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Heidenreich A.,RWTH Aachen | Abrahamsson P.-A.,Lund University | Artibani W.,University of Verona | Catto J.,Academic Urology Unit | And 4 more authors.
European Urology | Year: 2013

Background The recommendations and the updated EAU guidelines consider early detection of PCa with the purpose of reducing PCa-related mortality and the development of advanced or metastatic disease. Objective This paper presents the recommendations of the European Association of Urology (EAU) for early detection of prostate cancer (PCa) in men without evidence of PCa-related symptoms. Evidence acquisition The working panel conducted a systematic literature review and meta-analysis of prospective and retrospective clinical studies on baseline prostate-specific antigen (PSA) and early detection of PCa and on PCa screening published between 1990 and 2013 using Cochrane Reviews, Embase, and Medline search strategies. Evidence synthesis The level of evidence and grade of recommendation were analysed according to the principles of evidence-based medicine. The current strategy of the EAU recommends that (1) early detection of PCa reduces PCa-related mortality; (2) early detection of PCa reduces the risk of being diagnosed and developing advanced and metastatic PCa; (3) a baseline serum PSA level should be obtained at 40-45 yr of age; (4) intervals for early detection of PCa should be adapted to the baseline PSA serum concentration; (5) early detection should be offered to men with a life expectancy ≥10 yr; and (6) in the future, multivariable clinical risk-prediction tools need to be integrated into the decision-making process. Conclusions A baseline serum PSA should be offered to all men 40-45 yr of age to initiate a risk-adapted follow-up approach with the purpose of reducing PCa mortality and the incidence of advanced and metastatic PCa. In the future, the development and application of multivariable risk-prediction tools will be necessary to prevent over diagnosis and over treatment. © 2013 European Association of Urology.

Haynes L.,Trudeau Institute | Parker C.,Academic Urology Unit | Iversen P.,Copenhagen University
Journal of the National Cancer Institute | Year: 2012

Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results. © 2012 The Author (s). Published by Oxford University Press.

Brady D.,Queens University of Belfast | Parker C.C.,Academic Urology Unit | O'Sullivan J.M.,Queens University of Belfast
Cancer Journal (United States) | Year: 2013

Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class α-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. β-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the α-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer. Copyright © 2013 Lippincott Williams &Wilkins.

Parker C.C.,Academic Urology Unit | Pascoe S.,Derriford Hospital | Chodacki A.,Hospital Chomutov | O'Sullivan J.M.,Queens University of Belfast | And 4 more authors.
European Urology | Year: 2013

Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. Objective: To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. Design, setting, and participants: In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels. Outcome measurements and statistical analysis: Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. Results and limitations: The study met its primary end point with a statistically significant dose-response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline. Conclusions: Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses. Trial registration: ClinicalTrials.gov: NCT00337155. © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Burger M.,University of Wurzburg | Catto J.W.F.,Academic Urology Unit | Dalbagni G.,Sloan Kettering Cancer Center | Grossman H.B.,University of Houston | And 7 more authors.
European Urology | Year: 2013

Context: Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease. Objective: To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors. Evidence acquisition: A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected. Evidence synthesis: UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence. Conclusions: UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported. © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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