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In heavily pretreated castrate-resistant prostate cancer patients, the use of carboplatin monotherapy is supported by clinicians, despite the lack of recent clinical trial data. This retrospective study of 51 patients showed that a minority of these patients respond, and those responses are rarely durable, although toxicity was mild. Introduction: Many clinicians consider carboplatin monotherapy in advanced castrate-resistant prostate cancer (CRPC) patients who have progressed through all available hormonal and standard chemotherapy treatment options, despite the limited evidence to justify its use. Patients and Methods: This retrospective analysis aimed to evaluate the use of carboplatin monotherapy in patients with refractory prostate cancer in Australia. Efficacy (PSA response, duration, and survival) as well as toxicity was evaluated. Demographic data, PSA response rates, survival data and details of carboplatin treatment protocols, including dose and duration, were collected. Exploratory analyses were conducted on potential prognostic factors. Results: Fifty-one patients received carboplatin: median age 68 (range 55-86 years). Most patients (78.3%) received carboplatin AUC 5 at 3-week intervals. The median number of cycles of carboplatin received was 3 (range 1-17). The median duration of treatment was 63 days (range 1-441). The median overall survival was 6.8 months. Six (11.8%) patients had a PSA response ≥ 50%. The median time to PSA progression on carboplatin, as defined by PCWG, 2 was 67 days (range 15-418). Sixteen patients (31%) required dose delays or reductions and 8 patients (15.6%) ceased carboplatin due to treatment toxicity. Conclusion: Carboplatin is often used in Australia once all available standard treatment options have been exhausted in patients with CRPC. Toxicit y is mild, and a minorit y of patients have responses, but these responses are rarely durable. [ABSTRACT FROM AUTHOR]

Meningeal metastases (MM) are a rare progression in advanced prostate. Here we aimed to characterize the incidence, clinical presentation, and outcomes of patients with MM, including dural and leptomeningeal metastases, from primary prostate cancer. A systematic search was performed on MEDLINE, EMBASE, Scopus, and Web of Science. Studies that included patients who developed MM from primary prostate cancer were abstracted. Assessed outcomes included time from primary cancer to MM and MM to death, and clinical presentation of MM, among others. Case reports were compared qualitatively, while observational studies were pooled for quantitative synthesis. The systematic review was prospectively registered on PROSPERO (CRD42020205378). Our institutional series, 11 observational studies, and 46 case reports were synthesized, comprising a total of 191 patients. From the observational studies, the mean age at developing MM was 63.0 years (range: 58.4, 70.9). Presenting neurological symptoms were variable and largely depended on location of MM. The mean time from prostate cancer to MM was 54.6 months (range: 21.0, 101.5), and the mean time from MM to death was 9.0 months (range: 2.6, 23.0). Patients requiring resection for MM had shorter survival after disease progression compared to patients receiving radiation or supportive therapy. All articles had at least moderate risk of bias. We describe the largest synthesis of patients with progression to MM from prostate cancer. Current evidence is very low-quality and primarily stems from small observational studies. Neurological symptoms in the setting of advanced prostate cancer, especially in high-risk disease, warrants radiographic imaging for MM. Further prospective research on risk factors and treatment for MM is warranted. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small endogenous non-coding molecules that alters gene expression through post-transcriptional regulation of messenger RNA. Compelling evidence suggest the role of miRNA in cancer biology having potential as diagnostic, prognostic and predictive biomarkers. This review summarizes the current knowledge on miRNA deregulated in prostate cancer and their role as oncogene, tumor suppressor and metastasis regulators. The emerging information elucidating the biological function of miRNA is promising and may lead to their potential usefulness as diagnostic/prognostic markers and development as effective therapeutic tools for management of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The collection of preference-based health outcomes data (or utility values) is required to support cost-effectiveness analyses.Objective: This study aimed to collect health-related quality of life (HRQOL) data in men with metastatic castration-resistant prostate cancer (CRPC) stratified by disease states.Methods: Men with metastatic CRPC were recruited via UK patient associations, patient panels, and specialist recruiters and classified into four subgroups reflecting disease state: asymptomatic/mildly symptomatic before chemotherapy, symptomatic before chemotherapy, receiving chemotherapy, and postchemotherapy. HRQOL data (including five-level EuroQol five-dimensional questionnaire [EQ-5D-5L], European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire [EORTC QLQ-C30], and 25-item prostate cancer-specific questionnaire module designed to supplement the EORTC QLQ-C30) along with background and medical history data were collected via an online survey. The EQ-5D-5L and the EORTC-8D (EORTC-8D is an 8 dimensional utility index scored from QLQ-C30 data) were both used to estimate utilities.Results: Data were collected from a total sample of 163 men with metastatic CRPC. Utility values elicited by the EQ-5D-5L ranged from 0.830 for the asymptomatic/mildly symptomatic before chemotherapy disease state (95% confidence interval [CI] 0.795-0.865) to 0.625 for the symptomatic before chemotherapy disease state (95% CI 0.577-0.673). EORTC-8D utilities ranged from 0.856 (95% CI 0.831-0.882) to 0.697 (95% CI 0.664-0.731) for the same disease/treatment states.Conclusions: This online survey was designed to capture real-world HRQOL data describing men with CRPC. The study estimated utilities using two alternative methods, and the results show good agreement, suggesting that they are robust. This methodology offers a potentially higher quality alternative to vignette-based methods that are commonly used in oncology submissions. [ABSTRACT FROM AUTHOR]

Abstract: A prognostic model was derived from the population of the COU-AA-301 phase 3 trial for metastatic castrate-resistant prostate cancer patients treated with abiraterone after docetaxel, and it stratifies patients into three risk groups based on clinical parameters. We validated this model in an independent cohort of patients treated with abiraterone after docetaxel outside a clinical trial (group A; n =94) and explored its utility in patients treated with abiraterone in the prechemotherapy setting (group B; n =64). For group A, median overall survival (mOS) was significantly different across the three prognostic groups (good: n =39, mOS: 21.8 mo; intermediate: n =44, mOS: 10.6 mo; poor: n =7, mOS: 6.8 mo; p <0.001; area under the curve [AUC]: 0.71). Analysis of group B confirmed the ability of the model to prognosticate for survival in the prechemotherapy setting: (good: n =44, mOS: 45.6 mo; intermediate or poor: n =20, mOS: 34.5 mo; p =0.042; AUC: 0.61). These results serve to validate the prognostic model in an independent population treated with abiraterone after docetaxel and support clinical implementation of the score. Calibration of the model was poorer in patients receiving abiraterone prechemotherapy. Prospective evaluation of this model in clinical trials is needed. [Copyright &y& Elsevier]

Abstract: Prostate cancer is the second commonest cause of death from malignancy amongst men in the Western world. Whilst screening for prostate cancer could reduce this mortality rate, it is controversial as most screen-detected cancers are low risk and many more men require treatment than lives saved. Current evidence suggests screening in men with little co-morbidity is beneficial if treatment is stratified to the extent and risk of the detected disease. Treatment should be aimed at disease stage and risk of metastases, and be balanced against the patient's co-morbidities. Observational protocols (such as ‘active surveillance’) should be used for men with low-risk locally confined tumours or significant co-morbidity. Radical treatments (such as radical prostatectomy or radiotherapy) should be used in men with intermediate or high-risk disease that is either confined within the prostate or at risk of local invasion/spread within the pelvis (locally advanced). Less morbid approaches are being developed for locally confined tumours. These include radiotherapy through seed implants (brachytherapy) and targeted focal therapy to obliterate regions of the prostate (delivered using high-intensity focussed ultrasound, cryotherapy or photo-thermal (Tookad) energy). These approaches are less radical and so are likely to have lower cure rates and less side effects than radical treatments. In high-volume, poorly differentiated or locally advanced tumours, it is likely that multimodal treatments are needed to obtain the highest rates of disease cure or control. Current combinations include radical surgery followed by adjuvant radiotherapy or neo-adjuvant androgen deprivation treatment (ADT) before radical radiotherapy. Ongoing trials are evaluating the benefit of adding chemotherapy and other agents to these combinational regimens. Metastatic prostate cancer is initially treated with ADT in the form of surgical or medical castration. The latter may be continuous or intermittent. Almost all men with ADT-treated metastatic prostate cancer will develop castrate-resistant disease, if they live long enough. There are now many options for the treatment of castrate-resistant prostate cancer, including first- and second-line chemotherapy, immunotherapy (sipuleucel-T), further anti-androgens (abiraterone acetate and enzalutamide) and specific bone-targeted treatments. It is likely that there will be more treatment options for advanced prostate cancer over the next few years. [Copyright &y& Elsevier]

Summary: Until the publication of the SWOG 99-16 and TAX 327 trials in 2004, urologists understood that only purely palliative treatment was available for men with prostate cancer that was progressive despite androgen deprivation. However, following the establishment of docetaxel-based chemotherapy as an active treatment option for most men with metastatic disease, researchers have focused their questions on the optimal timing of treatment. Should docetaxel be considered after one or two lines of hormone manipulation? Is it necessary to wait until the patient has bone pain? In latter years, the research focus has widened to embrace second-line and even third-line chemotherapy for this patient group, raising the possibility of advanced prostate cancer being managed as a chronic condition. This article looks at the evolution of docetaxel-based chemotherapy in advanced prostate cancer, and considers the next likely developments. [ABSTRACT FROM AUTHOR]

Abstract: In castrate-resistant prostate cancer, beyond chemotherapy, existing guidelines suggest only supportive care. However, recent evidence suggests that continued targeting of androgen-dependent pathways may be an efficacious approach. Clinical data is now available for two mechanistically distinct agents (abiraterone and MDV3100) that both ultimately target these pathways. Abiraterone is a potent and irreversible inhibitor of CYP17, a critical enzyme in androgen biosynthesis. Phase II studies indicate substantial declines in PSA amongst castrate-resistant patients treated with abiraterone, both prior to and following cytotoxic chemotherapy. In contrast to abiraterone, MDV3100 is a direct inhibitor of the androgen receptor, binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide. A recent phase I/II trial of MDV3100 in castrate-resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level. On the basis of these compelling data, both abiraterone and MDV3100 will be examined in the phase III setting. [Copyright &y& Elsevier]

Abstract: Context: Current and emerging treatment options for advanced prostate, renal, and bladder cancer were discussed at the annual Interactive Genitourinary Cancer Conference (IGUCC) held in February 2009 in connection with the 2nd World Congress on Controversies in Urology (CURy). Objective: To provide practical clinical guidance for physicians and to promote the implementation of recent advances in the management of genitourinary cancers through closer collaboration among urologists, medical oncologists, and radiation oncologists. Evidence acquisition: This article was developed from presentations given at IGUCC 2009. Evidence synthesis: Docetaxel treatment is established as the standard first-line treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC), based on improvements in overall survival regardless of age, performance status, and pain. Treatment should be introduced according to risk-factor assessment, clinical status, and patient values and preferences. Similarly, management of senior adults with mCRPC should be individually adapted to the patient''s health status rather than chronologic age, especially since the benefits and toxicity associated with docetaxel treatment are similar in senior adults and younger patients. Asymptomatic patients with adverse prognostic factors for survival such as visceral metastases, anaemia, and new bone lesions may be candidates for chemotherapy. Prognostic nomograms based on pretreatment parameters aid in identifying patients for earlier chemotherapy. Second-line treatments for CRPC patients are needed, but currently no agent has demonstrated efficacy in phase 3 clinical trials. For patients with a prior response to docetaxel, retreatment at relapse can be effective and well tolerated. There is a strong rationale for targeting angiogenesis in renal cell carcinoma (RCC), and new targeted therapies have changed treatment paradigms for RCC. In contrast, little progress has been made in the treatment of advanced bladder cancer since the introduction of cisplatin-based chemotherapy; new strategies are needed. Conclusions: Docetaxel (every 3 wk) treatment is a therapeutic option in elderly and asymptomatic mCRPC patients. Docetaxel retreatment is effective in initial responders. [Copyright &y& Elsevier]

To discuss the symptom burden experienced among patients with castrate-resistant prostate cancer and bone metastases and the role of the oncology nurse practitioner in evaluation for palliative radiotherapy. These include PubMed, international consensus documents, and clinician experience. Men with advanced prostate cancer may live for several years after diagnosis of bone metastases; however, pain and other difficult symptoms are problematic. Pain is effectively treated with palliative radiotherapy, but careful assessment and intervention of other difficult symptoms must be addressed over time. Nurse practitioners in radiation oncology should be well-versed in the disease trajectory of this patient population. Careful symptom inquiry and comprehensive physical examination is a key responsibility. Palliative radiotherapy, alongside analgesics and supportive care measures, can effectively reduce symptoms and improve quality of life in men with prostate cancer metastatic to bone. [ABSTRACT FROM AUTHOR]

To identify hub genes and pathways involved in castrate-resistant prostate cancer (CRPC). The gene expression profiles of GSE70768 were downloaded from Gene Expression Omnibus (GEO) datasets. A total of 13 CRPC samples and 110 tumor samples were identified. The differentially expressed genes (DEGs) were identified, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis was performed. Protein-protein interaction (PPI) network module analysis was constructed and performed in Cytoscape software. Weighted correlation network analysis (WGCNA) was conducted to determine hub genes involved in the development and progression of CRPC. The gene expression profiles of GSE80609 were used for validation. A total of 1738 DEGs were identified, consisting of 962 significantly down-regulated DEGs and 776 significantly upregulated DEGs for the subsequent analysis. GO term enrichment analysis suggested that DEGs were mainly enriched in the extracellular matrix organization, extracellular exosome, extracellular matrix, and extracellular space. KEGG pathway analysis found DEGs significantly enriched in the focal adhesion pathway. PPI network demonstrated that the top 10 hub genes were ALB, ACACB, KLK3, CDH1, IL10, ALDH1A3, KLK2, ALDH3B2, HBA1, COL1A1. Also, WGCNA identified the top 5 hub genes in the turquoise module, including MBD4, BLZF1, PIP5K2B, ZNF486, LRRC37B2. Plus, the Venn diagram demonstrated that HBA1 was the key gene in both GSE70768 and GSE80609 datasets. These newly identified genes and pathways could help urologists understand the differences in the mechanism between CRPC and PCa. Besides, it might be promising targets for the treatment of CRPC. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Identifying patients with prostate cancer (CaP) who will ultimately develop bone metastasis (BM) or die of disease is essential. Alkaline phosphatase velocity (APV) has been shown to predict overall survival (OS) and bone metastasis-free survival (BMFS) in an earlier study of an equal access military patient cohort of patients with castrate-resistant prostate cancer (CRPC). To confirm these findings, we examined a cohort of patients from a high-volume cancer center to validate a previous observation that faster alkaline phosphatase (AP) kinetics are predictive of OS and BMFS in this second cohort of patients.Materials and Methods: A retrospective cohort study was conducted of patients with CRPC treated at Memorial Sloan Kettering Cancer Center between 1989 and 2010. All patients who received androgen deprivation therapy (ADT) as primary treatment in response to a rising PSA after definitive surgery for CaP were eligible. For those who received primary ADT or surgery followed by ADT, CRPC was defined as one rising PSA value after a PSA nadir ≤4ng/ml, and confirmed by a second rising PSA value, with concurrently documented testosterone levels <50ng/dl. APV was computed as the slope of the linear regression line of all AP values (>2 values per patient) plotted against time. Study outcome included BMFS and OS. Univariable Kaplan-Meier analysis was used to examine time-to-event outcomes. Multivariable Cox proportional hazards regression analysis was used to model time to BMFS and OS.Results: Of 89 patients with CRPC with evaluable data and CRPC, 17 (19%) experienced BM and 26 (29%) died. APV was dichotomized at the uppermost quartile split of all observed APV values:≥5.42U/l/y vs. the lower 3 quartiles combined,<5.42U/l/y. Patients with faster APV had significantly worse outcomes, including faster progression to BM and poorer OS when compared with those with slower APV (P = 0.0451 and P = 0.0109, respectively). There was strong correlation between PSA doubling time (PSADT) (<10,≥10mo) and APV (≥5.42U/l/y vs.<5.42U/l/y) (P = 0.0289), preventing simultaneous evaluation of both factors in multivariable analysis. Kaplan-Meier analysis showed that PSADT was also predictive of BM and OS (log-rank P<0.0001). Separate multivariable Cox proportional hazards regression models were used to examine PSADT and APV, as predictors of each study outcome (BMFS and OS). Both PSADT and APV were strongly predictive of BMFS and OS (respectively).Conclusions: APV and PSADT were predictors of BM and OS in patients with CRPC, respectively. These data are additional evidence of the potential value of AP kinetics in patients with advanced CaP. Prospective studies will be required to clarify these associations. However, given the restrictions on the current patient population in excluding metastatic disease within 12 months of ADT and a PSA nadir >4ng/ml, the findings are not inappropriately generalized to other men. [ABSTRACT FROM AUTHOR]

Summary: Cabazitaxel, a novel taxane that lacks susceptibility to the drug-resistance mechanism seen with previous drugs in the same class, has demonstrated a survival benefit in metastatic castrate-resistant prostate cancer (mCRPC), plus a manageable toxicity profile. It is the first active treatment to receive a European licence for the second-line treatment of mCRPC post-docetaxel. Novel non-chemotherapeutic treatments for this indication are at various stages of development and regulatory status. These new and emerging treatments bring a potential opportunity to extend the lives of patients with mCRPC, and improve quality of life in this setting, but they also raise pertinent questions about the optimal timing and sequencing of their use. Based on my clinical experience with cabazitaxel, first as a phase III trialist, and then as a participant in an expanded-access programme, I believe that the chemotherapeutic option should be offered before non-chemotherapeutic agents, where the patient''s performance status allows, so that there is an opportunity to gain the potential benefits of this treatment within the likely therapeutic window. Other second-line/third-line treatments, notably the hormonal agent abiraterone, are likely to remain useful even after a decline in the patient''s performance status. [Copyright &y& Elsevier]