Long-term use of 5-alpha-reductase inhibitors is safe and effective in men on active surveillance for prostate cancer.

BACKGROUND: Although 5-alpha-reductase inhibitors (5ARIs) have been shown to benefit men with prostate cancer (PCa) on active surveillance (AS), their long-term safety remains controversial. Our objective is to describe the long-term association of 5ARI use with PCa progression in men on AS. MATERIALS/SUBJECTS AND METHODS: The cohort of men with low-risk PCa was derived from a prospectively maintained AS database at the Princess Margaret (1995-2016). Pathologic, grade, and volume progression were the primary end points. Kaplan-Meier time-to-event analysis was performed and Cox proportional hazards regression was used to determine predictors of progression where 5ARI exposure was analyzed as a time-dependent variable. Patients who came off AS prior to any progression events were censored at that time. RESULTS: The cohort included 288 men with median follow-up of 82 months (interquartile range: 37-120 months). Among non-5ARI users (n = 203); 114 men (56.2%) experienced pathologic progression compared with 24 men (28.2%) in the 5ARI group (n = 85), (p < 0.001). Grade and volume progression were higher in the non-5ARI group compared with the 5ARI group (n = 82; 40.4% vs. n = 19; 22.4% respectively, p = 0.003 for grade progression; n = 87; 43.1% and n = 15; 17.7%, respectively for volume progression p < 0.001). Lack of 5ARI use was independently positively associated with pathologic progression (HR: 2.65; CI: 1.65-4.24), grade progression (HR: 2.75; CI: 1.49-5.06), and volume progression (HR: 3.15; CI: 1.78-5.56). The frequency of progression to high-grade (Grade Group 4-5) tumors was not significantly different between the groups. CONCLUSIONS: Use of 5ARIs diminished both grade and volume progression without an increased risk of developing Grade Groups 4-5 disease.

Dataset for the reporting of carcinoma of the bladder-cystectomy, cystoprostatectomy and diverticulectomy specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a not for profit organisation whose goal is to produce standardised internationally agreed and evidence-based datasets for pathology reporting. With input from pathologists worldwide, the datasets are intended to be uniform and structured. They include all items necessary for an objective and accurate pathology report which enables clinicians to apply the best treatment for the patient. This dataset has had input from a multidisciplinary ICCR expert panel. The rationale for some items being required and others recommended is explained, based on the latest literature. The dataset incorporates data from the World Health Organization (WHO) 2016, and also from the latest (8th edition) TNM staging system of the American Joint Committee on Cancer (AJCC). Fifteen required elements and eight recommended items are described. This dataset provides all the details for a precise and valuable pathology report required for patient management and prognostication. This dataset is intended for worldwide use, and should facilitate the collection of standardised comparable data on bladder carcinoma at an international level.

Dataset for the reporting of urinary tract carcinoma-biopsy and transurethral resection specimen: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is an alliance of major pathology organisations in Australasia, Canada, Europe, United Kingdom, and United States of America that develops internationally standardised, evidence-based datasets for the pathology reporting of cancer specimens. This dataset was developed by a multidisciplinary panel of international experts based on previously published ICCR guidelines for the production of cancer datasets. It is composed of Required (core) and Recommended (noncore) elements identified on the basis of literature review and expert consensus. The document also includes an explanatory commentary explaining the rationale behind the categorization of individual data items and provides guidance on how these should be collected and reported. The dataset includes nine required and six recommended elements for the reporting of cancers of the urinary tract in biopsy and transurethral resection (TUR) specimens. The required elements include specimen site, operative procedure, histological tumor type, subtype/variant of urothelial carcinoma, tumor grade, extent of invasion, status of muscularis propria, noninvasive carcinoma, and lymphovascular invasion (LVI). The recommended elements include clinical information, block identification key, extent of T1 disease, associated epithelial lesions, coexistent pathology, and ancillary studies. The dataset provides a structured template for globally harmonized collection of pathology data required for management of patients diagnosed with cancer of the urinary tract in biopsy and TUR specimens. It is expected that this will facilitate international collaboration, reduce duplication of effort in updating current national/institutional datasets, and be particularly useful for countries that have not developed their own datasets.

EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.

Grading of prostate cancer: a work in progress.

Grading of prostate cancer has evolved substantially over time, not least because of major changes in diagnostic approach and concomitant shifts from late- to early-stage detection since the adoption of PSA testing from the late 1980s. After the conception of the architecture-based nine-tier Gleason grading system more than 50 years ago, several changes were made in order to increase its prognostic impact, to reduce interobserver variation and to improve concordance between prostate needle biopsy and radical prostatectomy grading. This eventually resulted in the current five-tier grading system, with a much more detailed description of the individual architectural patterns constituting the remaining three Gleason patterns (i.e. grades 3-5). Nevertheless, there is room for improvement. For instance, distinction of common grade 4 subpatterns such as ill-formed and fused glands from the grade 3 pattern is challenging, blurring the division between low-risk patients who could be eligible for deferred therapy and those who need curative therapy. The last few years have witnessed the publication of several studies on the prognostic impact of individual architectural subpatterns showing that, in particular, the cribriform pattern exceeded the prognostic impact of other grade 4 subpatterns. This review provides an overview of the changes in prostate cancer grading over time and provides a thorough description of the various Gleason subpatterns, the current evidence of their prognostic impact and areas of contention. Potential practical ways for improvements of the current grading system are also put forward.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer.

Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E-cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-ß1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-ß1 they did not exhibit tumorigenicity. The TGF-ß1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-ß1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-ß1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-ß1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the ability to reverse the EMT phenotype of tumor cells and potentially inhibit bladder cancer progression and metastasis.

Young-age prostate cancer.

Although prostate cancer is a disease of the elderly, its diagnosis is not uncommonly made in men younger than 55 years. Both ethnic, familial and genetic factors play a role in the early onset of prostate cancer, but the biology, particularly of low-grade prostate cancers detected at young age is not well understood. Autopsy studies have shown a high prevalence of Gleason score 6 prostate cancers in men under 55 years, but mortality of prostate cancer at this young age is almost negligible. Recently, a number of susceptibility genes such as BRCA2 and HOXB13 were reported, each with their own specific biological and histopathology features. In this review, we provide an update on the most recent findings in young-age prostate cancer.

Diagnostic prostate biopsy performed in a non-academic center increases the risk of re-classification at confirmatory biopsy for men considering active surveillance for prostate cancer.

BACKGROUND: To examine whether diagnostic biopsy (B1), for patients on active surveillance (AS) for prostate cancer, performed at an outside referral centre (external) compared with our in-house tertiary center (internal), increased the risk of re-classification on the second (confirmatory) biopsy (B2). METHODS: Patients on AS were identified from our tertiary center database (1997-2012) with PSA<10, Gleason sum (GS) ⩽6, clinical stage ⩽cT2, ⩽3 positive cores, <50% of single core involved, age ⩽75 years and having a B2. Patients who had <10 cores at B1 and delay in B2 >24 mo were excluded. Depending on center where B1 was performed, men were dichotomized to internal or external groups. All B2 were performed internally. Multivariate logistic regression examined if external B1 was a predictor of re-classification at B2. RESULTS: A total of 375 patients were divided into external (n=71, 18.9%) and internal groups (n=304, 81.1%). At B2, more men in the external group re-classified (26.8%) compared with the internal group (13.8%) (P=0.008). On multivariate analysis, external B1 predicted grade-related re-classification (odds ratio (OR) 4.14, confidence interval (CI) 2.01-8.54, P<0.001) and volume-related re-classification (OR 3.43, CI 1.87-6.25, P<0.001). Other significant predictors for grade-related re-classification were age (OR 2.13 per decade, CI 1.32-3.57, P<0.001), PSA density (OR 2.56 per unit, CI 1.44-4.73, P<0.001), maximum % core involvement (OR 1.04 per percentage point, CI 1.01-1.09, P=0.02) and time between B1 and B2 (OR 1.43 per 6 months, CI 1.21-1.71, P<0.001). CONCLUSION: At our institution, patients on AS who had their initial B1 performed externally were more likely to have adverse pathological features and re-classify on internal B2.

A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer.

BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.

Angiosarcoma of the prostate: a more frequent finding in the future owing to radiotherapy? A literature review with treatment implications based on a case report.

OBJECTIVE: An increase in the incidence of prostate angiosarcoma may be expected owing to the exponential increase in the use of radiotherapy for prostate carcinoma in recent decades and the possible aetiology of radiation exposure on the development of angiosarcoma in general. The objective of this study was to give an overview of cases in the literature based on a case report of prostate angiosarcoma in a hospital in the Netherlands, and to discuss optimal treatment. MATERIAL AND METHODS: All (related) articles In PubMed/Medline and Embase with possible cases of angiosarcoma were screened on title and abstract. A case of prostate angiosarcoma identified in the authors' institution was included. RESULTS: The literature search yielded 13 cases of prostate angiosarcoma. The earliest six publications lack essential data. Four patients had a history of radiotherapy. The present patient developed angiosarcoma following brachytherapy for prostate cancer. Therapy consisted of radical surgery with or without chemotherapy in five cases. In eight cases curative therapy was not reported or not possible. Mean follow-up was only 1 year. Four patients died within 1 year of diagnosis, irrespective of treatment choice. One patient, treated with a combination of radical surgery and adjuvant chemotherapy, was still alive 36 months after therapy. CONCLUSIONS: The findings confirm that prostate angiosarcoma is mostly radiation induced. This patient is the first case of prostate angiosarcoma after primary brachytherapy. Angiosarcoma may occur more often in the future owing to widespread use of brachytherapy and radiotherapy of the prostate. Current guidelines on management of angiosarcoma suggest radical surgery in local disease as the primary treatment of choice.

Guidelines on processing and reporting of prostate biopsies: the 2013 update of the pathology committee of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

The histopathological examination of a prostate biopsy is the basis of prostate cancer diagnostics. Prostate cancer grade and extent of cancer in the diagnostic biopsy are important determinants of patient management. Quality of the prostate biopsy and its processing may influence the outcome of the histopathological evaluation. Further, an unambiguous and concise pathology reporting is essential for an appropriate clinical decision process. Since our initial report in 2003, there have been several practice changes, including the increased uptake of follow-up biopsies of patients who are under active surveillance, increasingly taken under guidance of MRI, or who underwent a prostate-sparing therapy. Therefore, we investigated the literature on the current pathology practices and recommendations with regard to prostate biopsy processing and reporting, both at initial diagnosis and in the context of follow-up biopsies in order to update our guidelines on the optimal processing and reporting of prostate biopsies.

Should follow-up biopsies for men on active surveillance for prostate cancer be restricted to limited templates?

OBJECTIVE: To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. METHODS: At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage ≤cT2, Gleason sum ≤6, ≤3 cores positive for cancer, <50% of single core involved, and age ≤75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. RESULTS: For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum ≥7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). CONCLUSION: When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates.

Biopsy diagnosis of intraductal carcinoma is prognostic in intermediate and high risk prostate cancer patients treated by radiotherapy.

AIM: We investigated the prognostic significance of intraductal carcinoma of the prostate (IDC-P) in biopsies and transurethral resections prior to external beam radiotherapy with or without androgen deprivation. METHODS: Cohort 1 consisted of 118 intermediate risk prostate cancer patients treated by radiotherapy, with biochemical relapse as primary end-point (median follow-up 6.5 years). Cohort 2 consisted of 132 high risk patients, enrolled in a phase III randomised trial (EORTC 22863) comparing radiotherapy alone to radiotherapy with long-term androgen deprivation (LTAD) with clinical progression free survival as primary end-point (median follow-up 9.1 years). Presence of IDC-P was identified after central review. Multivariable regression modelling and Kaplan-Meier analysis were performed with IDC-P as dichotomous variable. RESULTS: IDC-P was a strong prognosticator for early (<36 months) biochemical relapse (HR 7.3; p = 0.007) in cohort 1 and for clinical disease-free survival in both arms of cohort 2 (radiotherapy arm: HR 3.5; p < 0.0001; radiotherapy plus LTAD arm: HR 2.8, p = 0.018). IDC-P retained significance after stratification for reviewed Gleason score in the radiotherapy arm (HR 2.3; p = 0.03). IDC-P was a strong prognosticator for metastatic failure rate (radiotherapy arm: HR 5.3; p < 0.0001; radiotherapy plus LTAD arm: HR 3.6; p = 0.05). CONCLUSIONS: IDC-P in diagnostic samples of patients with intermediate or high risk prostate cancer is an independent prognosticator of early biochemical relapse and metastatic failure rate after radiotherapy. We suggest that the presence of IDC-P in prostate biopsies should routinely be reported.

SU-E-J-95: Towards Optimum Boundary Conditions for Biomechanical Model Based Deformable Registration Using Intensity Based Image Matching for Prostate Correlative Pathology.

PURPOSE: Deformable registration of histology to MRI is an essential tool to validate in vivo prostate cancer imaging. However, direct registration of histology to in vivo MR is prone to error due to geometric differences between the tissue sections and the in vivo imaging planes. To increase the accuracy of registration, an ex vivo high resolution MRI is acquired to compensate for the direct registration difficulties. A novel intensity-based deformable registration algorithm based on local variation in image intensities is proposed to register the histology to ex vivo MRI of prostatectomy specimens. METHODS: Four sets of ex vivo MR and whole mount pathology images from four patients were used to investigate and validate the technique. In addition, 9 synthetically deformed ex vivo MR images were used. The standard deviation in local windows within the images was calculated to generate intermediate images based on both MR and histology. The intermediate images were registered using the Drop package (Munich, Germany). To further increase the accuracy, a final refinement of the registration was performed using Drop with a finer B-spline rid. The registration parameters were tuned to achieve a visually acceptable registration. Magnitude of Differences (MOD) and Angular Error (AE) were used to validate the synthetic data, and the Target Registration Error (TRE) of manually indicated landmarks was used for the clinical data. RESULTS: MOD of 0.6mm and AE of 8.3 degrees showed the efficacy of using intermediate images, compared to 0.8mm and 10.0 degrees achieved with Drop without the intermediate images. The average mean±std TRE among the four patients was 1.0±0.6 mm using the proposed method compared to 1.6±1.1 mm using Elastix (Utrecht, The Netherlands). CONCLUSIONS: An intensity-based deformable registration algorithm which uses intermediate images was evaluated on prostatectomy specimens and synthetically deformed clinical data, indicating improvement in overall accuracy and robustness. OICR, Terry Fox Ultrasound for Cancer Therapy. Dr. Brock is a Cancer Care Ontario Research Chair in Cancer Imaging and has financial interest in deformable registration technology through the licensing of Morfeus to RaySearch Laboratories.

[EAU guidelines on prostate cancer. Part I: screening, diagnosis, and treatment of clinically localised disease]. / Guía de la EAU sobre el cáncer de próstata. Parte I: cribado, diagnóstico y tratamiento del cáncer clínicamente localizado.

OBJECTIVE: Our aim was to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the screening, diagnosis, and treatment of clinically localised cancer of the prostate (PCa). METHODS: The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and level of evidence and grade of recommendation were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. RESULTS: A full version is available at the EAU office or Web site (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. PSA doubling time in < 3 yr or a biopsy progression indicates the need for active intervention. In men with locally advanced PCa in whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT) with equivalent oncologic efficacy. Active treatment is mostly recommended for patients with localised disease and a long life expectancy with radical prostatectomy (RP) shown to be superior to WW in a prospective randomised trial. Nerve-sparing RP represents the approach of choice in organ-confined disease; neoadjuvant androgen deprivation demonstrates no improvement of outcome variables. Radiation therapy should be performed with at least 74Gy and 78Gy in low-risk and intermediate/high-risk PCa, respectively. For locally advanced disease, adjuvant ADT for 3 yr results in superior disease-specific and overall survival rates and represents the treatment of choice. Follow-up after local therapy is largely based on PSA, and a disease-specific history with imaging is indicated only when symptoms occur. CONCLUSIONS: The knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice.

[EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer]. / Guía de la EAU sobre el cáncer de próstata. Parte II: tratamiento del cáncer de próstata avanzado, recidivante y resistente a la castración.

OBJECTIVES: Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). METHODS: The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. RESULTS: Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. CONCLUSION: The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.