Side Effects Of Androgen Deprivation Therapy Research Articles

Metabolic Response to Androgen Deprivation Therapy of Prostate Cancer.

Prostate cancer (PC) stands as the most frequently diagnosed non-skin cancer and ranks as the second highest cause of cancer-related deaths among men in the United States. For those facing non-metastatic PC necessitating intervention, solely local treatments may not suffice, leading to a possible transition toward systemic therapies, including androgen deprivation therapy (ADT), chemotherapy, and therapies targeting androgen. Yet, these systemic treatments often bring about considerable adverse effects. Additionally, it is observed that overweight men are at a higher risk of developing aggressive forms of PC, advancing to metastatic stages, and succumbing to the disease. Consequently, there is a pressing demand for new treatment options that carry fewer side effects and enhance the current standard treatments, particularly for the majority of American men who are overweight or obese. In this article, we will review the metabolic response to ADT and how lifestyle modulation can mitigate these ADT-associated metabolic responses with a particular focus on the two clinical trials, Carbohydrate and Prostate Study 1 (CAPS1) and Carbohydrate and Prostate Study 2 (CAPS2), which tested the effects of low-carbohydrate diets on the metabolic side effects of ADT and PC progression, respectively. Furthermore, we will summarize the findings of serum metabolomic studies to elucidate the potential mechanisms by which ADT and low-carbohydrate diets can affect the metabolic response to mitigate the metabolic side effects while maximizing therapeutic efficacy.

Analysis of androgen receptor expression and activity in the mouse brain

Androgen deprivation therapy (ADT) is the core treatment for advanced prostate cancer (PCa), with a proven survival benefit. ADT lowers circulating testosterone levels throughout the body, but with it comes a variety of reported side effects including fatigue, muscle wastage, weight gain, hot flushes and importantly cognitive impairment, depression, and mood swings. Testosterone has a key role in brain masculinization, but its direct effects are relatively poorly understood, due both to the brain’s extreme complexity and the fact that some of testosterone activities are driven via local conversion to oestrogen, especially during embryonic development. The exact roles, function, and location of the androgen receptor (AR) in the adult male brain are still being discovered, and therefore the cognitive side effects of ADT may be unrecognized or under-reported. The age of onset of several neurological diseases overlap with PCa, therefore, there is a need to separate ADT side effects from such co-morbidities. Here we analysed the activity and expression level of the AR in the adult mouse brain, using an ARE-Luc reporter mouse and immunohistochemical staining for AR in all the key brain regions via coronal slices. We further analysed our data by comparing to the Allen Mouse Brain Atlas. AR-driven luciferase activity and distinct nuclear staining for AR were seen in several key brain areas including the thalamus, hypothalamus, olfactory bulb, cerebral cortex, Purkinje cells of the cerebellum and the hindbrain. We describe and discuss the potential role of AR in these areas, to inform and enable extrapolation to potential side effects of ADT in humans.

Treatment of Osteoporosis in Men on Androgen Deprivation Therapy in Japan.

Background and Objectives: Androgen deprivation therapy (ADT) for prostate cancer has greatly improved treatment outcomes. As patient survival rates have increased, reports of decreased bone density and increased bone fractures as side effects of ADT have emerged. The prevalence of osteoporosis in Japanese men was 4.6%. The purpose of this study was to evaluate the effect of osteoporosis treatment in prostate cancer patients who underwent ADT in Japan. Materials and Methods: The subjects were 33 male patients who had undergone ADT for prostate cancer, who were noted to have decreased bone density. Mean age was 76.2 ± 7.7 years (64-87). Medications included vitamin D in one case, bisphosphonates (BP) in 27 cases, and denosumab in five cases. The evaluation method examined the rate of change in bone mineral density (BMD) before osteoporosis treatment and 1 year after. For comparison, a group without osteoporosis treatment intervention (n = 33) was selected, and matched for prostate cancer treatment and age. The rate of change in trabecular bone score (TBS) was also calculated. Results: The percentage changes in BMD before and 1 year after treatment were as follows: lumbar spine, 7.1 ± 5.8% in the treatment group versus -3.9 ± 4.1% in the no treatment group; femoral neck, 5.5 ± 6.2% in the treatment group versus -0.9 ± 3.9% in the no treatment group; total femur, 6.6 ± 6.4% in the treatment group versus the no treatment group which was -1.7 ± 3.2%. In all cases, there was a clear significant difference (p < 0.01). The percent change in TBS was further calculated in the same manner. There was no significant difference between the two groups: +1.7 ± 3.8% in the treated group versus +0.3 ± 4.1% in the untreated group. Conclusions: Osteoporosis treatment in Japanese patients with prostate cancer on ADT therapy was found to significantly increase BMD compared to the untreated group. BP and denosumab were found to be very effective in increasing BMD.

A comparison of aerobic- and resistance-emphasised exercise on cardiometabolic health and quality of life in men receiving androgen deprivation therapy for prostate cancer: Protocol for a feasibility trial

BackgroundThose with intermediate and high-risk prostate cancer typically receive androgen deprivation therapy (ADT) as part of their treatment. ADT often results in extensive side effects including increased risk of cardiometabolic disease. Many ADT side effects can be influenced by exercise, both resistance and aerobic training. Exercise regimes typically combine aerobic and resistance exercise but the appropriate emphasis for achieving the broadest range of therapeutic benefits has yet to be determined. We propose to determine the feasibility of undertaking a larger trial comparing a resistance- vs an aerobic-emphasised exercise intervention in men with prostate cancer undergoing ADT. The trial will also investigate preliminary evidence of difference between arms for cardiometabolic health and quality of life outcomes. MethodsThis is a 6-month randomised two-armed feasibility trial. Prostate cancer patients undergoing ADT and radiotherapy will be recruited (n = 24) and randomised to either a resistance- or aerobic-emphasised group. Participants will attend twice-weekly supervised individual or small group sessions, with 75% of exercise time in the primary exercise modality. The primary outcome will be feasibility, determined via assessment of recruitment, retention, adherence, safety, and acceptability. Secondary outcomes will include quality of life, body composition, vascular indices, aerobic and muscular fitness and cardiometabolic health blood biomarkers. ConclusionIt is envisaged that the trial will provide valuable information and preliminary difference data that will aid in the design of an efficacious larger trial that will adopt a major and minor emphasis approach to the scheduling of resistance and aerobic exercise.

Changes in the gut microbial profile during long-term androgen deprivation therapy for prostate cancer.

Recent studies have highlighted the association between androgen deprivation therapy (ADT) and the gut microbiota in prostate cancer. However, the impact of long-term ADT remains to be explored. To examine changes in the gut microbial profile from short-term (a median of 7 months), and middle-term (a median of 18 months) to long-term ADT (>33 months), 16S rRNA data from56 fecal samples were reanalyzed. Additionally, a two-sample Mendelian randomization was employed to investigate the relationships between particular microbial signatures and prostate cancer as well as testosterone levels. In contrast to the short- and middle-term ADT groups, the long-term ADT group had significant changes in alpha and beta diversity. In particular, the relative abundance of generasuch as Catenibacterium and Holdemanella decreased in the long-term ADTgroup, whereas the opportunistic bacterium (Erysipelatoclostridium) and Ruminococcus gnavus showed increased abundance over ADT time. Moreover, atwo-sample Mendelian randomization analysis revealed the negative associations between genetically predicated genera Coprobacter, Ruminococcaceae UCG002/011, and Defluviitaleacea-UCG-011, and testosterone levels. In conclusion, long-term ADT use in prostate cancer patients was associated with detrimental changes in gut microbiota, including an increase in genera related to testosterone synthesis and opportunistic bacteria. These changes may be related to disease progression and side effects of long-term ADT while further longitudinal studies are required to prove this relationship.

Efficacy of multidisciplinary interventions in preventing metabolic syndrome and improving body composition in prostate cancer patients treated with androgen deprivation therapy: A systematic review and meta-analysis

Exercise is known to reduce adverse side effects of androgen-deprivation therapy (ADT) on quality of life, bone health and fatigue for prostate cancer (PCa) patients. We conducted a systematic review with meta-analysis to evaluate the effect of multidisciplinary interventions on body composition and metabolic syndrome (MetS) in ADT-treated PCa patients. A systematic review and meta-analysis were conducted based on searches of EMBASE, MEDLINE, CENTRAL and Scopus databases from inception to March 2023. Participants included ADT-treated PCa patients who received multidisciplinary interventions including exercise, diet, nutrition, pharmacotherapy, bariatric surgery, or psychological/behavioural therapy. Primary outcomes were changes in body composition and MetS, with prostate-specific antigen (PSA) as a secondary outcome. After meta-analysis, results were reported in mean difference, 95% confidence interval and p-value, with forest plots. Additionally, we conducted subgroup analyses to compare the effect of different interventions. Thirty-three articles met the eligibility criteria out of 1443 articles and 28 studies were included in meta-analysis. Of 33 studies, 17 included exercise-only interventions and 10 included exercise+diet/nutrition interventions, but no studies included diet/nutrition-only interventions. All studies employed multidisciplinary approaches in developing or delivering the interventions. Most studies (85%) had low-moderate risk of bias, thus providing good evidence to this review. Overall, interventions had a positive effect on body composition measures; lean mass (LM):0.82kg (95% CI:0.47,1.17;p<0.00001), body fat mass (BFM):-0.68kg (95% CI:-1.12,-0.24;p=0.002), fat-free mass:0.75kg (95% CI:0.14,1.37;p=0.02) and body fat percentage (BFP):-0.99% (95% CI:-1.29,-0.68;p<0.00001), as well as on MetS; waist circumference:-1.95cm (95% CI:-3.10,-0.79;p=0.0009), systolic blood pressure:-3.43mmHg (95% CI:-6.36,-0.50;p=0.02) and diastolic blood pressure:-2.48mmHg (95% CI:-4.19,-0.76;p=0.005). Subgroup-analyses showed that a combined approach including exercise+diet/nutrition was most effective in improving BFP, WC, SBP and DBP whereas exercise was more effective in improving LM and BFM. In ADT-treated PCa patients, multidisciplinary interventions, especially those combining exercise and diet/nutrition, can improve body composition and metabolic health.

Nutrition services during prostate cancer androgen deprivation therapy

ObjectiveDietary interventions are effective strategies to mitigate multiple side effects from androgen deprivation therapy (ADT) in prostate cancer, however the perception of, and access to, nutrition services is relatively unknown.MethodsA...

PSOR7 Presentation Time: 12:00 PM: Toxicity and Efficacity of Whole Gland Salvage HDR Brachytherapy After Primary Radiation for Prostate Cancer

<h3>Purpose</h3> Androgen Deprivation Therapy (ADT) is the most common treatment for relapsing prostate cancer after primary radiation therapy. However, an effective local treatment could be used to obtain local control of the disease while limiting the systemic side effects of ADT. We designed a single institution prospective pilot study to assess the efficacy and safety of whole gland prostate HDR brachytherapy. <h3>Materials and Methods</h3> Fifty (50) patients with local relapse after primary radiation therapy were included in this study. A biopsy-proven local relapse, a negative bone scan, and a negative CT scan of the abdomen and pelvis were mandatory. A dose of 32Gy in 4 fractions was delivered to the whole prostate by HDR brachytherapy using CT-based treatment planning. The use of ADT was allowed if deemed clinically indicated by the treating physician. The primary objective was to evaluate early and late gastrointestinal (GI) and genitourinary (GU) toxicities, assessed with CTCAE v5 scale and IPS score. Biochemical disease-free survival (bDFS) was evaluated as a secondary outcome. <h3>Results</h3> Median follow-up was 61,1 months (0.8-106.8 months). Sixteen (16) patients received short-course ADT prior to brachytherapy. GI toxicities were low, with no grade 3 toxicities reported. 4.1% and 14,6% of patients had early and late grade 2 toxicities. Only one patient had a grade 3 GU early toxicity. However, 16,7% of patients experienced late grade 3 toxicities (12.0% at the last follow-up). Interestingly, none of the patient using neoadjuvant ADT developed late grade 3 toxicities although this association was not statistically significant (Chi-Square p-value 0.171). Mean IPSS value presented a predictable rise to 15.9 at 1 month follow-up. A subsequent decline was observed to mean IPSS under 10 after 24 months. A bDFS of 73,5% was observed after 48 months. <h3>Conclusion</h3> Whole gland salvage HDR brachytherapy is an effective treatment with an excellent biochemical disease-free survival. However, it is associated with a significant risk of late GU toxicities. In this perspective, our treatment protocol has been modified to allow for focal therapy using MR guidance. That will allow us to evaluate if a similar local control can be maintained while reducing the incidence of severe toxicities.

The Beneficial Effect of a Healthy Dietary Pattern on Androgen Deprivation Therapy-Related Metabolic Abnormalities in Patients with Prostate Cancer: A Meta-Analysis Based on Randomized Controlled Trials and Systematic Review.

Metabolic abnormalities as side effects of androgen-deprivation therapy (ADT) can accelerate progression of prostate cancer (PCa) and increase risks of cardiovascular diseases. A healthy dietary pattern (DP) plays an important role in regulating glycolipid metabolism, while evidence about DP on ADT-related metabolic abnormalities is still controversial. To explore the effect of DP on metabolic outcomes in PCa patients with ADT, PubMed, Embase, Cochrane, and CINAHL were searched from inception to 10 September 2022. Risk of biases was evaluated through Cochrane Collaboration’s Tool. If heterogeneity was low, the fixed-effects model was carried out; otherwise, the random-effects model was used. Data were determined by calculating mean difference (MD) or standardized MD (SMD) with 95% confidence intervals (CIs). Nine studies involving 421 patients were included. The results showed that healthy DP significantly improved glycated hemoglobin (MD: −0.13; 95% CI: −0.24, −0.02; p = 0.020), body mass index (MD: −1.02; 95% CI: −1.29, −0.75; p < 0.001), body fat mass (MD: −1.78; 95% CI: −2.58, −0.97; p < 0.001), triglyceride (MD: −0.28; 95% CI: −0.51, −0.04; p = 0.020), systolic blood pressure (MD: −6.30; 95% CI: −11.15, −1.44; p = 0.010), and diastolic blood pressure (MD: −2.94; 95% CI: −5.63, −0.25; p = 0.030), although its beneficial effects on other glycolipid metabolic indicators were not found. Additionally, a healthy DP also lowered the level of PSA (MD: −1.79; 95% CI: −2.25, −1.33; p < 0.001). The meta-analysis demonstrated that a healthy DP could improve ADT-related metabolic abnormalities and be worthy of being recommended for PCa patients with ADT.

Sexual Function in Men Undergoing Androgen Deprivation Therapy

With an increase in the use of androgen deprivation therapy (ADT) in men diagnosed with prostate cancer, there are several adverse effects that accompany its utilization. Among these, sexual dysfunction has contributed to significant deleterious effects on quality of life (QoL) and overall satisfaction. This has prompted clinicians to pursue modalities of ADT that may mitigate these adverse sexual effects, which include continuous versus intermittent ADT, changes in the duration of ADT, and novel methods of cyclical androgen exposure during treatment. Importantly, this must not come at the expense of oncological outcomes. In addition, some men treated with ADT experience persistent hypogonadism and side effects from these medications that linger well after treatment is completed. In this systematic review we discuss the pharmaceutical, mechanical, and psychological methods that play an important role in the mitigation of these sexual side effects, including erectile dysfunction and decreased libido, and their uses and benefits are further discussed. Ultimately, the benefits of ADT and the possible morbidity that these men may experience from use of ADT, as well as options to minimize their side effects need to be discussed with the patient and their partner to make an informed decision and ensure patient autonomy while providing the most up-to-date evidence. Given the prevalence of prostate cancer in the aging male population, this systematic review aims to further explain the different ADT regimens and options for men, as well as discuss the sexual side effects that accompany these treatments and ways in which to mitigate these side effects to improve patient QoL.

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.

Association between Androgen Deprivation Therapy and the Risk of Inflammatory Rheumatic Diseases in Men with Prostate Cancer: Nationwide Cohort Study in Lithuania.

Background: The aim of this study was to assess the association between androgen deprivation therapy (ADT) and the risk of inflammatory rheumatic diseases in men with prostate cancer. Methods: Patients with prostate cancer between 2012 and 2016 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database, on the basis of rheumatic diseases diagnoses and information on prescriptions for androgen deprivation therapy. Cox proportional hazard models were used to estimate hazard ratios (HR) to compare the risks of rheumatic diseases caused by androgen deprivation therapy exposure in groups of prostate cancer patients. Results: A total of 12,505 prostate cancer patients were included in this study, out of whom 3070 were ADT users and 9390 were ADT non-users. We observed a higher risk of rheumatic diseases in the cohort of prostate cancer patients treated with ADT compared with ADT non-users (HR 1.55, 95% confidence interval (CI) 1.01–2.28). Detailed risk by cumulative use of ADT was performed for rheumatoid arthritis, and a statistically significant higher risk was found in the group with longest cumulative ADT exposure (>105 weeks) (HR 3.18, 95% CI 1.39–7.29). Conclusions: Our study suggests that ADT usage could be associated with increased risk of rheumatoid arthritis, adding to the many known side effects of ADT.

Biomarkers to Evaluate Androgen Deprivation Therapy for Prostate Cancer and Risk of Alzheimer's Disease and Neurodegeneration: Old Drugs, New Concerns.

Androgen deprivation therapy (ADT) is a standard treatment for prostate cancer patients, routinely used in the palliative or in the curative setting in association with radiotherapy. Among the systemic long-term side effects of ADT, growing data suggest a potentially increased risk of dementia/Alzheimer’s disease in prostate cancer patients treated with hormonal manipulation. While pre-clinical data suggest that androgen ablation may have neurotoxic effects due to Aβ accumulation and increased tau phosphorylation in small animal brains, clinical studies have measured the impact of ADT on long-term cognitive function, with conflicting results, and studies on biological changes after ADT are still lacking. The aim of this review is to report on the current evidence on the association between the ADT use and the risk of cognitive impairment in prostate cancer patients. We will focus on the contribution of Alzheimer’s disease biomarkers, namely through imaging, to investigate potential ADT-induced brain modifications. The evidence from these preliminary studies shows brain changes in gray matter volume, cortical activation and metabolism associated with ADT, however with a large variability in biomarker selection, ADT duration and cognitive outcome. Importantly, no study investigated yet biomarkers of Alzheimer’s disease pathology, namely amyloid and tau. These preliminary data emphasize the need for larger targeted investigations.

MP24-13 PERCENTAGE AND RATIONALE OF GUIDELINE-DISCORDANT ANDROGEN DEPRIVATION THERAPY IN PROSTATE CANCER PATIENTS

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (MP24)1 Sep 2021MP24-13 PERCENTAGE AND RATIONALE OF GUIDELINE-DISCORDANT ANDROGEN DEPRIVATION THERAPY IN PROSTATE CANCER PATIENTS Renée Hogenhout, Ivo de Vos, Sebastiaan Remmers, Martijn Busstra, Lionne Venderbos, Monique Roobol, and the ERSPC Rotterdam Study Group Renée HogenhoutRenée Hogenhout More articles by this author , Ivo de VosIvo de Vos More articles by this author , Sebastiaan RemmersSebastiaan Remmers More articles by this author , Martijn BusstraMartijn Busstra More articles by this author , Lionne VenderbosLionne Venderbos More articles by this author , Monique RoobolMonique Roobol More articles by this author , and the ERSPC Rotterdam Study Group More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002015.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recommendations on Androgen Deprivation Therapy (ADT) for prostate cancer (PCa) patients arise from a critical appraisal of scientific evidence which is a lot of work. Despite these efforts, the known side-effects of ADT and the lack of benefit in certain risk groups, guidelines may not always be adhered to. Here, we determined guideline adherence to ADT recommendations and analyzed the physicians’ motivation in case of disconcordance. METHODS: We included subjects from the Rotterdam section of the European Randomized Study of Screening for PCa who were diagnosed with PCa in all stages since the publication of the first EAU guidelines on PCa in 2001 up to and including 2019, and received any form of ADT within the first year after diagnosis. They were categorized into guideline-concordant or -discordant ADT according to the EAU guidelines recommendations within the study period. RESULTS: A total of 1037/3211 (32%) men diagnosed with PCa received ADT within the first year after diagnosis, of which 162/1037 (16%) men received guideline-discordant ADT. In 79% (823/1037) ADT was administered guideline-concordant and in 4% (45/1037) adherence was not assessable due to incomplete medical files. In seven patients (4%) who were unfit/unwilling for curative treatment, lower urinary tract symptoms (LUTS) contributed to the decision to prescribe ADT monotherapy. These cases were also considered as not assessable since LUTS is not clearly defined as “symptomatic” in the guideline. Most of the guideline discordance was noticed in patients receiving ADT monotherapy for intermediate- and high-risk PCa (73%). A common reason for discordant prescription of ADT as monotherapy in this group was suspicion of (lymph node) metastases due to high PSA level (28%). Other reasons were unwillingness (24%) and/or unfitness (51%) to undergo curative treatment without being symptomatic. Three patients (3%) were symptomatic but not unfit or unwilling for curative treatment. In 16% of the discordant cases, prescription of ADT monotherapy was not motivated. CONCLUSIONS: Guidelines and clinical practice do not necessarily correspond. Physicians did not adhere to EAU guidelines on ADT in a Dutch cohort in 16% of the cases. However, guideline-discordant prescription of ADT may not always indicate “inappropriate” treatment. Physicians are able to make a more nuanced clinical assessment taking into account comorbidities, patients’ wishes and social context. Although guidelines support clinical decision-making, better defined and more tailored guidelines are needed. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e416-e417 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Renée Hogenhout More articles by this author Ivo de Vos More articles by this author Sebastiaan Remmers More articles by this author Martijn Busstra More articles by this author Lionne Venderbos More articles by this author Monique Roobol More articles by this author the ERSPC Rotterdam Study Group More articles by this author Expand All Advertisement Loading ...

Using Exercise and Nutrition to Alter Fat and Lean Mass in Men with Prostate Cancer Receiving Androgen Deprivation Therapy: A Narrative Review.

Fat mass (FM) gain and lean mass (LM) loss are common side effects for patients with prostate cancer receiving androgen deprivation therapy (ADT). Excess FM has been associated with an increased risk of developing obesity-related comorbidities, exacerbating prostate cancer progression, and all-cause and cancer-specific mortality. LM is the predominant contributor to resting metabolic rate, with any loss impacting long-term weight management as well as physical function. Therefore, reducing FM and preserving LM may improve patient-reported outcomes, risk of disease progression, and ameliorate comorbidity development. In ADT-treated patients, exercise and nutrition programs can lead to improvements in quality of life and physical function; however, effects on body composition have been variable. The aim of this review was to provide a descriptive overview and critical appraisal of exercise and nutrition-based interventions in prostate cancer patients on ADT and their effect on FM and LM. Our findings are that FM gain and LM loss are side effects of ADT that could be reduced, prevented, or even reversed with the implementation of a combined exercise and nutrition program. However, the most effective combination of specific exercise and nutrition prescriptions are yet to be determined, and thus should be a focus for future studies.

Optimizing Treatment in Intermediate-Risk Prostate Cancer: Secondary Analysis of a Randomized Phase 3 Trial

To identify patients with intermediate-risk prostate cancer (IRPC) benefiting from de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiation therapy (DERT), we performed a secondary analysis of a phase 3 trial by measuring biochemical failure (BF), distant metastases, prostate cancer-specific mortality, overall survival (OS), and distant metastases-free survival (DMFS) rates according to prognostic intermediate risk factors (IRF). The initial trial randomized 600 patients with IRPC to a 3-arm trial with 200 patients per arm, consisting of 6 months of ADT plus 70 Gy radiation therapy (ADT+RT70) versus ADT plus a DERT of 76 Gy (ADT+DERT76) versus DERT of 76 Gy alone (DERT76). We performed an analysis based on IRF: clinical stage, prostate-specific antigen level, Gleason score, percentage of positive biopsy cores (PBC) ≥50%, and Gleason pattern. Patients were allocated to 2 groups: favorable intermediate risk (FIR), defined as patients with only 1 IRF without Gleason pattern 4+3 or PBC ≥50%; and unfavorable intermediate risk (UIR), defined as all other patients. BF, distant metastases, prostate cancer-specific mortality, OS, and DMFS were compared between FIR and UIR. The median follow-up was 11.3 years (interquartile range, 10.9-11.7). In the FIR cohort, BF and OS were not significantly different between arms. UIR patients had significantly worse DMFS (hazard ratio [95% confidence interval], 1.61 [1.20-2.15]; P=.026) and OS (1.51 [1.12-2.04]; P=.0495) and a nonsignificant higher cumulative incidence of BF rate (1.55 [0.98-2.47]; P=.08). In UIR patients, a significant improvement in BF was seen in the arms receiving ADT compared to DERT76 alone. On multivariable analysis, Gleason pattern 4+3 and prostate-specific antigen >10 ng/mL independently affected BF and OS, regardless of the treatment arm. In IRPC, therapeutic optimization appears possible. To avoid ADT side effects, DERT76 alone appears sufficient in patients harboring only 1 risk factor without Gleason pattern 4+3 and PBC ≥50% (FIR). All other UIR patients seem to benefit from ADT+DERT76.

Sexual function in men undergoing androgen deprivation therapy.

Androgen deprivation therapy (ADT) has a deleterious effect on sexual functions and general well-being in men. Despite this evidence, however, patient and couple knowledge about ADT side effects as well as their management is poor. Similar considerations can be made for physician endorsement of management strategies. In this paper, we summarize and critically discuss available evidence regarding the possible associations between ADT and sexual dysfunction as well as the best therapeutical options. Preclinical data show that ADT is associated with penile contractility impairment as well as lower response to phosphodiesterase type 5 inhibitors (PDE5i). Available data indicate that ADT resulted in a five to sixfold increased risk of reduced libido and in a threefold increased risk of ED confirming the main role of testosterone in regulating sexual desire. Despite this evidence, sexuality remains an important aspect of health and well-being for men and their partner. The best therapeutical options depend on patient and couple desires and needs. When nonpenetrative erections are still possible, nonpenetrative activities should be encouraged to maintain sexual intimacy. A combined and personal educational program including the collaboration of different professional figures (including general physicians, oncologists, andrologists, sexologists, and psychologists) trained in sexual medicine is advisable in order to provide the best support to subjects undergoing ADT.

Treatment of aggressive prostate cancers in real life: Initiation, schedule, and management of triptorelin treatment (TALISMAN)—Design of the study.

TPS173 Background: Prostate cancer (PCa) treatment management mostly depends on tumor aggressiveness and patient frailty. Guidelines recommend an intensification of treatment in high risk PCa, with a longer duration of androgen deprivation therapy (ADT), and, for more advanced cases, an administration for life, on top of which additional treatments may be proposed. This implies a holistic management of the patient, including management of comorbidities and ADT side effects. Triptorelin is a widely used gonadotropin-releasing hormone agonist (GnRHa). Generating data on the use of triptorelin in real life will help physicians to analyze the parameters influencing the choice of the planned duration of treatment. Methods: This prospective, multicenter, non-interventional study is conducted in France. Patients are recruited by urologists, radiation oncologists and medical oncologists. Main inclusion criteria are a histologically confirmed PCa, eligible for triptorelin therapy in its label, with a planned total duration of triptorelin treatment of at least 12 months. Decision of triptorelin treatment is made before the inclusion in the study, in the routine practice. 3 visits are planned: V1 (baseline), V2 (at 6 months), V3 (at 12 months). Primary objective of the study is to describe the proportion of patients treated continuously with triptorelin during 12 months following treatment initiation. 786 patients are planned to be enrolled, this will allow to estimate the proportion of patients treated continuously with triptorelin during 12 months following treatment initiation for an expected proportion of 80% with a precision of 3 % taking into account a drop out rate of 15%. Main secondary objectives are to describe the planned total duration of triptorelin treatment and main reason of choice, to identify parameters (tumor aggressiveness criteria, patient frailty...) associated with this planned duration, to describe the formulation and route of administration of triptorelin and reasons of choice, to identify parameters associated with this choice, to describe the change from baseline in quality of life evaluated through QLQ-PR25 questionnaire, and to describe the safety of triptorelin in the real world setting. An interim analysis on baseline data will be performed once 50% of patients are enrolled. It will focus on planned total duration of triptorelin at initiation, main reasons of choice according to circumstances of prescription, formulation and route of administration, and their reasons of choice. Clinical trial information: NCT04593420.

Androgen Deprivation Therapy in Pedophilic Disorder: Exploring the Physical, Psychological, and Sexual Effects From a Patient's Perspective

BackgroundThe use of androgen deprivation therapy (ADT) shows promising results in the treatment of paraphilic disorders. Although the side effects of ADT can be intrusive, there is no research into the experiences of patients with pedophilic disorder themselves. AimThis research aims to explore the psychological, physical, and sexual experiences of ADT from the perspective of sex offenders diagnosed with pedophilic disorder. MethodsTwelve semistructured in-depth interviews with male adults diagnosed with pedophilic disorder were conducted using a phenomenological approach. Six of the 12 respondents were on luteinizing hormone-releasing hormone agonists and the remaining on anti-androgens. Half of each group were inpatients, and the other half outpatients. The respondents were recruited in collaboration with one psychiatric hospital. The data were analyzed with help of a qualitative software application NVivo. OutcomesThe respondents described experiences on the use of ADT on a physical, psychological, and sexual level. ResultsThe most prominent physical side effects mentioned were bone loss, weight gain, and breast formation. The respondents generally described a positive influence of the medication on their well-being. They felt more relaxed and experienced a reduction in frequency and intensity of sexual fantasies, anger, and aggressive feelings in general. In addition, all the respondents noticed a lower frequency of sexual contact and masturbation. Most of the participants experienced the use of ADT as a mandatory decision made by the treating psychiatrist. Clinical implicationsThis study recommends informing patients and their loved ones on the potential side effects of ADT. Furthermore, training forensic counselors on potential side effects of ADT and methods to alleviate them can promote the dissemination of information and will encourage the informed consent procedure. Strengths & limitationsThis is the first qualitative study about the experiences of ADT in men diagnosed with pedophilic disorder in Belgium. Future studies should include more than one treatment center. ConclusionThe majority of the participants had a positive attitude towards ADT in general.Boons L, Jeandarme I, Vervaeke G. Androgen Deprivation Therapy in Pedophilic Disorder: Exploring the Physical, Psychological, and Sexual Effects From a Patient's Perspective. J Sex Med 2021;18:353–362.

Abstract 5750: The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats

Abstract First-line treatment for prostate cancer includes androgen deprivation therapy (ADT). However, this intervention can induce severe cognitive impairments in more than half of patients and increases the likelihood of dementia or Alzheimer's disease. Long-term occurrence of these impairments can significantly reduce quality of life for cancer survivors and ultimately impacts their families and caregivers. Thus, it is important to improve the cognitive side effects of ADT, as 45% of prostate cancer patients will undergo ADT, and the five-year relative survival rate is greater than 99%. The clinical literature indicates that ADT-induced impairments typically occur in the cognitive domains of spatial memory and executive function, which are associated with function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC), respectively. The cognitive symptoms that develop can also increase in severity with duration of treatment, suggesting that it may be possible to slow or reverse the impairment. To address the mechanisms underlying these effects, we used the Attentional Set-shifting Test (AST) and the Novel Object Location (NOL) Test to assess cognitive function after surgical castration as a rodent model of ADT. ADT induced impairments in cognitive flexibility on the AST (p&amp;lt;0.001, n=10-12) and visuospatial memory on the NOL task (p&amp;lt;0.05, n=8-11) in male Sprague Dawley rats. These deficits were reversed by chronic administration of a multimodal antidepressant drug, vortioxetine (28 mg/kg/day for 2 weeks). Vortioxetine is FDA-approved for the treatment of Major Depressive Disorder, and it has been shown to improve cognitive impairment associated with depression. Our data indicate that vortioxetine may also represent a novel therapeutic approach to alleviate ADT-induced cognitive impairments. To increase the translational relevance our rodent model of ADT, we are investigating potential cognitive impairments induced by chemical castration with degarelix, a gonadotropin releasing hormone antagonist. Experiments are underway to test the hypothesis that vortioxetine will also reverse cognitive impairments induced by androgen depletion with degarelix. The results of this study will be compared to those obtained with surgical castration. In sum, these studies aim to identify possible therapeutic interventions by which cognitive impairment induced by ADT as a treatment for prostate cancer can be reversed or prevented. This research was funded by the Cancer Prevention &amp; Research Institute of Texas grant RP180055, and by NIH grant R01 CA224672. Citation Format: Alexandra M. Vaiana, Jonathan Gelfond, Teresa Johnson-Pais, Robin Leach, Michael Liss, Anna Sullivan, Ian Thompson, David A. Morilak. The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5750.