Androgen Deprivation Therapy,Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer

Androgen deprivation therapy (ADT) is successfully used in patients with advanced prostatic cancer, but there are many concerns about its systemic side effects, especially due to advanced age and frequent comorbidities in most patients. In patients treated with ADT there are metabolic changes involving the glycaemic control and lipid metabolism, increased thrombotic risk, an increased risk of myocardial infarction, severe arrhythmia and sudden cardiac death. Still, these adverse effects can be also due to the subsequent hypogonadism. Men with heart failure or coronary artery disease have a lower level of serum testosterone than normal men of the same age, and hypogonadism is related to higher cardiovascular mortality. Many clinical studies compared the cardiovascular effects of hypogonadism post orchiectomy or radiotherapy with those of ADT but their results are controversial. However, current data suggest that more intensive treatment of cardiovascular risk factors and closer cardiological follow-up of older patients under ADT might be beneficial. Our paper is a narrative review of the literature data in this field.     

Depression,Anxiety, and Patterns of Mental Health Care Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy

BackgroundAndrogen deprivation therapy (ADT) use is associated with an increased risk of developing depression and anxiety. Little is known about how the mental health of these men is treated.Materials and MethodsWe identified men with prostate cancer who received ADT between 2001 and 2015 using Optum’s de-identified Clinformatics Data Mart Database. We determined the incidence of depression or anxiety diagnoses, mental health treatments, and the specialty of providers initiating psychotropic medications, after the start of ADT. Outcomes were compared with those of men with prostate cancer not receiving ADT and men without prostate cancer.ResultsOf 37 388 men with prostate cancer treated with ADT, 3964 (10.6%) received a new diagnosis of depression or anxiety. Of those 3964 men, 1892 (47.7%) did not receive a documented treatment, 10 (0.3%) received psychotherapy, 1321 (33.3%) a selective serotonin reuptake inhibitor, and 744 (18.8%) a benzodiazepine. The median time from initiation of ADT to a depression or anxiety diagnosis was 9.3 months. Primary care physicians were the most common prescribers of psychotropic medications (72.2%). The proportion of men not receiving mental health treatments of interest (47.7%) was similar compared to men without prostate cancer (49.1%), but statistically significantly lower compared to men with prostate cancer not receiving ADT (52.7%).ConclusionsIn men with prostate cancer receiving ADT with a new diagnosis of depression or anxiety, nearly half are not receiving mental health care while one in five is introduced to a benzodiazepine. Further investigation toward improving the mental health care for men on ADT is needed.     

Changes in Magnetic Resonance Imaging Radiomic Features in Response to Androgen Deprivation Therapy in Patients with Intermediate- and High-risk Prostate Cancer

AimsThe benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT.Materials and methodsPatients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test.ResultsTwenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82–105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters.ConclusionEnergy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours.     

雄激素剥夺疗法和免疫疗法在前列腺癌治疗中的研究进展

前列腺癌在美国成年男性中发病率位居第一,癌症相关致死率位居第二。雄激素剥夺治疗是最常用的前列腺癌治疗方法,而且通常伴随患者的终身治疗。雄激素和雄激素剥夺疗法对免疫系统有着重要的影响,在目前免疫治疗受到持续关注的情况下这一发现显得尤为重要。研究表明,雄激素剥夺治疗可能对免疫治疗起到促进或者抑制的作用。本文综述了不同类型雄激素剥夺治疗药物的作用机制,探讨了其对前列腺癌细胞及患者免疫系统的影响,以及联合使用雄激素剥夺药物和免疫治疗的前景,为前列腺癌的治疗提供了新的视野和思路。     

Genetic Polymorphism in Sex Hormone-binding Globulin With a Prognosis of Androgen Deprivation Therapy in Metastatic Prostate Cancer Among Japanese Men

IntroductionTestosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer.Patients and MethodsThis study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined.ResultsThe serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P = .027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P = .012).ConclusionsThis study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.     

Risk Factors for Clinical Metastasis in Men Undergoing Radical Prostatectomy and Immediate Adjuvant Androgen Deprivation Therapy

Background: Adjuvant androgen deprivation therapy (ADT) is a treatment option for prostate cancer(PC) patients after radical prostatectomy (RP). Although it can achieve a good progression-free survival rate,some patients still develop clinical metastasis. We here investigated risk factors of clinical metastasis in postprostatectomypatients who received immediate adjuvant ADT. Materials and Methods: We identified 197 patientswith non-metastatic PC who underwent RP at our institution between 2000 and 2012, followed by adjuvantADT. The associations of various clinicopathologic factors with clinical metastasis (primary endpoint) andcancer-specific survival (secondary endpoint) were assessed. Multivariate analysis was conducted using a Coxproportional hazards model. Median follow-up was 87 months after RP. Results: Nine (4.6%) patients developedclinical metastasis and six (3.0%) died from PC. Eight of nine metastatic patients had a pathologic Gleason score(GS) 9 and developed bone metastasis, while the remaining one had pathologic GS 7 and developed metastasisonly to para-aortic lymph nodes. On multivariate analyses, pathologic GS ≥9 and regional lymph node metastasis(pN1) were independent predictors of clinical metastasis and pathologic GS ≥9 was an independent predictor ofcancer-specific death. Conclusions: Pathologic GS ≥9 and pN1 were independent predictors of clinical metastasisin post-prostatectomy patients who received immediate adjuvant ADT. Furthermore, pathologic GS ≥9 was anindispensable condition for bone metastasis, which may imply that patients with GS ≤8 on adjuvant ADT areunlikely to develop bone metastasis.     

Population-Based Referrals for Adjuvant Radiotherapy After Radical Prostatectomy in Men With Prostate Cancer: Impact of Randomized Trials

IntroductionTo examine the impact of published randomized controlled trial (RCT) data on referrals for adjuvant radiotherapy (RT) in patients who had high-risk pathologic features after radical prostatectomy (RP).MethodsIn this population-based, retrospective Canadian study, all patients who received a diagnosis of prostate adenocarcinoma and underwent RP from 2003-2008 were identified through the Manitoba Cancer Registry. Manual review of pathology reports was performed, and patients who had high-risk pathologic features of extracapsular extension, seminal vesicle invasion, or positive surgical margins were included. Referrals for adjuvant RT were examined before and after publication of RCT data to determine their influence on practice. Multivariable logistic regression was used to identify factors related to referral.ResultsOf the 1080 identified patients, 546 (50.6%) had ≥ 1 high-risk pathologic feature. Only 78 (14.3%) of the 546 patients were referred for adjuvant RT within 6 months of RP. Year of diagnosis, in relation to the publication of the RCT, was not significantly associated with referral (P = .60). Higher pT stage (P < .0001), Gleason score (P = .035), and increased distance from cancer center (P = .004) were associated with referral.ConclusionIn patients who had high-risk pathologic features after RP, referral rates for adjuvant RT were low and did not increase after presentation of RCT. Men who had higher pT stage, Gleason score, and rural residence were more likely to be referred.     

Effect of Diphosphonates on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Patients receiving androgen deprivation therapy are associated with increasing loss of bone mineral density (BMD) and higher risk of skeletal-related events. We reviewed and analyzed the influence of diphosphonates on BMD change. A systemic literature research was conducted in PubMed and related bibliographies. The focus of data extraction was BMD percentage change of lumbar spine, total hip, and femoral neck after 12 months. Standardized mean difference (SMD) was pooled with the random-effects model, and metaregression and subgroup analysis were performed to explore heterogeneity. Nine articles (n = 920) were included and finally analyzed after screening 118 articles. We found significant improvement in BMD percentage changes of the lumbar spine, total hip, and femoral neck at 1 year (respectively, SMD = 6.379, 95% confidence interval [CI] = 3.740-9.018, P < .001, I² = 98.8%, P < .001; SMD = 4.870, 95% CI, 2.256-7.485, P < .001, I² = 98.9%, P < .001; SMD = 3.634, 95% CI, 1.989-5.279, P < .001, I² = 97.3%, P < .001). In individual variable metaregression analysis, application zoledronic acid or not showed a statistically significant influence on BMD percentage change of total hip (P = .018). In subgroup analyses, both zoledronic acid and alendronate showed a significant improvement in BMD percentage changes. Diphosphonates significantly increased BMD percentage changes of the lumbar spine, total hip, and femoral neck in men receiving androgen deprivation therapy for prostate cancer. Patients with androgen deprivation therapy should be evaluated BMD loss, and timely therapy with diphosphonates may be an appropriate strategy to prevent osteoporosis.     

Outcomes for Young Men With Localized Intermediate-Risk Prostate Cancer: An Analysis of the NCDB

BackgroundPrimary management of localized, intermediate-risk prostate cancer consists of radical prostatectomy (RP), radiotherapy (RT) with short-course androgen deprivation therapy (ADT), or RT alone. The purpose of this study was to determine if these treatment strategies have equivalent overall survival (OS) in patients < 55 years old with intermediate-risk prostate cancer.Patients and MethodsWe identified 35,134 patients in the National Cancer Data Base with localized intermediate-risk prostate cancer treated with RP, RT + ADT, or RT from 2004 to 2013. Ten-year OS rates were estimated by the Kaplan-Meier method. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed by multivariate Cox regression.ResultsA total of 29,920 patients (85.2%) underwent RP, 1393 (4.0%) RT + ADT, and 3821 (10.9%) RT. Median patient age was 51 years old, and median follow-up was 59.9 months. Ten-year OS was estimated to be 94.2% for RP, 80.7% for RT + ADT, and 85.2% for RT (P < .0001). On multivariate analysis, treatment with RT + ADT or RT was associated with significantly worse OS compared to treatment with RP (RT + ADT HR = 2.06, 95% CI 1.67-2.54, P < .0001; RT HR = 2.0, 95% CI 1.71-2.33, P < .0001). Patients who met all 3 of the intermediate-risk criteria showed worse OS compared to patients who met only one criterion (HR = 1.80; 95% CI, 1.32-2.44; P = .0002).ConclusionRP is significantly more likely than RT + ADT or RT to be used as a primary treatment for young men with localized intermediate prostate cancer. RP was also associated with improved OS compared to RT + ADT and RT.