MRI evaluation of obturator internus muscle: its relationship with body composition and prognostic implications in prostate cancer patients undergoing ADT.

Sarcopenia is an emerging health problem, and its detection in prostate cancer patients undergoing androgen deprivation therapy (ADT) is of rising importance. This study aims to evaluate the relationship between sarcopenia parameters such as estimated skeletal muscle index (SMI) using the gallium-68 labeled prostate-specific membrane antigen-11 positron-emission tomography/computed tomography ([68Ga] Ga-PSMA-11 PET/CT) imaging performed for oncological staging, hand grip strength (HGS) with dynamometer and Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls (SARC-F) questionnaire score in prostate cancer patients, and to assess how these relationships are influenced by androgen deprivation duration. 20 patients with prostate cancer without ADT and 39 men on ADT with a mean duration of 34.8 ± 21.8 months in a hypogonadal state were included. SMI using the psoas muscle area on the third lumbar vertebra (L3) level was measured on [68Ga]Ga-PSMA-11 PET/CT images, adjusted to height, HGS, and SARC-F score were also assessed. SMI and HGS demonstrated a strong positive correlation (r = 0.85, p < 0.001) among all participants. SMI and SARC-F scores showed a moderate negative link (r = -0.74, p < 0.001), while HGS and SARC-F scores were strongly negatively associated (r = -0.95, p < 0.001). In hypogonadal men, SMI and HGS were both negatively correlated with ADT duration (r = -0.57, p < 0.001; and r = -0.82, p < 0.001). A strong positive correlation was found between SARC-F score and ADT duration (r = 0.43, p < 0.001). The present results confirm that prolonged ADT in prostate cancer patients is associated with a significant decline in muscle mass and strength, and support the integration of both imaging ([68Ga]Ga-PSMA-11 PET/CT-derived SMI) and simple clinical tools (HGS, SARC-F) in the routine assessment of prostate cancer patients receiving ADT.

Computed tomography (CT) scans used in treatment response assessment in prostate cancer (PCa) patients are a useful tool for nutritional status evaluation. The aim of this study was to assess the nutritional status, including sarcopenia development based on CT scans, in PCa patients and its association with progression-free survival (PFS). Sixty-four PCa patients were included (group 1: 34 patients undergoing androgen deprivation therapy (ADT) with docetaxel due to newly diagnosed, hormone-sensitive, metastatic PCa and group 2: 30 patients with castration-resistant metastatic PCa continuing ADT therapy with enzalutamide or abiraterone acetate). Nutritional status was evaluated with anthropometrical parameters, Nutritional Risk Score (NRS), and CT scans at the L3 vertebrae. Survival analyses were performed. According to NRS, nutritional status was significantly related to PFS. In both groups, there was a significant reduction in muscle tissue (total muscle tissue and skeletal muscle index). A significant increase in the distribution of adipose tissue (subcutaneous fat, visceral fat, subcutaneous adipose tissue index, and visceral adipose tissue index) in group one was observed. Sarcopenia was diagnosed in patients but with no influence on PFS. Significant reduction in muscle mass and increase in fat mass was observed in patients treated for PCa with no impact on PFS. The NRS was related to PFS in PCa patients and associated with body composition, assessed by CT after the castration therapy. Long-term castration combined with abiraterone therapy with prednisone or enzalutamide significantly influenced muscle tissue and may lead to sarcopenia development.

Objective. To compare the effects of a group-mediated cognitive behavioral (GMCB) exercise and dietary (EX+D) intervention with those of standard-of-care (SC) treatment on select social cognitive outcomes in prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Methods. In the single-blind, 2-arm, randomized controlled Individualized Diet and Exercise Adherence–Pilot (IDEA-P) trial, 32 PCa patients (mean age = 66.2 years; SD = 7.8) undergoing ADT were randomly assigned to a 12-week EX+D intervention (n = 16) or SC treatment (n = 16). The exercise component of the personalized EX+D intervention integrated a combination of supervised resistance and aerobic exercise performed twice per week. The dietary component involved counseling and education to modify dietary intake and composition. Blinded assessments of social cognitive outcomes were obtained at baseline and 2-month and 3-month follow-up. Results. Intent-to-treat analysis of covariance demonstrated that the EX+D intervention resulted in significantly greater improvements in scheduling (P < .05), coping (P < .01), and exercise self-efficacy (P < .05), and satisfaction with function (P < .01) at 3 months relative to SC. Results of partial correlation analysis also demonstrated that select social cognitive outcomes were significantly correlated with primary trial outcomes of mobility performance and exercise participation (P < .05) at 3-month follow-up. Conclusions: The GMCB lifestyle intervention yielded more favorable improvements in relevant social cognitive outcomes relative to SC among PCa patients undergoing ADT. Additionally, more favorable social cognitive outcomes were associated with superior mobility performance and exercise participation following the independent maintenance phase of the EX+D intervention.

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

Evidence suggests that prostate cancer (PC) patients undergoing androgen deprivation therapy (ADT) are at risk for cognitive decline (CD), but the underlying mechanisms are less clear. In the present study, changes in cognitive performance and structural brain connectomes in PC patients undergoing ADT were assessed, and associations of cognitive changes with endocrine status and risk genotypes were explored. Thirty-seven PC patients underwent cognitive assessment, structural MRI, and provided blood samples prior to ADT and after 6 months of treatment. Twenty-seven age- and education-matched healthy controls (HCs) underwent the same assessments. CD was determined using a standardized regression-based approach and defined as z-scores ≤ -1.64. Changes in brain connectomes were evaluated using graph theory. Associations of CD with testosterone levels and genotypes (APOE, COMT, BDNF) were explored. Compared with HCs, PC patients demonstrated reduced testosterone levels (p < 0.01) and higher rates of decline for 13 out of 15 cognitive outcomes, with three outcomes related to two cognitive domains, i.e., verbal memory and visuospatial learning and memory, reaching statistical significance (p ≤ 0.01-0.04). Testosterone level changes did not predict CD. COMT Met homozygote PC patients evidenced larger reductions in visuospatial memory compared with Val carriers (p = 0.02). No between-group differences were observed in brain connectomes across time, and no effects were found of APOE and BDNF. Our results indicate that PC patients undergoing ADT may evidence CD, and that COMT Met homozygotes may be at increased risk of CD. The results did not reveal changes in brain connectomes or testosterone levels as underlying mechanisms. More research evaluating the role of ADT-related disruption of the dynamics of the hypothalamic-pituitary-gonadal axis is needed.

Osteoporosis is a well-known adverse effect of androgen deprivation therapy for prostate cancer. This study aimed to reveal the factors associated with the diagnosis of osteoporosis in prostate cancer patients undergoing androgen deprivation therapy. This retrospective cross-sectional study included 106 prostate cancer patients treated with androgen deprivation therapy. Patients with bone metastasis at the initiation of androgen deprivation therapy and those with castration-resistant prostate cancer were excluded. Bone mineral density was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Osteoporosis was defined as bone mineral density equal to or below either -2.5 SD or 70% of the mean in young adults. The association between clinicopathological variables and bone mineral density or diagnosis of osteoporosis was investigated. Thirty-six (34%) patients were found to have osteoporosis. The incidence of osteoporosis increased in a stepwise manner depending on the duration of androgen deprivation therapy. Multivariate logistic regression analysis identified a longer duration of androgen deprivation therapy (months, odd's ratio = 1.017, P=0.006), lower body mass index (kg/m2, odd's ratio = 0.801, P=0.005) and higher serum alkaline phosphatase value (U/l, odd's ratio 1.007, P=0.014) as the factors independently associated with the diagnosis of osteoporosis. Eleven out of 50 (22%), 14 out of 35 (40%) and 11 out of 20 patients (55%) were osteoporotic in the patients with serum alkaline phosphatase values <238U/l, 238-322U/l and >322U/l, respectively (P=0.022). Osteoporosis is common in prostate cancer patients undergoing androgen deprivation therapy; furthermore, its incidence increases depending on the duration of androgen deprivation therapy. Bone mineral density testing should be considered for all patients on androgen deprivation therapy, especially for those with a lower body mass index and higher serum alkaline phosphatase value.

Efficacy of metformin drug in preventing metabolic syndrome associated with androgen deprivation therapy (ADT) in prostate cancer patients: A systematic review and meta-analysis

Purpose: Prostate cancer survivors (PCS) on androgen deprivation therapy (ADT) experience adverse side effects such as skeletal muscle loss and adiposity gain, together called sarcopenic obesity, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance exercise can increase skeletal muscle mass, but no exercise interventions to date in PCS on ADT have concomitantly improved sarcopenic obesity and cardiometabolic risk factors. Utilizing a 12-week intervention of progressive resistance exercise designed to target skeletal muscle mass, this ongoing pilot trial investigates sarcopenic obesity and as a secondary analyses, MetS components, in PCS on ADT. Methods: Eighteen PCS (65.6±8.8 yr) on current or previous ADT were recruited from the USC Norris Comprehensive Cancer Center and randomized to resistance training (RT; n=9) or a control stretching program (CS; n=9). Body composition, measured through dual-x-ray absorptiometry, and MetS outcomes, including waist circumference, blood pressure, fasting blood glucose, triglycerides and HDL, were assessed at baseline and after the 12-week intervention. Appendicular skeletal muscle index (ASMI), a common index of sarcopenia, was calculated from body composition. RT performed a supervised total-body resistance exercise and stretching program 3 times/week. CS performed home-based stretching 3 times/week. Baseline differences were tested with univariate ANOVA. Differences in all outcomes were tested with 2(group) x 2(time) ANOVA. Results: No significant differences in ADT duration, Gleason score, body fat, skeletal muscle mass, or MetS components were found between groups at baseline (P&amp;gt;0.05). RT program compliance was 98.3%, while CS program compliance was 75.5%. Post-intervention, significant increases were observed in RT compared to CS for appendicular skeletal mass (mean±SE; 0.8±.4 kg; P=0.04) and ASMI (0.3±.1 kg/m2; P=0.041). A nonsignificant decrease in body fat (%) was observed in RT compared to CS (1.3±.7 %; P=.067; d=0.89). No differences were found in MetS components. Conclusions: While 12 weeks of resistance exercise in PCS on ADT improved skeletal muscle mass, no changes in adiposity and MetS variables were observed. Future interventions are needed for PCS to determine the optimal exercise prescription to target both sarcopenic obesity and cardiometabolic risk factors. Citation Format: Jacqueline L. Kiwata, Tanya B. Dorff, E. T. Schroeder, Christina M. Dieli-Conwright. Effect of a supervised exercise intervention on sarcopenic obesity and metabolic syndrome in prostate cancer patients: A randomized pilot study [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 988. doi:10.1158/1538-7445.AM2017-988

Hyperinsulinemia, obesity and related metabolic diseases are associated with prostate cancer development. Prostate cancer patients undergoing androgen deprivation therapy (ADT) are at increased risk for metabolic syndrome, cardiovascular disease and diabetes, while pre-existing metabolic conditions may be exacerbated. An integrative approach is used to describe the interactions between insulin, glucose metabolism, obesity and prostate cancer. The potential role of nutrition and exercise will also be examined. Hyperinsulinemia is associated with prostate cancer development, progression and aggressiveness. Prostate cancer patients who undergo ADT are at risk of diabetes in survivorship. It is unclear whether this is a direct result of treatment or related to pre-existing metabolic features (e.g. hyperinsulinemia and obesity). Obesity and metabolic syndrome are also associated with prostate cancer development and poorer outcomes for cancer survivors, which may be driven by hyperinsulinemia, pro-inflammation, hyperleptinemia and/or hypoadiponectinemia. Independently evaluating changes in glucose metabolism near the time of prostate cancer diagnosis and during long-term ADT treatment is important to distinguish their unique contributions to the development of metabolic disturbances. Integrative approaches, including metabolic, clinical and body composition measures, are needed to understand the role of adiposity and insulin resistance in prostate cancer and to develop effective nutrition and exercise interventions to improve secondary diseases in survivorship.

BackgroundThe prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa.MethodsTwo hundred eighty PCa patients undergoing androgen deprivation therapy (ADT) as first line therapy at three centers were enrolled. The serum albumin levels and peripheral lymphocyte count were measured at the time of diagnosis. PNI was calculated as 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (per mm3). Patients were categorized in two groups using a cut-off point of 50.2 as calculated by the receiver-operating curve analysis. Univariate and multivariate cox regression analyses were performed to evaluate PNI as a favorable prognostic factor for progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index.ResultsMultivariate analyses identified PNI as an independent prognostic indicator with respect to PFS (hazard ratio (HR) = 0.521, p = 0.001), CSS (HR = 0.421, p = 0.002) and OS (HR = 0.429, p = 0.001). Patients with elevated PNI had better clinical outcomes. The addition of PNI to the final models improved predictive accuracy (c-index: 0.758, 0.830 and 0.782) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.736, 0.801 and 0.752), which included Gleason score and incidence of metastasis.ConclusionsElevated pretreatment PNI was a favorable prognostic indicator for PCa patients treated with ADT.

ObjectivesAndrogen deprivation therapy (ADT) has seen increasing use as a prostate cancer treatment in recent years and has proven medically effective in numerous contexts. The treatment, however, is associated with a host of side effects including depression. Managing the psychological wellbeing of prostate cancer patients is important for maximizing their survival outcomes. Thus, this study aimed to evaluate depressive symptomatology in patients with androgen deprivation therapy (ADT) compared with that in patients who underwent prostatectomy and to explore the factors that affect depressive symptoms, which might occur during ADT.MethodsOne hundred and seven patients undergoing ADT (ADT group) and prostatectomy (Operation group) were enrolled. Adjustments were made for differences in characteristics between groups using a propensity score model with stabilized weights before treatment. Depressive symptoms between groups were compared using the Beck Depression Inventory (BDI) before treatment and six months after treatment initiation. To identify factors affecting depressive symptoms during ADT, multivariate regression analysis was performed on the mean change in BDI score, age, body mass index, testosterone level, prostate-specific antigen level, the international index of erectile function (IIEF), and the Gleason score.ResultsThe BDI score significantly increased in the ADT group compared to the operation group six months after treatment initiation (p < 0.001). Multivariate regression analysis revealed that before ADT, the BDI score was higher by 0.446 according to the IIEF. During ADT, the BDI score increased by 1.579 according to changes in BMI (p = 0.021) and decreased by 0.01 according to changes in testosterone levels (p = 0.034).ConclusionDepressive symptoms can be exacerbated in prostate cancer patients undergoing ADT. Efforts are needed to diagnose and treat depression appropriately, especially if depressive symptoms change in ADT patients with a high IIEF score before ADT, or reduced testosterone levels or increased BMI during ADT.

BackgroundThe study aimed to assess the value of circulating tumor cells (CTCs) as a prognostic and treatment response marker in patients undergoing androgen deprivation therapy (ADT) plus cryosurgery vs. ADT alone for metastatic prostate cancer (mPCA).MethodsThis retrospective analysis included 43 patients with mPCA: 23 receiving ADT alone (control) and 20 receiving additional cryosurgery (cryosurgery group). CTCs and progression-free survival (PFS) were compared between the two groups. Cox proportional hazards regression was conducted to identify variables associated with PFS.ResultsMedian PFS was 35 months (IQR, 33‑37) in the cryosurgery group vs. 30 months (IQR, 27‑32) in the control (p < 0.001). CTCs count was significantly lower in the cryosurgery group at both 3 months (z = 2.170, p = 0.030) and 12 months (z = 2.481; p = 0.013). In comparison to the baseline, the number of CTCs at both 3 and 12 months was lower in the cryosurgery group (p = 0.004 and p < 0.001, respectively), but not in the ADT alone group. In multivariate Cox regression, shorter PFS was associated with baseline PSA ≧100 ng/ml (HR 6.584, 95% CI, 5.309‑8.166), biopsy Gleason score ≧ 8 (HR 2.064, 95% CI, 1.608‑2.650), clinic T stage>T2b (HR 5.021, 95% CI, 3.925‑6.421), number of bone metastases>3 (HR 3.421, 95% CI, 2.786‑4.202), positive CTCs at 3 months post-treatment (HR 6.833, 95% CI, 5.176‑9.022), positive CTCs 1 year post-treatment (HR 6.051, 95% CI, 4.347‑8.424). Prostate cryosurgery was associated with longer PFS (HR 0.062, 95% CI, 0.048‑.080).ConclusionsCTC was a prognostic and treatment response marker for mPCA. ADT plus cryosurgery could reduce CTCs and prolong PFS vs. ADT alone in mPCA patients with low metastatic volume.

46 Background: Recent literature has suggested an association between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients.1,2 The 1-year incidence of major adverse cardiovascular events (MACE) in patients ≥45 years old was 1.4%,3 whereas a recent study of PCa patients on ADT reported MACE in 2.9% of patients treated with an LHRH antagonist (relugolix) and 6.2% of patients treated with an LHRH agonist (leuprolide acetate) over 48 weeks.4 Thus, MACE risk is an important consideration for PCa patients on ADT. This study aims to evaluate MACE risk after ADT initiation with LHRH agonists vs. LHRH antagonists using real-world data. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate the rate of MACE-free survival after ADT initiation by drug class. The database contained 178,388 LHRH agonist and antagonist injection entries and 965 documented MACE events. Exclusion criteria included taking more than one class of ADT and MACE within 6 months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause based on a recent study in this field.4 Kaplan-Meier event-free survival curves were constructed to compare the risk of MACE between patients on agonist vs. antagonist. Statistical significance between survival curves was evaluated by log-rank test. Results: Overall MACE risk for all patients was 1.0% at one year. MACE risk was significantly higher for patients treated with LHRH antagonist compared to agonists in the first seven years after ADT initiation. Conclusions: Risk of MACE was lower than previously reported. Although this may potentially be due to underreporting, our analysis of data over 10 years from &gt;45,000 PCa patients is likely an accurate reflection of the real world. A recent study using large real-world dataset with &gt;50,000 PCa patients over approximately 2 years showed no difference in CV risk following treatment with GnRH agonists and antagonists.5 However, in our analyses MACE risk was lower in patients treated with LHRH agonists vs. antagonists in the first seven years after ADT initiation. Further, we plan to evaluate baseline comorbidities and demographics for imbalances. Future studies evaluating the impact of ADT class and comorbidities on MACE risk for PCa patients during ADT may be helpful to identify CV predictors. 1Ng C-F, et al. Scientific Reports. 2020. 2Zhao J, et al. PLoS One. 2014. 3Miao B, et al. J of the American Heart Association. 2020. 4Shore ND, et al. New England Journal of Medicine. 2020. 5George G, et al. Int J Cancer. 2021.

Effects of Exercise on Cancer-related Fatigue and Quality of Life in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Meta-analysis of Randomized Clinical Trials.

We investigated the impact of prostate-specific membrane antigen (PSMA) PET/CT compared with conventional imaging on treatment outcomes for node-positive prostate cancer (PCa) patients who underwent androgen deprivation therapy (ADT) and external radiotherapy (RT). A multicentric, retrospective study recruited patients with node-positive PCa patients who underwent conventional radiological evaluation or PSMA PET/CT and received ADT and RT at 3 hospitals from 2009 to 2021 were enrolled. Patients underwent prostate and pelvis RT, accompanied by a minimum of 6 months of ADT. The primary endpoints were progression-free survival (PFS) and PCa-specific survival (PCSS). Cox regression analyzed the association of survival with potential prognostic factors, whereas logistic regression identified the predictors of bone and lymph node metastasis. The median follow-up time was 64.0 months. The majority of patients (64.1%) underwent PSMA PET/CT for staging. The 5-year rates of PFS and PCSS were 63.7% and 83.7%, respectively. Disease progression was observed in 90 patients (36.3%). In multivariable analysis, ADT duration of less than 24 months and post-RT prostate-specific antigen (PSA) nadir were prognostic for PFS. Early clinical T stage and PSMA PET/CT predicted better PCSS. Patients staged with PSMA PET/CT had exhibited significantly higher 5-year PCSS rates than compared with those staged with conventional imaging (95.1% vs 76.9%; P = 0.01). Shorter ADT duration and higher PSA levels after RT independently predicted bone metastasis in multivariable logistic regression. Advanced T stage, shorter ADT duration, and higher PSA levels after neoadjuvant ADT predicted nonregional lymph node recurrence. ADT with pelvis RT is an effective treatment option for node-positive PCa patients. The PSMA PET/CT outperformed conventional imaging in PCSS, emphasizing the importance of precise clinical staging for patients undergoing definitive RT.