cancer patients receiving ADT was included in this study with an average age of 67.08 ± 7.48 years old. The median prostate specific antigen (PSA) level of this group of patients is 19.6 ng/mL and the lowest and highest value of 3.4 and 278 ng/mL respectively. ADT administration is found to cause a significant elevation of 2-hour postprandial blood glucose (121.12 ± 21 mg/mL vs 134.64 ± 33.35 mg/mL, p-value=0.011) and Glycosylated hemoglobin (5 ± 0.5% vs 5.5 ± 0.79%, p-value=0.000) (HbA1c) after 6 months of therapy. Additionally, ADT administration within 3 and 6 months of duration had also significantly increased triglyceride (TG) level when compared to before treatment (104.4 ± 38.67 vs 131.2 ± 32.27 vs 127 ± 33.43 respectively, p-value=0.005). Conclusion: ADT treatment in prostate cancer patients increase triglyceride levels after 3 and 6 months of treatment followed by 2-hour postprandial blood glucose and HbA1C levels after 6 months of the treatment.

Abstract 478: Regulation of cross talk between AR and wnt/beta-catenin pathways in prostate cancer

Abstract Prostate Cancer (PCa) is the second most commonly diagnosed cancer in the United States with 180,890 males diagnosed and is predicted to cause approximately 26,000 deaths in 2016. The current treatment of androgen deprivation therapy (ADT) initially depletes circulating androgens; however, intratumoral androgens rescue androgen receptor (AR) signaling and promotes the development of castration resistant prostate cancer (CRPC). The dysregulation of the Wnt/β-catenin signaling pathway has been implicated in the development of many cancers including PCa. The disruption of this signaling leads to the stabilization of β-catenin which upregulates many genes involved in tumorigenesis. Additionally, β-catenin acts as AR cofactor. Our previous studies show that AR is a direct target of miR-644a. We hypothesized that targeting the expression of both the β-catenin pathway and AR by conventional drugs and/or tumor suppressor miR-644a would have synergistic therapeutic benefits. In this study, we are investigating miR-644a mediated posttranscriptional downregulation of GSK3-β and β-catenin in the wnt/β-catenin signaling pathway. The effect of miR-644a in combination with inhibitors (β-catenin or GSK3-β) was also assessed using proliferation assays and a significant downregulation was observed. We will further study the posttranscriptional effects of tumor suppressor miR-644a on the wnt/β-catenin pathway and also the processing and regulation of miR-644a in PCa. Citation Format: Alexis Plaga, Girish C. Shukla. Regulation of cross talk between AR and wnt/beta-catenin pathways in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 478. doi:10.1158/1538-7445.AM2017-478

Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

ImportanceThere is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies.ObjectivesTo identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment.Design, Setting, and ParticipantsThe PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes.Main Outcomes and MeasuresMetastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes.ResultsAmong the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction).Conclusions and RelevanceLuminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer

To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer. From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function. Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy. ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction.

Flexible modeling of the hazard rate and treatment effects in long-term survival studies.

The effects of predictors on time to failure may be difficult to assess in cancer studies with longer follow-up, as the commonly used assumption of proportionality of hazards holding over an extended period is often questionable. Motivated by a long-term prostate cancer clinical trial, we contrast and compare four powerful methods for estimation of the hazard rate. These four methods allow for varying degrees of smoothness as well as covariates with effects that vary over time. We pay particular attention to an extended multiresolution hazard estimator, which is a flexible, semi-parametric, Bayesian method for joint estimation of predictor effects and the hazard rate. We compare the results of the extended multiresolution hazard model to three other commonly used, comparable models: Aalen's additive model, Kooperberg's hazard regression model, and an extended Cox model. Through simulations and the analysis of a large-scale randomized prostate cancer clinical trial, we use the different methods to examine patterns of biochemical failure and to estimate the time-varying effects of androgen deprivation therapy treatment and other covariates.

Association between ischaemic bowel syndromes and androgen deprivation therapy in patients with prostate cancer: a retrospective cohort study

ObjectiveThis study investigated the risk of ischaemic bowel syndrome (IBS) in androgen deprivation therapy (ADT) users to explore the long-term outcomes of patients with prostate cancer (PC) receiving ADT treatment.MethodsWe...

Impact of treatment on progression to castration-resistance, metastases, and death in men with localized high-grade prostate cancer.

Men with high‐grade prostate cancer (HGPC) are at greatest risk of disease progression. Clinical risk factors associated with castration‐resistant prostate cancer (CRPC), metastases, and prostate cancer‐specific mortality (PCSM) were identified in a contemporary HGPC cohort. Clinical data was collected from men diagnosed with Gleason sum (GS) ≥8 at the Greater Los Angeles Veterans Affairs (GLA‐VA) Healthcare System between 2000 and 2013. Multivariable competing risks regression analyses assessed progression to CRPC, metastases, and PCSM within three treatment strata. The cumulative incidence of disease progression was calculated at 2, 5, and 10‐year time points. Review of 2149 prostate cancer cases yielded 322 with HGPC. Median survival times for cancer‐specific and overall mortality were significantly shorter in men treated with primary androgen deprivation therapy (ADT) (P = 0.0002 and P < 0.0001). Multivariable analyses revealed that clinical stage N1, GS 10, and treatment with primary ADT were significantly associated with increased risk of CRPC, metastases, and PCSM. Significant differences in these outcomes were not observed in men treated with radical prostatectomy (RP) when compared to those treated with radiation therapy combined with short‐term ADT (XRT‐ADT). Ten‐year event rates of progression to CRPC, metastases, and PCSM, for men treated with primary ADT, were 45.5%, 25.4%, and 25.1%, respectively. In conclusion, GS 10 and lymph node involvement, as well as primary ADT treatment in men with HGPC was associated with increased risk of CRPC, metastases, and PCSM. Curative‐intent treatment with RP or XRT‐ADT is associated with reduced progression rates and death in men with HGPC.

Androgen Deprivation Therapy Use in the Setting of High-Dose Radiation Therapy and the Risk of Prostate Cancer–Specific Mortality Stratified by the Extent of Competing Mortality

The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is standard of care for men with intermediate and high-risk prostate cancer (PC). However, whether competing mortality impacts the ability of ADT to improve survival remains unanswered. We calculated a competing mortality (CM) risk score using a Fine-Gray semi-parametric model including age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for non-metastatic PC. Fine and Gray competing risk regression was used to assess whether ADT reduced the risk of prostate cancer-specific mortality (PCSM) for men with low vs. high risk of CM amongst the 4,550 patients within the intermediate and high-risk cohort adjusted for established PC prognostic factors, year of treatment, site, and ADT treatment propensity score. After a median follow-up of 8.4 years 1,065 men died; 89 (8.36%) from PC. Among men with a low CM score, ADT use was associated with a significant reduction in the risk of PCSM (adjusted HR (AHR) = 0.35, 95% CI = 0.14 to 0.87, P = 0.02) but not in men with a high CM score (AHR = 1.33, 95% CI = 0.77 to 2.30, P = 0.30). Given the differing direction of the AHR for ADT use amongst men with high vs low CM score the interaction term was significant (P = 0.01). Adding ADT to high-dose RT appears to be associated with decreased PCSM in men with low but not high CM. These data should serve to heighten awareness about the importance of considering competing risks when determining whether or not to add ADT to RT to treat men with intermediate or high-risk PC.

Development and Validation of Genomic Signature That Predicts Androgen Deprivation Therapy Treatment Failure

Development and Validation of Genomic Signature That Predicts Androgen Deprivation Therapy Treatment Failure

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer

Objective: The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients.Materials and methods: Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1–73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7–89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6–42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation.Results: After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (< 50 ng/dl). A multivariate analysis was performed to find factors related to testosterone recovery (testosterone >50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan–Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5–22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6–39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029).Conclusions: Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Race and mortality risk after radiation therapy in men treated with or without androgen-suppression therapy for favorable-risk prostate cancer.

African American (AA) men are more likely than non-AA men to have a comorbid illness that could interact with androgen-deprivation therapy (ADT) and shorten survival. This study assessed the impact that race had on the risk of all-cause mortality (ACM) and other-cause mortality (OCM) among men definitively treated for favorable-risk prostate cancer (PC). Between 1997 and 2013, 7252 men with low-risk or favorable intermediate-risk PC were treated with brachytherapy with neoadjuvant ADT (n = 1501) or without neoadjuvant ADT (n = 5751) for a 4-month median duration. Cox and Fine-Gray multivariate regressions were used to analyze whether the risk of ACM and OCM increased among AA men versus non-AA men receiving ADT; adjustments were made for the age at brachytherapy, year of brachytherapy, cardiometabolic comorbidity status, risk group, and ADT treatment propensity score. After a median follow-up of 8.04 years, 869 men (12.0%) died: 48 (5.52%) of PC and 821 (94.48%) of other causes. There was a significant association between AA race and an increased risk of both ACM (adjusted hazard ratio [AHR], 1.77; 95% confidence interval [CI], 1.06-2.94; P = .028) and OCM (AHR, 1.86; 95% CI, 1.08-3.19; P = .024) among AA men versus non-AA men who received ADT but not among those who did not receive ADT (AHR for ACM, 1.33; 95% CI, 0.93-1.91; P = .12; AHR for OCM, 1.39; 95% CI, 0.96-2.02; P = .08). ADT use may shorten survival in AA men with favorable-risk PC; therefore, its reservation for the treatment of higher risk PC, for which level 1 evidence supports its use, should be considered. Cancer 2016;122:3608-14. © 2016 American Cancer Society.

An Update on Triptorelin: Current Thinking on Androgen Deprivation Therapy for Prostate Cancer.

Androgen deprivation therapy (ADT) is the mainstay palliative treatment for men with locally advanced and metastatic prostate cancer, and aims to reduce testosterone to levels obtained by surgical castration. Use of gonadotropin-releasing hormone (GnRH) agonists predominates among the ADT options. The GnRH agonist, triptorelin is a first-line hormonal therapy that has demonstrated efficacy and safety in clinical trials of patients with locally advanced non-metastatic or metastatic disease. Sustained-release 1-, 3- and 6-month formulations of triptorelin, administered intramuscularly or subcutaneously, have been developed to provide improved flexibility and convenience for the patient. Head-to-head studies of GnRH agonists are lacking in the field of prostate cancer. Despite the inevitable progression to castration-resistant prostate cancer (CRPC) in most patients receiving ADT, monitoring of testosterone levels needs to improve in routine practice and physicians should not overlook the benefits of continued ADT in their patients when introducing one of the various new treatment options for CRPC. For improved survival outcomes, there remains a need to tailor ADT treatment regimens, novel hormonal agents and chemotherapy according to the individual patient with advanced prostate cancer.

Development and validation of genomic signature to predict ADT treatment failure.

5018Background: Androgen deprivation therapy (ADT) is one of the main treatment options for locally advanced, recurrent and metastatic prostate cancer. Neuroendocrine prostate cancer (NEPC) is inhe...

Resistance Training Improves Muscular Strength in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy

Prostate cancer (PC) patients treated with androgen deprivation therapy (ADT) are at risk for an increased rate of adipose tissue accumulation and skeletal muscle wasting, which may lead to reductions in muscular strength and ultimately functional decline and loss of independence. Resistance training that includes at least 2 sessions per week, targeting all major muscle groups, may offer one strategy to arrest these declines. PURPOSE: To examine i) changes in upper body (seated chest press) and a lower body (leg extension) muscular strength in older PC patients on ADT treatment and ii) the associations between age, time on treatment with ADT, muscular strength and body composition in 32 PC patients in the IDEA-P trial. METHODS: 32 PC patients were randomized to resistance training coupled with exercise and dietary counseling (16) or a standard care control group (16). The treatment group attended 2 sessions p/week of resistance training (supervised month 1&2, independent month 3). Muscular strength was assessed with a 1RM protocol for both upper (UB) and lower body (LB) at baseline and again after 2 and 3 months. Body composition (%BF) was measured with the BODpod, while time on treatment (TOT) was measured in months. RESULTS: At baseline PC patients were M=66±7.7 years of age, had been on ADT treatment for M=22 ±22 months and were obese according to their body composition (% Body fat M=38.2±9.1). At baseline, there were significant bivariate correlations between age, UB and LB muscular strength (r=-0.537, p=<0.01) (r=-0.392, p=<0.05) respectively. TOT was not associated with baseline scores but was associated with 2 month change in LB muscular strength. A 2 (treatment) x 3 (time) ANCOVA controlling for age revealed a significant treatment by time interaction for UB (F=6.721, p=<0.01) and LB (F=3.988, p=<0.05) strength. CONCLUSION: Resistance training is a safe and feasible means of improving and maintaining muscular strength in older men undergoing ADT for prostate cancer. Increases in muscular strength may protect aging PC patients against future declines in physical function. However, increasing adherence to home based exercise programs outside of supervised sessions is key to changing lifestyles and health outcomes for prostate cancer patients over the long term. Supported by NIH/NCI R03 CA16296901; 5R25 CA122061

The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism.

Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism. This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases. Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT. Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

ADT Linked to Increased Risk of Alzheimer's Disease

The use of androgen deprivation therapy for treatment of prostate cancer was associated with increased risk of Alzheimer's disease, and patients with greater duration of ADT use had higher risks, according to medical records data analysis. ADT use was significantly associated with Alzheimer's disease risk, with a hazard ratio (HR) of 1.88 by propensity score–matched Cox regression analysis (95% CI, 1.10–3.20; P = .021), and HR of 1.66 by traditional multivariable-adjusted Cox regression analysis (95% CI, 1.05–2.64; P = .031). Patients who used ADT for 12 months or more had the greatest risk observed (HR, 2.12; 95% CI, 1.11–4.03; P = .011), and the risk increased by category of ADT duration.Investigators used a novel text-processing pipeline to analyze clinical data, extracting disease and terminology codes, medication lists, and positive-present mentions of drug and disease concepts from clinical notes. “Use of the electronic medical record in this way allows rapid investigation of a rich data source to study a broad range of postmarketing outcomes, including those unlikely to be seen in smaller clinical trials,” wrote Kevin T. Nead, MD, of the University of Pennsylvania, Philadelphia, and his colleagues [J Clin Oncol 2015 Dec 7. doi: 10.1200/JCO.2015.63.6266]. The study evaluated 16,888 patients with prostate cancer; in total, 2,397 received ADT and 125 were diagnosed with Alzheimer's disease during a median follow-up of 2.7 years. The median time to Alzheimer's disease diagnosis was 4 years. The analysis replicated previously known associations between Alzheimer's disease and age (HR, 1.06; P < .001) and cardiovascular disease (HR, 1.60; P = .031), supporting the validity of the method, according to the researchers. Jennifer Shepphird is a Frontline Medical News freelance writer based in Hermosa Beach, CA.

Hypercholesterolemia Is Associated with a Shorter Time to Castration-Resistant Prostate Cancer in Patients Who Have Undergone Androgen Deprivation Therapy.

PurposeThe goal of this study was to investigate the association between hypercholesterolemia and the time required for progression to castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy (ADT).Materials and MethodsData from 154 patients with prostate cancer between 2005 and 2012 were reviewed retrospectively. ADT was employed as a treatment modality for these patients either due to multiple bone metastases at the time of diagnosis or due to old age in combination with other morbidities. Serum cholesterol levels and statin use were reviewed. We analyzed the factors associated with the development of CRPC after ADT treatment. The mean follow-up period was 34.8 months.ResultsThe mean age of the patients was 71.3 years old and their mean prostate-specific antigen level was 141.8±212.6 ng/mL. Their mean cholesterol level was 175.9±37.7 mg/dL, and 14 patients (9.1%) were statin users. CRPC developed in 44 patients (28.6%), and the mean duration from ADT treatment to CRPC was 24.1 months. In a multivariate analysis, hypercholesterolemia was associated with the development of CRPC (hazard ratio [HR]=1.017, p<0.001), depending on clinical T stage (p=0.005) and the presence of bone metastasis (p<0.001). A subanalysis showed that hypercholesterolemia was associated with the development of CRPC in patients with bone metastasis (HR=1.032, p<0.001), but not in patients without bone metastasis.ConclusionsHypercholesterolemia may be associated with the development of CRPC after ADT in patients with bone metastasis. Further studies with longer follow-up periods and larger samples are needed to validate this finding.

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy.

BackgroundProstate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation.MethodsThe human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 μmol/L abiraterone acetate (AA) generating the abiraterone-tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L 68Ga-labelled PSMA-HBED-CC peptide (100–300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 106 cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR.ResultsPSMA expression increased dependently on intensified ADT in all three basic cell lines. 68Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01).ConclusionsThe investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA-based therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0145-8) contains supplementary material, which is available to authorized users.

Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer

ObjectiveTo determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC).DesignCost-utility analysis using decision analytic modelling by a Markov model.Setting and methodsCompared SC and androgen...