Androgen Deprivation Therapy In Prostate Cancer Patients Research Articles

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Association of Androgen Deprivation Therapy with Metabolic Disease in Prostate Cancer Patients: An Updated Meta-Analysis.

Androgen deprivation therapy (ADT), a backbone treatment for advanced prostate cancer (PC), is known to have a variety of metabolic side effects. We conducted an updated meta-analysis to quantify the metabolic risks of ADT. We searched PubMed, Web of Science, and Scopus in May of 2022 for studies investigating the risk of metabolic syndrome (MetS), diabetes, and hypertension from ADT in PC patients using keywords. Only full-length studies with a control group of PC patients not on ADT were included. All results compatible with each outcome domain in each included study were sought. For included studies, relative risk (RR) was pooled using a random effects model and a trim-fill approach was used to adjust for publication bias. 1,846 records were screened, of which 19 were found suitable for data extraction. Five studies, including 891 patients, were evaluated for MetS as an outcome, with the random effects model showing a pooled RR of 1.60 ([95% Confidence Interval (CI), 1.06-2.42]; P=0.03) for patients on ADT while twelve studies, including 336,330 patients, examined diabetes as an outcome, and the random effects model showed a RR of 1.43 ([95% CI, 1.28-1.59]; P< 0.01). After adjustment for publication bias, ADT was associated with a 25% increased risk for diabetes but was not associated with MetS. 4 studies, including 7,051 patients, examined hypertension as an outcome, and the random effects model showed a RR of 1.30 ([95% CI, 1.08-1.55]; P=0.18) in ADT patients. In patients with PC, ADT was not associated with MetS and the association with diabetes was not as strong as previously reported. Our novel meta-analysis of hypertension showed that ADT increased the risk of hypertension by 30%. These results should be understood in the context of collaborating care between a patient's oncologist and primary care provider to optimize care.

Abstract 12761: Association of Androgen Deprivation Therapy With Metabolic Disease in Prostate Cancer Patients: An Updated Meta-Analysis

Introduction: Androgen deprivation therapy (ADT), a backbone treatment for advanced prostate cancer (PC) is known to have a variety of metabolic side effects. We conducted an updated meta-analysis to quantify metabolic risks of ADT. Hypothesis: We hypothesized that ADT would increase the risk for metabolic diseases compared to PC patients not on ADT. Methods: We searched PubMed, Web of Science, and Scopus in May of 2022 for studies that investigated the risk of metabolic syndrome (MetS), diabetes, and hypertension from ADT in PC patients using keywords. 4 blinded reviewers screened studies. Only studies that had a comparison group of PC patients not on ADT were included. For included studies, relative risk (RR) was pooled using a random effects model. Results: 1846 records were screened, of which 19 were found suitable for data extraction (Figure 1). 5 studies including 831 patients had MetS as an outcome, with the random effects model showing a pooled RR of 1.49 ([95% Confidence Interval (CI), 1.01-2.21]; I 2 =59%: p=0.04) for patients on ADT. 12 studies including 409,490 patients examined diabetes as an outcome, and the random effects model showed a RR of 1.40 (95% CI, 1.28-1.54), while 4 studies including 7,051 patients examined hypertension as an outcome, and the random effects model showed a RR of 1.30 (95% CI, 1.08-1.55) in ADT patients. Conclusions: ADT was shown to increase the risk of MetS, diabetes, and hypertension in patients with PC undergoing ADT compared to PC patients not on ADT. These results should be understood in the context of collaboration between a patient’s oncologist and primary care provider to optimize care.

Melatonin in the Management of Mood and Sleep Problems Induced by Androgen Deprivation Therapy in Prostate Cancer Patients: A Randomized Double-blinded, Placebo-controlled Clinical Trial.

Androgen deprivation therapy (ADT) has been considered as a mainstay of treatment for advanced prostate cancer. Considering ADT for cancer patients is accompanied with many side effects, such as behavioral and neurologic side effects that adversely affect the quality of life. This study aimed to evaluate the effects of melatonin administration on sleep problems and mood changes induced by ADT in prostate cancer patients. The randomized, double-blind, placebo-controlled trial was designed in the oncology-hematology outpatient clinic of Omid Hospital, Isfahan, Iran. After screening by the hospital anxiety and depression scale (HADS), patients were divided into either an intervention group receiving 6 mg melatonin daily for four weeks or an identical placebo. After that, patients were evaluated by the Pittsburgh sleep quality index (PSQI), the Hamilton Anxiety Rating Scale (HAM-A), and Beck Depression Inventory (BDI) questionnaires at baseline and after 4-week follow-ups. Forty-three patients, including 21 and 22 patients in melatonin and placebo groups, respectively completed follow-ups period. Melatonin administration significantly improved PSQI scores in four domains of sleep quality, sleep latency, sleep efficacy, and daytime dysfunction. After 4-week melatonin supplementation, the severity of depression and anxiety assessed by BDI and HAM-A questionnaires, respectively, decreased non-statistically significant in both melatonin and placebo groups. In our study, melatonin supplementation ameliorated ADT-induced sleep problems in patients with prostate cancers; however, for more conclusive results, further future large and well-designed clinical studies is warranted.

Increased cytokine gene expression and cognition risk associated with androgen deprivation therapy.

BackgroundAndrogen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high‐risk, and metastatic hormone‐sensitive prostate cancer. Long‐term ADT treatment likely develops side‐effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses.MethodsGene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced‐stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database.ResultsA total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine‐cytokine signaling with an over representation of cytokine‐cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T‐cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll‐like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL‐17A, CCL2, IL‐10, IL‐6, IL‐1RN, LIF/LIFR were further validated by quantitative RT‐PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen‐responsive prostate cancer cells, compared to no‐androgen antagonist treatment.ConclusionsOur findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.

Detailed Evaluation of Androgen Deprivation Overtreatment in Prostate Cancer Patients Compared to the European Association of Urology Guidelines Using Long-term Data from the European Randomised Study of Screening for Prostate Cancer Rotterdam

BackgroundGuidelines on androgen deprivation therapy (ADT) for prostate cancer (PCa) arise from a critical appraisal of scientific evidence, which is a costly effort. Despite these efforts and the side effects of ADT, guidelines may not always be adhered to. ObjectiveTo determine ADT overtreatment in PCa patients compared to the European Association of Urology (EAU) guidelines, and to identify predictors and physicians’ motivations for this overtreatment. Design, setting, and participantsMen were included from the European Randomised study of Screening for Prostate Cancer (ERSPC) Rotterdam who were diagnosed with PCa between 2001 and 2019, and received ADT <1 yr after diagnosis. Outcome measurements and statistical analysisPatients were categorised into the concordant ADT or discordant ADT group following the EAU guidelines. Physicians’ motivations for discordancy were reported. Multivariable logistic regression was performed to identify predictors for guideline-discordant ADT including the nonlinear fit of the year of diagnosis. Results and limitationsOf 3608 PCa patients, 1037 received ADT <1 yr after diagnosis. Adherence improved gradually over the study period, resulting in overall discordancy of 15%. A patient diagnosed in 2011 had 3.3 times lower risk on guideline-discordant ADT than a patient diagnosed in 2004 (odds ratio [OR] 0.30; 95% confidence interval [CI] 0.18–0.50). The most common reason for discordancy was unwillingness or unfitness for curative treatment of asymptomatic patients. Age (OR 1.19; 95% CI 1.15–1.24) and Gleason score ≥4 + 3 (OR 1.70; 95% CI 1.06–2.74) were associated with guideline-discordant ADT. ConclusionsIn a Dutch cohort, slow adaptation of the EAU guidelines on ADT for PCa patients between 2001 and 2019 resulted in overall overtreatment of 15%, mostly in asymptomatic patients who were unfit or unwilling for curative treatment. Clear, structured presentation, or integration of these tailored guidelines into the electronic health record might accelerate the adaptation of future guidelines. Patient summarySlow adaptation of the guidelines on hormonal therapy resulted in overtreatment in 15% of prostate cancer patients, mostly in asymptomatic patients who were unfit or unwilling for curative treatment.

Does Androgen Deprivation for Prostate Cancer Affect Normal Adaptation to Resistance Exercise?

Background: Loss of muscle mass and muscle function is a common side effect from androgen deprivation therapy (ADT) for prostate cancer (PCa). Here, we explored effects of heavy-load resistance training (RT) on lean body mass and muscle strength changes reported in randomized controlled trials (RCTs) among PCa patients on ADT and in healthy elderly men (HEM), by comparison of results in separate meta-analysis. Methods: RCTs were identified through databases and reference lists. Results: Seven RCTs in PCa patients (n = 449), and nine in HEM (n = 305) were included. The effects of RT in lean body mass change were similar among PCa patients (Standardized mean difference (SMD): 0.4, 95% CI: 0.2, 0.7) and HEM (SMD: 0.5, 95% CI: 0.2, 0.7). It is noteworthy that the within group changes showed different patterns in PCa patients (intervention: 0.2 kg; control: −0.6 kg) and HEM (intervention: 1.2 kg; control: 0.2 kg). The effects of RT on change in muscle strength (measured as 1 RM) were similar between PCa patients and HEM, both for lower body- (PCa: SMD: 1.9, 95% CI: 1.2, 2.5; HEM: SMD: 2.2, 95% CI: 1.0, 3.4), and for upper body exercises (PCa: SMD: 2.0, 95% CI: 1.3, 2.7; HEM: SMD: 1.9, 95% CI: 1.3, 2.6). Conclusions: The effects of RT on lean body mass and 1 RM were similar in PCa patients on ADT and HEM, but the mechanism for the intervention effect might differ between groups. It seems that RT counteracts loss of lean body mass during ADT in PCa patients, as opposed to increasing lean body mass in HEM.

Association of statins use and mortality outcomes in prostate cancer patients who received androgen deprivation therapy: a systematic review and meta-analysis.

IntroductionWhile several recent studies investigated the influence of statins on survival outcomes in prostate cancer (PCa) patients on androgen deprivation therapy (ADT), definitive conclusions are still missing. The present systematic review and meta-analysis aimed to develop an overarching framework for the association of statins use and survival outcomes in PCa patients who receive ADT.Material and methodsWe conducted a systematic review and meta-analysis of the literature assessing the survival outcomes for statin compared to non-statin users in PCa patients who received ADT. We searched PubMed and Web of Science for studies published before March 1, 2021. We used the random effect model in the presence of heterogeneity and the fixed-effects model in the absence of heterogeneity per the I 2 statistic. We did two meta-analyses; the primary meta-analysis was accomplished for articles reporting cancer-specific survival (CSS) as an outcome. A secondary meta-analysis was completed for articles reporting overall survival (OS) as an outcome.ResultsTen studies were eligible for inclusion. Nine studies included in the first meta-analysis comprising 136,285 patients showed no statistically significant difference in CSS (HR 0.77; 95% CI 0.49–1.21) between statin users and non-users in PCa patients who received ADT. In four studies included in the second meta-analysis comprising 95,032 patients, statin users had a significantly better OS compared to non-users (HR 0.67; 95% CI 0.62–0.73).ConclusionsAlthough the combination of statins and ADT in PCa patients significantly improves OS, it seems not to be through an effect on cancer-specific factors.

Abstract PO-133: AGE:RAGE signaling pathway as a target in neuroendocrine prostate cancer

Abstract Advanced Glycation End products, or AGEs are non-enzymatically attached sugar metabolites that can contribute to prostate cancer development and progression. AGEs are formed when reducing sugars interact with amino acids, proteins, lipids or nucleic acids under physiological conditions, and are categorized as either endogenous (biological-AGEs) or exogeneous (dietary-AGEs). Dietary AGEs contribute to the body’s total AGE pool, and are responsible for increased AGE accumulation, that in turn facilitates interaction with the major AGE receptor, the Receptor for Advance Glycation End products, RAGE. RAGE is a transmembrane member of the Ig superfamily of cell surface molecules and is overexpressed in a variety of tumor types, including prostate cancer. Increased AGE accumulation upregulates RAGE expression, amplifying the signaling cascade with impacts on cytokinesis. This is especially relevant, as we have shown that both AGE and RAGE are significantly elevated in tumors from AA men when compared to EA men at the same stage. De novo neuroendocrine prostate cancer (NEPC) is rare constituting only 1% of all prostate cancer cases. However, recent studies have shown that individual cells within a prostate tumor can undergo a process termed neuroendocrine differentiation to become neuroendocrine-like. Studies have shown that androgen deprivation therapy (ADT) can drive neuroendocrine differentiation leading to the development of the castrate resistant prostate cancer phenotype. These latter cancers are referred to as neuroendocrine prostate cancer (NEPC) or aggressive variant prostate cancer (AVPC). Transformation to a neuroendocrine phenotype is one proposed mechanism of resistance to contemporary AR-targeted treatments, is associated with increased tumor progression, poor prognosis, and is thought to represent ~25% of lethal prostate cancers. Due to the increased application of ADT in prostate cancer patients, neuroendocrine prostate cancer is thought to be on the rise and therefore poses a significant health problem. Our studies show that AGEs can induce neuroendocrine differentiation in AR-positive prostate adenocarcinoma cells in vitro with a concomitant loss of the AR. In addition, we observe that AGEs promote more aggressive tumor growth in both syngeneic xenograft and spontaneous mouse models in vivo. Using shRNA and pharmacological inhibitors to RAGE, we show that AGE-mediated neuroendocrine differentiation is RAGE- dependent. Results from our studies could implicate RAGE inhibitors as therapeutic treatments to reduce the increased mortality observed in AA men with prostate cancer that disproportionately have increased levels of both AGE and RAGE. Citation Format: Bradley A. Krisanits, Arabia Satterwhite, Lourdes M. Nogueira, Ashley Evans-Knowell, David P. Turner, Victoria J. Findlay, DeMarcus D. Woolfork. AGE:RAGE signaling pathway as a target in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-133.

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.

BackgroundFor specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well‐described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk‐benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review.MethodsA 14‐member panel comprised of urologic and medical oncologists were chosen for an expert review panel, to provide guidance on a more judicious use of ADT in advanced PC patients. Panel members were chosen based upon their academic and community experience and expertise in the management of PC patients. Four academic members of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, and were tasked with addressing the role of ADT in specific PC settings.ResultsThis article describes the practical recommendations of an expert panel for the use of ADT throughout the PC disease continuum, as well as an algorithm summarizing the key recommendations. The target for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting.ConclusionThe panel has provided recommendations for monitoring PC patients while on ADT, recognizing that PC patients will progress despite testosterone suppression and, therefore, early identification of conversion from castrate‐sensitive to castration resistance is critical. Also, the requirement to both identify and mitigate side effects of ADT as well as the importance of quality of life maintenance are essential to the optimization of patient care, especially as more combinatorial therapeutic strategies with ADT continue to emerge.

Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells.

Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.

Left Ventricular Strain and Strain Rate Responses to Submaximal Exercise in Prostate Cancer Patients Treated with Androgen Deprivation Therapy

IntroductionAndrogen Deprivation Therapy (ADT), like that used to treat prostate cancer patients, increases cardiovascular disease risk and mortality. Administration of ADT impairs left ventricular mechanics in animal models, however, it remains poorly understood how ADT influences cardiac function in human prostate cancer patients. Therefore, the aim of the current investigation was to non‐invasively measure left ventricular mechanics at rest and during submaximal exercise in prostate cancer patients with and without a history of ADT treatment. We hypothesized that change in left ventricular strain, strain rate, and tissue velocities during the rest‐to‐exercise transition would be impaired in those with a history of ADT treatment compared to those with no prior ADT.MethodsTo date, 7 prostate cancer patients (66 ± 7 yrs) have completed the experimental protocol. Cancer subjects (n=3 treated with ADT; n=4 no history of ADT) performed echocardiographic measurements at rest and during a supine submaximal cycling exercise to a target heart rate of 100 beats/min. Tissue Doppler echocardiography was used to measure myocardial tissue velocities in systole (S′) and early diastole (E′). In addition, myocardial deformation was assessed via measurements of left ventricular strain (S), and strain rate (SR) from the mid‐interventricular septum. Systolic and diastolic reserve indices were calculated from myocardial velocities.ResultsThe change in systolic S from rest to exercise was significantly different between groups (ADT: 2.8 ± 1.5 %; Non‐ADT: −3.3 ± 4.2 %; p=0.03). The change in systolic SR from rest to exercise was significantly different between groups (ADT: −0.037 ± 0.6 1/s; Non‐ADT: −0.23 ± 0.15 1/s; p=0.03). There were no changes observed between groups from rest to exercise in early diastolic filling SR (ADT: 0.74 ± 0.47 1/s; Non‐ADT: 0.86 ± 0.35 1/s; p=0.35), systolic reserve index (ADT: 2.27 ± 0.07; Non‐ADT: 0.86 ± 1.4; p=0.07), and diastolic reserve index (ADT: −5.05 ± 2.1; Non‐ADT: −2.9 ± 2.5; p=0.14). There were also no significant changes observed between groups in S′ (ADT: 0.034 ± 0.033 cm s−1; Non‐ADT: 0.0017 ± 0.02 cm s−1; p=0.09), and E′ (ADT: 0.046 ± 0.025 cm s−1; Non‐ADT: 0.033 ± 0.033 cm s−1; p=0.31).ConclusionThis preliminary evidence suggests that ADT in prostate cancer patients significantly impairs left ventricular function as determined by changes in systolic SR and S in response to submaximal exercise. These findings may hold significant value beyond the basic characterization of left ventricular function, in particular as part of a risk‐stratification strategy in prostate cancer patients receiving ADT.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ventricular‐arterial Coupling in Prostate Cancer Patients Treated with Androgen Deprivation Therapy at Rest and During Exercise

IntroductionAndrogen‐deprivation therapy (ADT) in prostate cancer has been suggested to promote an unfavorable cardiovascular disease risk profile and long‐term cardiovascular mortality. Impairments in vascular structure (increased arterial stiffness) and function (decreased endothelial‐dependent dilation) are known to occur with ADT, however, it remains unknown if the changes in structure‐function relationship adversely impacts the interaction between ventricular and arterial systems. Ventricular‐arterial coupling is a measure of effective arterial elastance (Ea) and left ventricular end‐systolic elastance (Ees) and is a central determinant of cardiovascular performance and cardiac energetics. Therefore, this study sought to evaluate ventricular‐arterial coupling at rest and during submaximal exercise in prostate cancer patients with and without a history of ADT.MethodsTo date, 7 prostate cancer patients with (n=3) and without (n=4) a history of androgen‐deprivation therapy treatment have completed the study. Ea, Ees, and ventricular‐arterial coupling (Ea/Ees) were measured at rest and during supine submaximal exercise. A high Ea/Ees is reflective of a compromised interaction between ventricular and arterial systems. To minimize the effect of heart rate on each parameter submaximal exercise was performed at a work rate corresponding to a heart rate of 100 beats/min.ResultsAt rest Ea (ADT: 2.9±0.2 mmHg/mL; non‐ADT: 3.4±0.8 mmHg/mL; P=0.2), Ees (ADT: 3.2±1.9 mmHg/mL; non‐ADT: 3.6±0.6 mmHg/mL; P=0.2), and Ea/Ees (ADT: 0.79±0.39; non‐ADT: 0.97±0.30; P=0.5) were similar between ADT and non‐ADT groups. Ea was not different between groups during exercise (ADT: 7.0±1.1 mmHg/mL; non‐ADT: 6.6±0.6 mmHg/mL; P=0.3). Moderate‐intensity exercise‐induced increases in Ees trended to be decreased in the ADT group (ADT: 3.5±1.2 mmHg/mL; non‐ADT: 4.7±0.5 mmHg/mL; P=0.05). Ea/Ees was also higher in the ADT group during exercise compared to the non‐ADT group, but did not reach statistical significance (ADT: 0.93±0.16; non‐ADT: 0.77±0.16; P=0.1).ConclusionsThe findings from this study provide preliminary data that indicates ADT in prostate cancer patients may adversely alter left ventricular end‐systolic elastance during exercise, but does not significantly alter ventricular‐arterial coupling. Additional data will contribute to the evaluation of the interaction between ventricular and arterial systems in patients receiving ADT.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

036 Testosterone Recovery Profiles after Cessation of Androgen Deprivation Therapy (ADT)

It has been demonstrated that the combination use of ADT improves overall and cancer-specific survival in men with unfavorable prostate cancer (PCa). After cessation of ADT, testosterone (T) levels are expected to recover from castrate to normal levels. However, very little is known about T recovery profiles in this population, and many patients remain on castrate levels indefinitely. The aim of this study was to evaluate T recovery after cessation of ADT in PCa patients. We reviewed our prospectively maintained database for PCa patients who received ADT therapy at our institution. Serum early morning total T (TT) levels were measured at baseline and periodically after ADT cessation. Multivariable time-to-event analysis (Cox proportional hazards) was performed to determine predictors of TT recovery after ADT cessation and included the following variables: patient age, baseline T level, and duration of ADT. 1641 men with a mean age of 66 (43-94) years were included. Primary treatment for PCa was RP in 36%, while the remainder had either RT or primary ADT. The majority received a GnRH agonist as mainstay for ADT. Mean duration of ADT was 28.8±39 months [0.5 to 324]. Distribution of ADT exposure was: <6 months (m) 33%, 6-12m 19%, 12-24m 16%, >24m 33%. Median follow-up was 47.5±45 months. Mean TT values were: baseline 358 ng/dl, 6-12m post ADT cessation 96 ng/dl, 12-18 174 ng/dl, 18-24m 228 ng/dl, >24m 273 ng/dl. At last follow-up: 77% men had TT level above castrate level, 45% had TT >300ng/dl and 39% returned to pre-treatment TT level. On multivariable analysis age over 65 years (HR 2.01, 95%CI 1.48-2.71, P<0.0001), ADT duration of 6 months or greater (HR 1.42, 95%CI 1.07-1.90, P=0.02), and baseline T of 400 ng/dl or more (HR 1.80, 95%CI 1.36-2.40, P<0.0001) were all significantly associated with a slower recovery time.

Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study.

Osteoporosis is a complication of androgen deprivation therapy (ADT) in men with prostate carcinoma. The best defense against osteoporosis in prostate cancer is to identify patients with a high risk for fracture during the first clinical visit, select an effective anti-osteoporosis agent, and advise the patient to change his lifestyle and diet to prevent further bone loss. New agents include denosumab, a human monoclonal antibody that inhibits the RANK ligand (RANKL). RANKL promotes the formation, activity, and survival of osteoclasts and, thus, supports the breakdown of bone. This is a multicenter, randomized, double-blind prospective study on use of denosumab versus alendronate in the therapy of secondary osteoporosis related to ADT in prostate cancer patients in three European countries (Italy, France, Switzerland). In this 24-month observation study we enrolled 234 patients with diagnosis of osteoporosis underwent ADT for prostate cancer. All patients aged ≥55 years and had a dual-energy X-ray absorptiometry (DEXA) T-score <-1.0 (hip or spine, measured within last 2 years) and ≥ 1 fragility fracture. Patients were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months or alendronate (70 mg weekly) for 2 years. All patient received supplemental vitamin D (600 IU per day) and supplemental calcium to maintain a calcium intake of 1200 mg per day. Effectiveness of therapy in both groups (denosumab group and alendronate group) was assessed by changes in bone turnover markers (BTMs), Bone Mineral Density (BMD), fracture incidence, Visual Analogue Scale (VAS) score for back pain, and Short Form-8 (SF-8TM) health survey score for health-related quality of life (HRQoL). Percent changes from baseline in BTMs and BMD were assessed using the paired t test; a P-value 0.05). Mean changes in BMD at final follow-up differed significantly between two groups. BMD changes at the lumbar spine at 24 months were 5.6% with denosumab vs -1.1% with alendronate (P<0.001). New vertebral fractures developed in fewer patients in the denosumab group than in the alendronate group during the 24-month period, although this difference was not significant (P=0.10). Back pain significantly (P<0.001) improved from baseline at all time points during the study in both study groups. SF-8 health survey scores significantly improved following treatment with both drugs. Incidence of adverse drug reactions were similar in both groups. In our study denosumab and alendronate showed similar clinical efficacy in the therapy of ADT-related osteoporosis in men with prostate carcinoma; both drugs provided significant improvements in back pain and general health conditions. Denosumab showed significant increase of BTMs and BMD than alendronate with lower rate of new vertebral fractures.

Diffusion-weighted imaging to evaluate for changes from androgen deprivation therapy in prostate cancer.

The objective of our study was to investigate the usefulness of apparent diffusion coefficient (ADC) values in evaluating for therapeutic changes from androgen deprivation therapy (ADT) in prostate cancer patients. Forty-eight patients with prostate cancer treated with ADT were enrolled in this retrospective study. Diffusion-weighted imaging (DWI) at 3 T was performed before and after ADT. Before and after treatment, ADC values were measured in the tumors and in the benign tissues of the prostate, and serum prostate-specific antigen (PSA) levels and prostate volumes were also assessed. Statistical analysis was performed using a paired Student t test, Wilcoxon signed rank test, and Spearman rank correlation. In 48 patients, 55 tumors were identified. After treatment, the mean ADC value of the tumors (1.06×10(-3) mm2/s) was significantly increased as compared with the pretreatment value (0.78×10(-3) mm2/s) (p<0.001), whereas the ADC values of the benign tissues after treatment were significantly decreased compared with the pretreatment values (p<0.001). The mean prostate volume and mean PSA level were significantly reduced from 42.8 cm3 and 153.60 ng/mL before treatment to 21.4 cm3 and 9.51 ng/mL, respectively, after treatment (p<0.001). Changes in tumor ADC values showed a weak negative correlation with changes in PSA levels after treatment (correlation coefficient, ρ=-0.320; p=0.028). DWI may have potential as a noninvasive tool for monitoring changes in response to ADT in prostate cancer patients.

Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: a systematic review and meta-analysis.

A recently published meta-analysis of randomized clinical trials (RCT) showed that androgen deprivation therapy (ADT) did not significantly increase cardiovascular mortality in prostate cancer patients. However, cardiovascular morbidity, which can impact quality of life, was not evaluated. To evaluate the risk of cardiovascular morbidity associated with ADT in patients with prostate cancer. We conducted a literature search from January 1960 to June 2012. RCT and large cohort studies that evaluated first-line endocrine therapy and ADT longer than 6 months were screened for inclusion. In total, 126,898 patients were included in four cohort studies, and 10,760 patients were included in nine RCTs. Analysis of the RCTs showed no differences in the development of acute myocardial infarction (AMI) (OR 1.23; 95 % CI 0.92-1.64; I (2): 0 %) among the patients receiving ADT or not. The analysis of randomized studies that reported other nonfatal cardiovascular events demonstrated a significant increase in such events in the group receiving ADT (OR 1.55; 95 % CI 1.09-2.20; I (2): 0 %). When the large cohort studies were included in the analysis, an increased risk of AMI among men with ADT was found (OR 2.01, 95 % CI 1.90-2.13; I (2): 91,3 %). The use of ADT in prostate cancer patients corresponded with a significant increase in cardiovascular morbidity associated with AMI and with nonfatal events. Therefore, ADT is linked to a significant negative impact on quality of life. Periodic cardiovascular evaluation is required for these patients.

Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: A systematic review and meta-analysis.

40 Background: A recently published meta-analysis of randomized clinical trials (RCT) showed that androgen deprivation therapy (ADT) did not significantly increase cardiovascular mortality in prostate cancer patients. However, cardiovascular morbidity, which can impact quality of life, was not evaluated. Objectives: To evaluate the risk of cardiovascular morbidity and mortality associated with long-term ADT in patients with prostate cancer. Methods: We conducted a literaturesearch from 1960 and June 2012. We selected RCT and large cohort studies that evaluated first-line endocrine therapy, ADT greater than 6 months, and follow up greater than 1 year. Results: Thirteen studies (137,658 patients) were included. Of four cohort studies, 126,898 patients were included and 10,760 patients were part of nine RCTs. Analysis of the RCTs showed no differences in development of acute myocardial infarction (AMI) (OR 1.23; 95% CI: 0.92 – 1.64; I2: 0%) or stroke (OR 1.02; 95% CI: 0.71 – 1.46; I2: 0%) among patients receiving ADT or not. The analysis of three randomized studies that reported other nonfatal cardiovascular events demonstrated a significant increase in such events in the group receiving ADT (OR 1.55; 95% CI: 1.09 – 2.20; I2: 0%). When large cohort studies were included in the analysis, an increased risk of AMI among men who had ADT was found ( OR 2.01, 95% CI:1.90 – 2.13; I2: 91.3%). Conclusions: ADT in prostate cancer patients for at least 6 months is not associated with cardiovascular mortality, acute myocardial infarct and stroke. However, patients receiving ADT had a significant increase in nonfatal cardiovascular events.

Abstract 3616: Androgen deprivation therapy and second primary lung cancer risk in prostate cancer patients in the US Veterans.

Abstract Background Previous observational studies have consistently reported decreased risk of lung cancers among prostate cancer patients. Recent literature suggests a role of estrogen receptor (ER) beta and aromatase, which can convert testosterone to estrogen, in development and progression of non small cell lung cancers. Second primary lung cancer risk among breast cancer patients appears to be higher in ER negative patients compared to ER positive patients probably from estrogen receptor blockade. As androgen deprivation therapy (ADT) has been well established for more than 70 years as an effective treatment modality for prostate cancer, we hypothesized the hormone modulation may decrease lung cancer risk and investigated the effect of ADT on second primary lung cancer risk among patients with prostate cancer. Methods We identified 62,589 men in VA Central Cancer Registry (VACCR) who were diagnosed with prostate cancer between 1999 and 2008, with follow-up available through 2010. The primary outcome was development of lung cancer, determined by VACCR. Descriptive statistics were used to compare basic characteristics between the groups. Cox proportional hazards model was used to assess the influence of ADT on the lung cancer incidence, adjusted for patient characteristics and prostate cancer stage. All the statistical analyses were performed using STATA 10 (Stata Corp, College Station, TX). Results Men who had ADT as part of their treatment for prostate cancer tend to be older (median age 71.3 vs 65.7, p &amp;lt; 0.01) and smoke slightly more (72.5% vs 71.4%, p=0.02). As expected, ADT group tend to have higher stage prostate cancers. There were 766 secondary lung cancers diagnosed in the cohort for the follow-up period. ADT group had significantly decreased secondary lung cancer risk by approximately 20% (HR 0.83, 95%CI=0.70-0.97) when adjusted for age, smoking status and prostate cancer stage at presentation. Conclusion Our study suggests that ADT in prostate cancer patients is associated with a decreased risk of second primary lung cancers. Independent validation studies and subgroup analyses to clarify the association is warranted. This work was supported by Veteran's Health Administration 1IK2BX001283-01 and NCI 5P50CA128613-02. Citation Format: Hyunseok Kang, Rathi N. Pillai, Johann C. Brandes. Androgen deprivation therapy and second primary lung cancer risk in prostate cancer patients in the US Veterans. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3616. doi:10.1158/1538-7445.AM2013-3616

Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase

Androgen deprivation therapy (ADT) facilitates the response of prostate cancer (PC) to radiation. Androgens have been shown to induce elevated basal levels of reactive oxygen species (ROS) in PC, leading to adaptation to radiation-induced cytotoxic oxidative stress. Here, we show that androgens increase the expression of p22phox and gp91phox subunits of NADPH oxidase (NOX) and ROS production by NOX2 and NOX4 in PC. Pre-radiation treatment of 22Rv1 human PC cells with NOX inhibitors sensitize the cells to radiation similarly to ADT, suggesting that their future usage may spare the need for adjuvant ADT in PC patients undergoing radiation.