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- The Use of Dietary Supplements to Alleviate Androgen Deprivation Therapy Side Effects during Prostate Cancer Treatment. [REVIEW]
- Nutrients 2014; 6(10):4491-4519.
Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.
- Risk of Acute Myocardial Infarction after Androgen Deprivation Therapy for Prostate Cancer in the Chinese Population. [JOURNAL ARTICLE]
- BJU Int 2014 Oct 18.
- To investigate the risk of acute myocardial infarction (AMI) after androgen deprivation therapy (ADT) for prostate cancer in the Chinese population.- All Chinese prostate cancer patients who were treated primarily with radical prostatectomy or radiotherapy, with or without further ADT at our hospital from year 2000 to 2009 were retrospectively reviewed. - We compared the risk of AMI in the patients who were given further ADT (ADT group) with those who were not given any ADT (non-ADT group). - Potential risk factors of AMI including age, diabetes mellitus, hypertension, hyperlipidemia, history of stroke, ischemic heart disease, ECOG performance status and duration of ADT were reviewed. - The risk of AMI after ADT was first analyzed with Kaplan-Meier method, followed by Cox regression analyses including the potential risk factors mentioned.- A total of 452 patients were included, consisting of 200 patients in the non-ADT group and 252 patients in the ADT group. - The mean age was 68.2+5.9 years in the non-ADT group and 69.5+6.5 years in the ADT group, and the difference was statistically significant (P = 0.031). - There was no significant difference in their pre-existing medical conditions and ECOG performance status. - The ADT group was associated with an increased risk of AMI when compared to the non-ADT group (P = 0.004) upon Kaplan-Meier analysis. - Upon multivariate Cox regression analysis, hyperlipidemia, poor ECOG performance status and the use of ADT were the only three significant factors that were associated with increased risk of developing new AMI.- There was increased risk of AMI after ADT for prostate cancer in the Chinese population. - Hyperlipidemia and poor ECOG performance status were also significant risk factors for developing AMI. - The risk of AMI should be considered while deciding on ADT, especially in patients with history of hyperlipidemia and relatively poor ECOG performance status. Prostate cancer, androgen deprivation therapy, myocardial infarction, Asian population.
- Adverse Effects of Androgen Deprivation Therapy in Prostate Cancer and Their Management. [JOURNAL ARTICLE]
- BJU Int 2014 Oct 18.
To provide an up-to-date summary of current literature on the management of adverse effects of androgen deprivation therapy (ADT).All men suffering from prostate cancer who are treated with androgen deprivation therapy.All relevant medical literature from 2005 to 2014 and older relevant papers were reviewed to formulate this article. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.There are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from cardiovascular disease, diabetes and osteoporosis to depression, cognitive decline and sexual dysfunction, the range of adverse effects is wide. Baseline assessment, monitoring, prevention and consultation from a multidisciplinary team are important in minimizing the harm from ADT.This review provides series of practical recommendations to assist with managing adverse effects of ADT.
- Predictors of castration-resistant prostate cancer after dose-escalated external beam radiotherapy. [JOURNAL ARTICLE]
- Prostate 2014 Oct 18.
Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT).During 1991-2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (<50 ng/dl) with progressive biochemical or radiographic disease.For the entire cohort (n = 2,478), the 10-year cumulative incidence rate for developing CRPC was 9.9%. For those that progressed to salvage ADT (n = 362), the 7-year cumulative incidence rates for developing CRPC from time of salvage ADT was 33.7%. Amongst this cohort, multivariable analysis demonstrated that PSA doubling-time (continuous; hazard ratio [HR], 0.98 [0.97-0.99], P < 0.001), higher Gleason score (HR, 1.96 [1.12-3.43]; P = 0.034), and duration of ADT at time of EBRT (continuous; HR, 1.02 [1.01-1.03]; P = 0.007) were associated with development of CRPC.This represents the first report of predictors of CRPC for patients treated with modern dose-escalated EBRT. We demonstrate that among the minority of patients not initially cured after EBRT, those treated with longer-course ADT have higher rates of resistance to the re-introduction of ADT. Future trials will need to test this subgroup with more aggressive or alternative forms of salvage therapies. Prostate © 2014 Wiley Periodicals, Inc.
- Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy. [Journal Article, Review]
- Prostate Int 2014 Sep; 2(3):105-13.
Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are sufficient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from different androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy.
- Ultra-early versus early salvage androgen deprivation therapy for post-prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer. [JOURNAL ARTICLE]
- BMC Urol 2014 Oct 16; 14(1):81.
The optimal timing of salvage androgen deprivation therapy (ADT) for biochemical recurrence after radical prostatectomy is controversial. We compared the outcomes of ultra-early versus early salvage ADT.Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 121 with adjuvant-treatment-naive pT2-4N0M0 prostate cancer who received salvage ADT for biochemical recurrence. These patients were divided into an ultra-early salvage ADT group (n = 51), who started salvage ADT before meeting the standardized definition of biochemical recurrence in Japan (two consecutive prostate-specific antigen [PSA] values >=0.2 ng/ml), and an early salvage ADT group (n = 70) who started salvage ADT when they met the definition. The ultra-early ADT group consisted of those who started salvage ADT with a single PSA value >=0.2 ng/ml (n = 30) or with two consecutive PSA values >0.1 ng/ml and rising (n = 21). The primary endpoint was biochemical recurrence after salvage ADT, defined as a single PSA value >=0.2 ng/ml after PSA nadir following salvage ADT. Secondary endpoints were clinical metastasis and cancer-specific survival. A Cox proportional hazards model was used for multivariate analysis. The median follow-up was 65.5 months.Biochemical recurrence occurred in one patient (2.0%) in the ultra-early group and in 12 (17.1%) in the early salvage ADT group. Multivariate analysis identified ultra-early salvage ADT and preoperative Gleason score <=7 as independent negative predictors of biochemical recurrence after salvage ADT. Only one patient in the early salvage ADT group developed clinical metastasis to a left supraclavicular lymph node, and no patient died from prostate cancer during follow-up. The major limitations of this study were its retrospective design, selection bias, and the possibility that the ultra-early salvage ADT group may have included patients without biochemical recurrence.Ultra-early salvage ADT was an independent negative predictor of biochemical recurrence after salvage ADT in post-prostatectomy patients. Further consideration should be given to the use of salvage ADT before meeting the current definition of biochemical recurrence.
- Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study. [JOURNAL ARTICLE]
- J Clin Oncol 2014 Oct 13.
Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression.A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy.The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority.LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.
- Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. [JOURNAL ARTICLE]
- Prostate 2014 Oct 13.
The mechanism(s) by which androgen receptor (AR) splice variants contribute to castration-resistant prostate cancer (CRPC) is still lacking.Expressions of epithelial-to-mesenchymal transition (EMT) and stem cell markers were molecularly tested using prostate cancer (PCa) cells transfected with AR and AR3 (also known as AR-V7) plasmids or siRNA, and also cultured cells under androgen deprivation therapy (ADT) condition. Cell migration, clonogenicity, sphere-forming capacity was assessed using PCa cells under all experimental conditions and 3,3'-diindolylmethane (DIM; BR-DIM) treatment. Human PCa samples from BR-DIM untreated or treated patients were also used for assessing the expression of AR3 and stem cell markers.Overexpression of AR led to the induction of EMT phenotype, while overexpression of AR3 not only induced EMT but also led to the expression of stem cell signature genes. More importantly, ADT enhanced the expression of AR and AR3 concomitant with up-regulated expression of EMT and stem cell marker genes. Dihydrotestosterone (DHT) treatment decreased the expression of AR and AR3, and reversed the expression of these EMT and stem cell marker genes. BR-DIM administered to PCa patients prior to radical prostatectomy inhibited the expression of cancer stem cell markers consistent with inhibition of self-renewal of PCa cells after BR-DIM treatment.AR variants could contribute to PCa progression through induction of EMT and acquisition of stem cell characteristics, which could be attenuated by BR-DIM, suggesting that BR-DIM could become a promising agent for the prevention of CRPC and/or for the treatment of PCa. Prostate © 2014 Wiley Periodicals, Inc.
- Permanent prostate brachytherapy and short-term androgen deprivation for intermediate-risk prostate cancer in Japanese men: Outcome and toxicity. [JOURNAL ARTICLE]
- Brachytherapy 2014 Oct 8.
To evaluate the interim outcomes of low-dose-rate permanent brachytherapy (PB) combined with short-term androgen deprivation therapy (ADT) in Japanese men with intermediate-risk prostate cancer excluding those with a Gleason score of 4+3.The Protocol-intermediate-risk group (Protocol-IRG) was defined as clinical stage T1c-T2c, Gleason score of 3+4, or lower and prostatic-specific antigen (PSA) level lower than 20ng/mL. A total of 308 patients underwent brachytherapy in the protocol-IRG group (n=152) or in the low-risk group (n=156). Patients in Protocol-IRG had received at least 6 months of ADT before and after PB. Supplemental external beam radiotherapy was not used. Planned followup by PSA was carried out every 3 months for the first 2 years and every 6 months thereafter. The PSA failure was defined as nadir+2ng/mL. Patients' Expanded Prostate Cancer Index Composite was recorded before and 3 years after treatment.The median followup was 68 and 68 months for the protocol-IRG and the low-risk groups, respectively. The 5-year biological disease-free survival rates in the low-risk and protocol-IRG groups were 94.8 and 94.6%, respectively. As far as survival rates were concerned, there were no significant differences between the two groups. Overall satisfaction and sexual function at 3 years after PB had significantly improved compared with pretreatment (p=0.01 and p=0.01, respectively).In intermediate-risk prostate patients, excluding those with a biopsy Gleason score of 4+3, brachytherapy with short-term ADT can be an effective treatment option for Japanese men.
- Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). [JOURNAL ARTICLE]
- Eur Urol 2014 Oct 6.
Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort.Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group.STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014.Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models.A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population.Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse.Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.