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- Quality indicators for prostate radiotherapy: Are patients disadvantaged by receiving treatment in a 'generalist' centre? [JOURNAL ARTICLE]
- J Med Imaging Radiat Oncol 2014 Oct 27.
The purpose of this retrospective review was to evaluate concordance with evidence-based quality indicator guidelines for prostate cancer patients treated radically in a 'generalist' (as distinct from 'sub-specialist') centre. We were concerned that the quality of treatment may be lower in a generalist centre. If so, the findings could have relevance for many radiotherapy departments that treat prostate cancer.Two hundred fifteen consecutive patients received external beam radiotherapy (EBRT) and/or brachytherapy between 1.10.11 and 30.9.12. Treatment was deemed to be in line with evidence-based guidelines if the dose was: (i) 73.8-81 Gy at 1.8-2.0 Gy/fraction for EBRT alone (eviQ guidelines); (ii) 40-50 Gy (EBRT) for EBRT plus high-dose rate (HDR) brachytherapy boost (National Comprehensive Cancer Network (NCCN) guidelines); and (iii) 145 Gy for low dose rate (LDR) I-125 monotherapy (NCCN). Additionally, EBRT beam energy should be ≥6 MV using three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT), and high-risk patients should receive neo-adjuvant androgen-deprivation therapy (ADT) (eviQ/NCCN). Treatment of pelvic nodes was also assessed.One hundred four high-risk, 84 intermediate-risk and 27 low-risk patients (NCCN criteria) were managed by eight of nine radiation oncologists. Concordance with guideline doses was confirmed in: (i) 125 of 136 patients (92%) treated with EBRT alone; (ii) 32 of 34 patients (94%) treated with EBRT + HDR BRT boost; and (iii) 45 of 45 patients (100%) treated with LDR BRT alone. All EBRT patients were treated with ≥6 MV beams using 3D-CRT (78%) or IMRT (22%). 84%, 21% and 0% of high-risk, intermediate-risk and low-risk patients received ADT, respectively. Overall treatment modality choice (including ADT use and duration where assessable) was concordant with guidelines for 176/207 (85%) of patients.The vast majority of patients were treated concordant with evidence-based guidelines suggesting that, within the limits of the selected criteria, prostate cancer patients are unlikely to be disadvantaged by receiving radiotherapy in this 'generalist' centre.
- Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway. [JOURNAL ARTICLE]
- Oncotarget 2014 October 15; 5(19):9335-9348.
Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.
- Long-term outcome of high-risk prostate cancer treated with brachytherapy combined with external-beam radiation therapy and androgen deprivation therapy. [Journal Article]
- Tumori 2014 Sep-Oct; 100(5):524-8.
Aims and background. To evaluate long-term outcome and biochemical progression-free survival (bPFS) in high-risk prostate cancer patients treated with brachytherapy combined with external-beam radiation therapy (EBRT) and androgen deprivation therapy (ADT). Methods and study design. We retrospectively analyzed 97 high-risk prostate cancer patients treated with brachytherapy combined with EBRT and ADT. During follow-up, the post-operation prostate-specific antigen (PSA) level was monitored regularly and biochemical relapse, progression to castration-resistant prostate cancer or metastases, and causes of death were documented. We evaluated bPFS, cause-specific survival (CSS) and overall survival (OS).
Results.The bPFS, CSS and OS of the patients were 81.4%, 88.7% and 81.4%, respectively. The bPFS of the subcategories of patients stratified based on the presence or absence of a Gleason pattern 5 were 55.6% and 87.7%, respectively.
Conclusion.Brachytherapy combined with EBRT and ADT can effectively control PSA level and delay biochemical relapse in localized high-risk prostate cancer. However, patients presenting with a Gleason pattern 5 should be managed with further treatment intensification.
- Optimized Grafting Density of End-Functionalized Polymers to Polar Dielectric Surfaces for Solution-Processed Organic Field-Effect Transistors. [JOURNAL ARTICLE]
- ACS Appl Mater Interfaces 2014 Oct 24.
Polystyrene (PS) grafted to silicon oxide (SiO2, referred to as gPS-SiO2) bilayers generated via a polymer grafting method were used as organic-oxide hybrid gate dielectrics to fabricate solution-processed triethylsilylethynyl anthradithiophene (TES-ADT) organic field-effect transistors (OFETs). The dielectric surface properties were significantly altered by the areal grafting densities of different molecular weight (Mw) PS chains with end-functionalized dimethylchlorosilane to the SiO2 surfaces. Lesser grafting densities of longer PS chains increased the surface roughness of the treated SiO2 surfaces from 0.2 nm to 1.5 nm, as well as the water contact angles from 94° to 88°. Below a critical Mw of the end-functionalized PS, the gPS chains on the SiO2 surfaces appeared to form a brush-like conformation with an areal density value greater than 0.1 chains∙nm(-2), but other high-Mw gPS chains formed a pan-cake structure, in which the polymeric layers were easily incorporated with solution-processed TES-ADT as a solute. These findings indicate that low-density gPS layers interfered with the self-assembly of TES-ADT in cast films, causing great decreases in crystal grain size and π-conjugated orientation. The compactly covered gPS chains on the SiO2 surface could yield high electrical performance of TES-ADT OFETs with a field-effect mobility of 2.1 cm(2)V(-1)s(-1), threshold voltage of -2.0 V, and on/off current ratio of greater than 10(7) when compared to those developed using less-concentrated gPS-SiO2 surfaces.
- Androgen Metabolic Pathway Involved in Current and Emerging Treatment for Men with Castration Resistant Prostate Cancer: Intraprostatic Androgens as Therapeutic Targets and Endocrinological Biomarkers. [JOURNAL ARTICLE]
- Curr Drug Targets 2014 Oct 24.
Androgen and androgen receptor (AR) play a critical role in the development of prostate cancer. Androgen deprivation therapy (ADT) has become the therapeutic mainstay for patients with metastatic prostate cancer. ADT can reduce the serum testosterone level from the normal range between 500 and 600 ng/dl to the castrate level. Following surgical castration, the serum testosterone level decreases to less than 20 ng/dL (0.69 nmol/L) in about three quarters of the patients. Although insufficient suppressions of the serum testosterone level following ADT have not been well recognized to date, the failure in achieving the castrate level of testosterone may have an adverse impact on survival in men with prostate cancer. Although circulating testosterone levels following castration do not necessarily reflect the amount of intraprostatic testosterone or dihydrotestosterone, testosterone during ADT mainly derives from intratumorally synthesized precursors and adrenal androgens. The advent of new agents represented by abiraterone acetate and enzalutamide, which target adrenal or intraprostatic androgen biosynthesis and AR signaling, respectively, has retrieved interest in testosterone levels during ADT. We critically reviewed androgen metabolism and its significance in prostate cancer biology and treatment to promote their better understanding and management of men with prostate cancer.
- 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.