Bertrand TOMBAL

The Prostate Cancer Programme of the European School of Oncology developed the concept of specialised interdisciplinary and multiprofessional prostate cancer care to be formalized in Prostate Cancer Units (PCU). After the publication in 2011 of the collaborative article "The Requirements of a Specialist Prostate Cancer Unit: A Discussion Paper from the European School of Oncology", in 2012 the PCU Initiative in Europe was launched. A multiprofessional Task Force of internationally recognized opinion leaders, among whom representatives of scientific societies, and patient advocates gathered to set standards for quality comprehensive prostate cancer care and designate care pathways in PCUs. The result was a consensus on 40 mandatory and recommended standards and items, covering several macro-areas, from general requirements to personnel to organization and case management. This position paper describes the relevant, feasible and applicable core criteria for defining PCUs in most European countries delivered by PCU Initiative in Europe Task Force.

Circulating prostate cells can be detected in cancer patients by using reverse transcriptase-PCR (RT-PCR) assay for prostate-specific antigen (PSA) and prostate- specific membrane antigen (PSM) mRNA. A quality- control study involving a conventional RT-PCR assay was performed and, surprisingly, detected both tran- scripts in many negative control cell lines and in normal blood samples. The existence of an illegitimate tran-

Intermittent endocrine treatment or cyclic therapy of prostate cancer aims at prolonging survival by delaying progression to androgen independence and at improving quality of life by avoiding the side effects of continuous androgen ablation. In this paper we first review the available experimental data suggesting the clinical application of this therapeutic strategy and interpret them with caution. We then examine the published reports of phase II clinical studies showing the feasibility of this approach. Intermittent endocrine treatment is capable of inducing multiple apoptotic regressions; improvement in the sense of well-being and quality of life - including sexual function - is regularly reported. A period of 6-9 months on therapy is usually recommended; the mean off-therapy interval approaches 50% of the duration of the treatment cycle. The mean time to disease progression was 32 months. The definitive answer to the important question of prolonged survival awaits the completion of ongoing randomized studies.

Despite several publications, the ability of the free/total (F/T) prostate-specific antigen (PSA) ratio to predict the pathologic extension of prostate cancer is still a matter of controversy. In addition, its ability to predict biochemical recurrence after radical prostatectomy has not yet been reported. Since January 6, 1996, the F/T PSA ratio was prospectively measured preoperatively in 343 patients undergoing radical prostatectomy as the first treatment for localized prostate cancer. The ability to predict organ-confined disease was measured by receiver operating characteristic analysis. The areas under the curve were 0.66 for PSA density, 0.61 for total PSA, 0.60 for Gleason score, and 0.587 for the F/T PSA ratio. In multiple logistic regression analyses, the F/T PSA ratio was not a relevant predictor of organ-confined disease (Wald statistic 0.345 for P = 0.55). Similar results were obtained in the subgroup of patients with a PSA level between 2.5 and 10 ng/mL. The biochemical survival for the 270 patients who did not receive adjuvant therapy was 86% at 61 months. Statistically significant univariate predictors (P <0.05) of PSA recurrence were pT stage (log-rank 18.2) and Gleason grade (log-rank 8.8). The F/T PSA ratio was not a significant predictor of recurrence in the univariate analysis (log-rank 3.6 for P = 0.314) and in multivariate analysis (Wald statistic 0.2 for P = 0.97). These results suggest that the F/T PSA ratio is not helpful for the prediction of organ-confined disease and PSA recurrence after radical prostatectomy.

Serum prostate-specific antigen (PSA) exists in different molecular forms, and their respective concentration has been proposed as a useful tool to improve discrimination between benign prostatic hypertrophy (BPH) and prostate cancer (PC). The relevance of the free to total PSA ratio was prospectively studied in a selected urology clinic population of 420 patients. Total serum PSA ranged from 2.1 to 30 ng/ml; 154 had PC and 266 had BPH. Receiver operating characteristic (ROC) curves were constructed for the total population (total-PSA range from 2.1 to 30 ng/ml) and for the diagnostic gray zone of 2.1-10 ng/ml. For the two groups, the free to total PSA ratio had a higher specificity than total-PSA for all sensitivity levels. Cut-off values were found to, vary with prostate weight. Although free to total PSA ratio demonstrated better performances than total-PSA, its use in screening appears problematic, due to the low prevalence of prostate cancer.

To predict poor outcome in patients with a biochemical recurrence (rising PSA) after radical prostatectomy (RP), urologists rely primarily on Gleason score, PSA doubling time, and time from surgery to biochemical (i.e., PSA) recurrence. In the present study, we assess the value of RT-PCR detection circulating prostate cells in blood of patients with a rising PSA. RNA from blood samples was obtained from 55 patients with a rising PSA and from 45 patients without evidence of biochemical failure (PSA < 0.1 ng/ml). Both groups were matched for age, Gleason score, pT stage, and interval between radical prostatectomy and PCR testing. PSA positive cells were detected in 1/45 (2%) patients without a PSA recurrence and 19/55 (34%) patients with a PSA recurrence. In the rising PSA group, mean PSA doubling time was significantly shorter in patients with positive RT-PCR (5 months) than in patients with negative RT-PCR (16 months; P = 0.001). An earlier onset of recurrence was also detected in patients with a positive RT-PCR (31 months for positive RT-PCR vs. 50 months for negative RT-PCR) but this result did not achieve statistical significance (P = 0.102). Salvage radiation therapy was administered in 15 patients. Three of the five patients with a positive RT-PCR progressed during radiotherapy whereas 7 of the 10 patients with a negative RT-PCR obtained a complete response and none have progressed. These preliminary results suggest that RT-PCR detection of prostate cells in blood of patients after RP correlates with rapidly progressing biochemical failure after RP.

There are no universally monitored outcomes relevant to men with advanced prostate cancer, making it challenging to compare health outcomes between populations. We sought to develop a standard set of outcomes relevant to men with advanced prostate cancer to follow during routine clinical care. The International Consortium for Health Outcomes Measurement assembled a multidisciplinary working group to develop the set. We used a modified Delphi method to achieve consensus regarding the outcomes, measures, and case mix factors included. The 25 members of the multidisciplinary international working group represented academic and nonacademic centers, registries, and patients. Recognizing the heterogeneity of men with advanced prostate cancer, the group defined the scope as men with all stages of incurable prostate cancer (metastatic and biochemical recurrence ineligible for further curative therapy). We defined outcomes important to all men, such as overall survival, and measures specific...

Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandr...

Phase 3 trials have made major contributions to advances in prostate cancer (PCa). However, funding limitations and excess bureaucracy are now making it difficult to conduct trials. To describe the collaborative groups in Europe and their academic phase 3 PCa trials. Leaders of collaborative groups from Scandinavia, the European Organisation for Research and Treatment of Cancer (EORTC), France, Spain, the United Kingdom, Germany, Switzerland, The Netherlands, and Ireland were asked to provide information. Approximately 40 academic European phase 3 trials focussing on PCa have been completed, and about 10 are accruing patients. Cross-border trials have been successfully conducted led by EORTC (11), Scandinavian Prostate Cancer Group (9), European Association of Urology (1), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficiency (STAMPEDE) (1), and the French Genito-Urinary Tumor Group (1). Among these studies were practise-changing trials showing the superiority of prostatectomy over watchful waiting in patients <65 yr of age, the benefits of combining androgen-deprivation therapy (ADT) with radiation therapy (RXT) in high-risk localised disease, the superiority of long-term versus short-term ADT, the benefit of RXT in men treated with ADT, and the role of adjuvant RXT. To bridge the numbers gap for phase 3 studies, the Prostate Cancer Consortium in Europe (PEACE) is a recently established initiative that aims to favour cross-border networks of investigators. PEACE 1 is testing the addition of abiraterone and that of RXT directed at the primary cancer in patients with de novo metastatic PCa treated with ADT. PEACE 2 is testing the addition of cabazitaxel and that of pelvic irradiation in patients with at least two criteria for high-risk localised PCa. European academic phase 3 trials have contributed to establishing the current standard treatment of PCa. The PEACE consortium was recently tasked with the goal of addressing unanswered questions and specific biology-related issues more efficiently. The Prostate Cancer Consortium in Europe was established to conduct comparative trials aiming at assessing new treatments for prostate cancer patients.

Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Amgen Inc.