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2.  Response to: Letter to the Editor, EURUROL-D-14-00573 
European urology  2014;66(5):e92.
doi:10.1016/j.eururo.2014.07.002
PMCID: PMC4294998  PMID: 25037640
3.  Diabetic Severity and Risk of Kidney Stone Disease 
European urology  2013;65(1):10.1016/j.eururo.2013.03.026.
Background
The prevalence of kidney stone disease is rising along with increasing rates of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome.
Objective
To investigate the associations among the presence and severity of T2DM, glycemic control and insulin resistance with kidney stone disease.
Design, Setting, and Participants
We performed a cross-sectional analysis of all adult participants in the 2007–2010 National Health and Nutrition Examination Survey (NHANES). A history of kidney stone disease was obtained by self-report. T2DM was defined by: self-reported history, T2DM-related medication usage, and reported diabetic comorbidity. Insulin resistance was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) definition. We classified glycemic control using HbA1c and fasting plasma glucose levels (FPG).
Outcome measurements and statistical analysis
Odds ratios (OR) for kidney stone disease were calculated for each individual measure of T2DM severity. Logistic regression models were fitted adjusting for age, sex, race/ethnicity, smoking history, and Quételet’s (body mass) index (BMI) (model A) as well as laboratory values and components of metabolic syndrome (model B).
Results and Limitations
Correlates of kidney stone disease included a self-reported history of T2DM (OR 2.44, 95% confidence interval [CI] 1.84–3.25) and history of insulin use (OR 3.31, CI 2.02-5.45). Persons with FPG 100–126 and >126 mg/dL had increased odds of kidney stone disease, OR 1.28 (CI 0.95–1.72) and OR 2.29 (CI 1.68-3.12), respectively. Corresponding results for persons with HgbA1c 5.7-6.4% and ≥6.5% were ORs 1.68 (CI 1.17–2.42) and OR 2.82 (CI 1.98–4.02), respectively. When adjusting for patient factors, a history of T2DM, the use of insulin, FPI and HgbA1c remained significantly associated with kidney stone disease. The cross-sectional design limits causal inference.
Conclusions
Among persons with T2DM, more severe disease is associated with a heightened risk of kidney stones.
doi:10.1016/j.eururo.2013.03.026
PMCID: PMC3866968  PMID: 23523538
diabetes mellitus; glycemic control; insulin resistance; kidney stone disease
4.  Long-term Continence Outcomes in Men Undergoing Radical Prostatectomy for Clinically Localized Prostate Cancer 
European urology  2013;65(1):52-57.
Background
Urinary incontinence is a common short-term complication of radical prostatectomy (RP). Little is known about the long-term impact of RP on continence.
Objective
To elucidate the long-term progression of continence after RP.
Design, setting, and participants
From October 2000 through September 2012, 1788 men undergoing open RP for clinically localized prostate cancer by a single surgeon at an urban tertiary care center prospectively signed consent to be followed before RP and at 3, 6, 12, 24, 96, and 120 mo after RP. A consecutive sampling method was used and all men were included in this study.
Intervention Men underwent open RP
Outcome measurements and statistical analysis
Regression models controlled for preoperative University of California, Los Angeles–Prostate Cancer Index urinary function score (UCLA-PCI-UFS), age, prostate-specific antigen level, Gleason score, stage, nerve-sparing status, race, and marital status were used to evaluate the association of time since RP with two dependent variables: UCLA-PCI-UFS and continence status.
Results and limitation
The mean UCLA-PCI-UFS declined between 2 yr and 8 yr (83.8 vs 81.8; p = 0.007) and marginally between 8 yr and 10 yr (81.8 vs 79.6; p = 0.036) after RP, whereas continence rate did not significantly change during these intervals. Men ≥60 yr old experienced a decline in mean UCLA-PCI-UFS between 2 yr and 8 yr (p = 0.002) and a marginal decline in continence rate between 2 yr and 10 yr (p = 0.047), whereas these variables did not change significantly in men <60 yr old. These outcomes are for an experienced surgeon, so caution should be exercised in generalizing these results.
Conclusions
Between 2 yr and 10 yr after RP, there were slight decreases in mean UCLA-PCIUFS and continence rates in this study. Men aged <60 yr had better long-term outcomes. These results provide realistic long-term continence expectations for men undergoing RP.
doi:10.1016/j.eururo.2013.08.006
PMCID: PMC4062360  PMID: 23957946
Incontinence; Outcomes; Prostate cancer; Prostatectomy; Quality of life
5.  Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam 
European urology  2013;64(5):693-699.
Background
Treatment decisions can be difficult in men with low-risk prostate cancer (PCa).
Objective
To evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries.
Design, setting, and participants
The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004.
Outcome measurements and statistical analysis
We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5 cm3, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood.
Results and limitations
A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model.
Conclusions
Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.
doi:10.1016/j.eururo.2013.04.040
PMCID: PMC3786059  PMID: 23683475
Prostate-specific antigen/blood; Prostatic neoplasms; Mass screening; Radical prostatectomy; Kallikrein-related peptidases
6.  A Systematic Review of the Volume–Outcome Relationship for Radical Prostatectomy 
European urology  2013;64(5):786-798.
Context
Due to the complexity and challenging nature of radical prostatectomy (RP), it seems reasonable to suppose that both short- and long-term outcomes strongly depend on the cumulative number of cases performed by the surgeon as well as within the hospital.
Objective
To review systematically the association between hospital and surgeon volume and perioperative, oncologic, and functional outcomes after RP.
Evidence acquisition
A systematic review of the literature was performed, searching PubMed, Embase, and Scopus databases for original and review articles between January 1, 1995, and December 31, 2011. Inclusion and exclusion criteria comprised RP, hospital and/or surgeon volume reported as a predictor variable, a measurable end point, and a description of multiple hospitals or surgeons.
Evidence synthesis
Overall 45 publications fulfilled the inclusion criteria, where most data originated from retrospective institutional or population-based cohorts. Studies generally focused on hospital or surgeon volume separately. Although most of these analyses corroborated the impact of increasing volume with better outcomes, some others failed to find any significant effect. Studies also differed with respect to the proposed volume cut-off for improved outcomes, as well as the statistical means of evaluating the volume–outcome relationship. Five studies simultaneously compared hospital and surgeon volume, where results appear to suggest that the importance of either hospital or surgeon volume largely depends on the end point of interest.
Conclusions
Undeniable evidence suggests that increasing volume improves outcomes. Although it would seem reasonable to refer RP patients to high-volume centers, such regionalization may not be entirely practical. As such, the implications of such a shift in practice have yet to be fully determined and warrant further exploration.
doi:10.1016/j.eururo.2013.04.012
PMCID: PMC4109273  PMID: 23664423
Prostatic neoplasms; Prostatectomy; Selective referral; Hospital volume; Surgeon volume; Regionalization
7.  Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study 
Bancroft, Elizabeth K. | Page, Elizabeth C. | Castro, Elena | Lilja, Hans | Vickers, Andrew | Sjoberg, Daniel | Assel, Melissa | Foster, Christopher S. | Mitchell, Gillian | Drew, Kate | Maehle, Lovise | Axcrona, Karol | Evans, D. Gareth | Bulman, Barbara | Eccles, Diana | McBride, Donna | van Asperen, Christi | Vasen, Hans | Kiemeney, Lambertus A. | Ringelberg, Janneke | Cybulski, Cezary | Wokolorczyk, Dominika | Selkirk, Christina | Hulick, Peter J. | Bojesen, Anders | Skytte, Anne-Bine | Lam, Jimmy | Taylor, Louise | Oldenburg, Rogier | Cremers, Ruben | Verhaegh, Gerald | van Zelst-Stams, Wendy A. | Oosterwijk, Jan C. | Blanco, Ignacio | Salinas, Monica | Cook, Jackie | Rosario, Derek J. | Buys, Saundra | Conner, Tom | Ausems, Margreet GEM | Ong, Kai-ren | Hoffman, Jonathan | Domchek, Susan | Powers, Jacquelyn | Teixeira, Manuel R. | Maia, Sofia | Foulkes, William D. | Taherian, Nassim | Ruijs, Marielle | Helderman-van den Enden, Apollonia T. J. M. | Izatt, Louise | Davidson, Rosemarie | Adank, Muriel A. | Walker, Lisa | Schmutzler, Rita | Tucker, Kathy | Kirk, Judy | Hodgson, Shirley | Harris, Marion | Douglas, Fiona | Lindeman, Geoffrey J. | Zgajnar, Janez | Tischkowitz, Marc | Clowes, Virginia E. | Susman, Rachel | Cajal, Teresa Ramon y | Patcher, Nicholas | Gadea, Neus | Spigelman, Allan | van Os, Theo | Liljegren, Annelie | Side, Lucy | Brewer, Carole | Brady, Angela F. | Donaldson, Alan | Stefansdottir, Vigdis | Friedman, Eitan | Chen-Shtoyerman, Rakefet | Amor, David J. | Copakova, Lucia | Barwell, Julian | Giri, Veda N. | Murthy, Vedang | Nicolai, Nicola | Teo, Soo-Hwang | Greenhalgh, Lynn | Strom, Sara | Henderson, Alex | McGrath, John | Gallagher, David | Aaronson, Neil | Ardern-Jones, Audrey | Bangma, Chris | Dearnaley, David | Costello, Philandra | Eyfjord, Jorunn | Rothwell, Jeanette | Falconer, Alison | Gronberg, Henrik | Hamdy, Freddie C. | Johannsson, Oskar | Khoo, Vincent | Kote-Jarai, Zsofia | Lubinski, Jan | Axcrona, Ulrika | Melia, Jane | McKinley, Joanne | Mitra, Anita V. | Moynihan, Clare | Rennert, Gad | Suri, Mohnish | Wilson, Penny | Killick, Emma | Moss, Sue | Eeles, Rosalind A.
European urology  2014;66(3):489-499.
Background
Men with germline BRCA1/2 mutations have a higher risk of developing prostate cancer than non-carriers. IMPACT is an international consortium of 62 centres in 20 countries evaluating the use of targeted PrCa screening in men with BRCA1/2 mutations.
Objective
To report the first year’s screening results for all men at enrolment in the study.
Outcome Measurements and Statistical Analysis
PSA levels, PrCa incidence, and tumour characteristics were evaluated. Fisher’s exact test was used to compare the number of PrCa cases between groups and differences between disease types.
Design, setting and participants
We recruited men aged 40–69 years with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their family. All men underwent PSA testing at enrolment and those with a PSA >3ng/ml offered prostate biopsy.
Results and limitations
We recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). 199 (8%) presented with a PSA >3ng/ml, 162 biopsies were performed and 59 PrCas diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of tumours were classified as intermediate or high-risk disease. The positive-predictive-value for biopsy using a PSA threshold of 3.0ng/ml in BRCA2 mutation carriers was 48%, double that reported in population screening studies. A significant difference in detecting intermediate or high-risk disease was observed in BRCA2 carriers. 95% of men were Caucasian thus the results cannot be generalised to all ethnic groups.
Conclusions
The IMPACT screening network will be useful for targeted PrCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this yields a high proportion of aggressive disease.
Patient Summary
In this report we demonstrate that germline genetic markers can be used to identify men at higher risk of PrCa. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
doi:10.1016/j.eururo.2014.01.003
PMCID: PMC4105321  PMID: 24484606
BRCA1; BRCA2; Prostate cancer; Prostate-Specific-Antigen; Targeted screening
8.  Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma 
European urology  2014;66(3):502-509.
Background
Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.
Objective
The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.
Design, Settings, and Participants
We conducted a pooled analysis of patients with mRCC treated from 2003-2011 on phase II and III trials.
Outcome Measurements and Statistical Analysis
Statistical analyses were performed using Cox regression and the Kaplan-Meier method.
Results and Limitations
We identified 2,749 patients treated with sunitinib (n=1,059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus + interferon-alpha (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. 285 patients (10.4%) received BT. The presence of BMs was associated with shorter overall survival (OS) (13.2 versus 20.2 months, p<0.0001) and progression-free survival (PFS) (5.1 versus 6.7 months, p<0.0008) when compared to those without BMs. When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. Overall, the use of BT in patients with BMs was not associated with improved OS (13.3 versus 13.1 months, p=0.3801) or PFS (5.1 versus 4.9 months, p=0.1785) compared to patients who did not receive BT. Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events compared to non-users (8.6% versus 5.8%, p=0.191). Additionally, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data was analyzed retrospectively.
Conclusions
We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not impact survival or SRE prevention and was associated with increased toxicity.
Patient Summary
In this analysis, we demonstrate that BMs are associated with shorter survival in patient with mRCC. Additionally, we call into question the utility of BT in this population.
doi:10.1016/j.eururo.2014.02.040
PMCID: PMC4145043  PMID: 24613250
Bisphosphonates; Bone metastases; mTOR inhibitors; Renal cell carcinoma; VEGF targeted therapy
9.  Patient-reported Outcomes in Randomised Controlled Trials of Prostate Cancer: Methodological Quality and Impact on Clinical Decision Making 
European urology  2013;66(3):416-427.
Context
Patient-reported outcomes (PRO) data from randomised controlled trials (RCTs) are increasingly used to inform patient-centred care as well as clinical and health policy decisions.
Objective
The main objective of this study was to investigate the methodological quality of PRO assessment in RCTs of prostate cancer (PCa) and to estimate the likely impact of these studies on clinical decision making.
Evidence acquisition
A systematic literature search of studies was undertaken on main electronic databases to retrieve articles published between January 2004 and March 2012. RCTs were evaluated on a predetermined extraction form, including (1) basic trial demographics and clinical and PRO characteristics; (2) level of PRO reporting based on the recently published recommendations by the International Society for Quality of Life Research; and (3) bias, assessed using the Cochrane Risk of Bias tool. Studies were systematically analysed to evaluate their relevance for supporting clinical decision making.
Evidence synthesis
Sixty-five RCTs enrolling a total of 22 071 patients were evaluated, with 31 (48%) in patients with nonmetastatic disease. When a PRO difference between treatments was found, it related in most cases to symptoms only (n = 29, 58%). Although the extent of missing data was generally documented (72% of RCTs), few reported details on statistical handling of this data (18%) and reasons for dropout (35%). Improvements in key methodological aspects over time were found. Thirteen (20%) RCTs were judged as likely to be robust in informing clinical decision making. Higher-quality PRO studies were generally associated with those RCTs that had higher internal validity.
Conclusions
Including PRO in RCTs of PCa patients is critical for better evaluating the treatment effectiveness of new therapeutic approaches. Marked improvements in PRO quality reporting over time were found, and it is estimated that at least one-fifth of PRO RCTs have provided sufficient details to allow health policy makers and physicians to make critical appraisals of results.
Patient summary
In this report, we have investigated the methodological quality of PCa trials that have included a PRO assessment. We conclude that including PRO is critical to better evaluating the treatment effectiveness of new therapeutic approaches from the patient's perspective. Also, at least one-fifth of PRO RCTs in PCa have provided sufficient details to allow health policy makers and physicians to make a critical appraisal of results.
doi:10.1016/j.eururo.2013.10.017
PMCID: PMC4150854  PMID: 24210091
Prostate cancer; Patient-reported outcomes; Clinical trials; Quality of life; Clinical decision making
10.  Potentiation of Inflammatory CXCL8 Signalling Sustains Cell Survival in PTEN-deficient Prostate Carcinoma 
European urology  2012;64(2):177-188.
Background:
Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised.
Objective:
To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa.
Design, setting, and participants:
Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten+/−) mice harbouring inactivation of one PTEN allele.
Interventions:
Small interfering RNA (siRNA)–or small hairpin RNA (shRNA)–directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions.
Outcome measurements and statistical analysis:
Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays.
Results and limitations:
Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten+/− murine prostate tissue relative to normal epithelium in wild-type PTEN (PtenWT) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study.
Conclusions:
PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium.
doi:10.1016/j.eururo.2012.08.032
PMCID: PMC4185293  PMID: 22939387
Inflammation; Apoptosis; CXCL8; CXCR2; Hypoxia; Prostate cancer; PTEN
11.  The Burden of Urinary Incontinence and Urinary Bother Among Elderly Prostate Cancer Survivors 
European urology  2013;64(4):672-679.
Background
Data describing urinary health in elderly, community-dwelling prostate cancer (PCa) survivors are limited.
Objective
To elucidate the prevalence of lower urinary tract symptoms, urinary bother, and incontinence in elderly PCa survivors compared with peers without PCa.
Design, setting, and participants
A cross-sectional analysis of 5990 participants in the Osteoporotic Fractures in Men Research Group, a cohort study of community-dwelling men ≥65 yr.
Outcome measurements and statistical analysis
We characterized urinary health using self-reported urinary incontinence and the American Urological Association Symptom Index (AUA-SI). We compared urinary health measures according to type of PCa treatment in men with PCa and men without PCa using multivariate log-binomial regression to generate prevalence ratios (PRs).
Results and limitations
At baseline, 706 men (12%) reported a history of PCa, with a median time since diagnosis of 6.3 yr. Of these men, 426 (60%) reported urinary incontinence. In adjusted analyses, observation (PR: 1.92; 95% confidence interval [CI], 1.15–3.21; p = 0.01), surgery (PR: 4.68; 95% CI, 4.11–5.32; p < 0.0001), radiation therapy (PR: 1.64; 95% CI, 1.20– 2.23; p = 0.002), and androgen-deprivation therapy (ADT) (PR: 2.01; 95% CI, 1.35–2.99; p = 0.0006) were each associated with daily incontinence. Daily incontinence risk increased with time since diagnosis independently of age. Observation (PR: 1.33; 95% CI, 1.00–1.78; p = 0.05), surgery (PR: 1.25; 95% CI, 1.10–1.42; p = 0.0008), and ADT (PR: 1.50; 95% CI, 1.26–1.79; p < 0.0001) were associated with increased AUA-SI bother scores. Cancer stage and use of adjuvant or salvage therapies were not available for analysis.
Conclusions
Compared with their peers without PCa, elderly PCa survivors had a two-fold to five-fold greater prevalence of urinary incontinence, which rose with increasing survivorship duration. Observation, surgery, and ADT were each associated with increased urinary bother. These data suggest a substantially greater burden of urinary health problems among elderly PCa survivors than previously recognized.
doi:10.1016/j.eururo.2013.03.041
PMCID: PMC3938018  PMID: 23587870
Aging male; Elderly; Epidemiology; Incontinence; Lower urinary tract symptoms; Prostate cancer; Prostate cancer treatment; Urinary bother
12.  The Role of Focal Therapy in the Management of Localised Prostate Cancer: A Systematic Review 
European Urology  2014;66(4):732-751.
Context
The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy.
Objective
To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy.
Evidence acquisition
Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included.
Evidence synthesis
A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2–100%, 29–40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting.
Conclusions
Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.
Take Home Message
The functional outcomes of focal therapy are encouraging, but there is a lack of high-quality evidence of long-term disease-control outcomes. Although this strategy could decrease the treatment-related side effects of men requiring active treatment, further robust comparative effectiveness research is required.
doi:10.1016/j.eururo.2013.05.048
PMCID: PMC4179888  PMID: 23769825
Brachytherapy; Cryotherapy; High-intensity focused ultrasound; Laser therapy; Photodynamic therapy; Prostate cancer
13.  The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center 
European urology  2010;58(4):574-580.
Background
The prognostic impact of primary tumor location on outcomes for patients with upper-tract urothelial carcinoma (UTUC) is still contentious.
Objective
To test the association between tumor location and disease recurrence and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for UTUC.
Design, setting, and participants
Prospectively collected data were retrospectively reviewed from 324 consecutive patients treated with RNU between 1995 and 2008 at a single tertiary referral center. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UTUC, or metastatic disease at presentation were excluded. This left 253 patients for analysis. Tumor location was categorized as renal pelvis or ureter based on the location of the dominant tumor. Recurrences in the bladder only, in nonbladder sites, and in any site were analyzed.
Intervention
All patients were treated with RNU.
Measurements
Recurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and Cox regression analyses.
Results and limitations
Median follow-up for survivors was 48 mo. The 5-yr recurrence-free probability (including bladder recurrence) and CSS estimates were 32% and 78%, respectively. On multivariable analysis, pathologic stage was the only predictor for disease recurrence (p = 0.01). Tumor location was not an independent predictor for recurrence (hazard ratio: 1.19; p = 0.3), and there was no difference in the probability of disease recurrence between ureteral and renal pelvic tumors (p = 0.18). On survival analysis, we also found no differences between ureteral and renal pelvic tumors on probability of CSS (p = 0.2). On multivariate analysis, pathologic stage (p < 0.0001) and nodal status (p = 0.01) were associated with worse CSS. This study is limited by its retrospective nature.
Conclusions
Our study did not show any differences in recurrence and CSS rates between patients with ureteral and renal pelvic tumors treated with RNU.
doi:10.1016/j.eururo.2010.07.003
PMCID: PMC4174409  PMID: 20637540
Nephroureterectomy; Recurrence; Renal pelvis; Survival; Urothelial carcinoma; Ureter
14.  Comparison Between Laparoscopic and Open Radical Nephroureterectomy in a Contemporary Group of Patients: Are Recurrence and Disease-Specific Survival Associated with Surgical Technique? 
European urology  2010;58(5):645-651.
Background
Open radical nephroureterectomy (ORN) is the current standard of care for upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LRN) is emerging as a minimally invasive alternative. Questions remain regarding the oncologic safety of LRN and its relative equivalence to ORN.
Objective
Our aim was to compare recurrence-free and disease-specific survival between ORN and LRN.
Design, setting, and participants
We retrospectively analyzed data from 324 consecutive patients treated with radical nephroureterectomy (RN) between 1995 and 2008 at a major cancer center. Patients with previous invasive bladder cancer or contralateral UTUC were excluded. Descriptive data are provided for 112 patients who underwent ORN from 1995 to 2001 (pre-LRN era). Comparative analyses were restricted to patients who underwent ORN (n = 109) or LRN (n = 53) from 2002 to 2008. Median follow-up for patients without disease recurrence was 23 mo.
Intervention
All patients underwent RN.
Measurements
Recurrence was categorized as bladder-only recurrence or any recurrence (bladder, contralateral kidney, operative site, regional lymph nodes, or distant metastasis). Recurrence-free probabilities were estimated using Kaplan-Meier methods. A multivariable Cox model was used to evaluate the association between surgical approach and disease recurrence. The probability of disease-specific death was estimated using the cumulative incidence function.
Results and limitations
Clinical and pathologic characteristics were similar for all patients. The recurrence-free probabilities were similar between ORN and LRN (2-yr estimates: 38% and 42%, respectively; p = 0.9 by log-rank test). On multivariable analysis, the surgical approach was not significantly associated with disease recurrence (hazard ratio [HR]: 0.88 for LRN vs ORN; 95% confidence interval [CI], 0.57–1.38; p = 0.6). There was no significant difference in bladder-only recurrence (HR: 0.78 for LRN vs ORN; 95% CI, 0.46–1.34; p = 0.4) or disease-specific mortality (p = 0.9). This study is limited by its retrospective nature.
Conclusions
Based on the results of this retrospective study, no evidence indicates that oncologic control is compromised for patients treated with LRN in comparison with ORN.
doi:10.1016/j.eururo.2010.08.005
PMCID: PMC4167427  PMID: 20724065
Laparoscopy; Nephroureterectomy; Recurrence; Survival; Transitional cell carcinoma; Urothelial carcinoma
15.  Mortality After Prostate Cancer Treatment with Radical Prostatectomy, External-Beam Radiation Therapy, or Brachytherapy in Men Without Comorbidity 
European urology  2013;64(3):372-378.
Background
Medical comorbidity is a confounding factor in prostate cancer (PCa) treatment selection and mortality. Large-scale comparative evaluation of PCa mortality (PCM) and overall mortality (OM) restricted to men without comorbidity at the time of treatment has not been performed.
Objective
To evaluate PCM and OM in men with no recorded comorbidity treated with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT).
Design, setting, and participants
Data from 10 361 men with localized PCa treated from 1995 to 2007 at two academic centers in the United States were prospectively obtained at diagnosis and retrospectively reviewed. We identified 6692 men with no recorded comorbidity on a validated comorbidity index. Median follow-up after treatment was 7.2 yr.
Intervention
Treatment with RP in 4459 men, EBRT in 1261 men, or BT in 972 men.
Outcome measurements and statistical analysis
Univariate and multivariate Cox proportional hazards regression analysis, including propensity score adjustment, compared PCM and OM for EBRT and BT relative to RP as reference treatment category. PCM was also evaluated by competing risks analysis.
Results and limitations
Using Cox analysis, EBRT was associated with an increase in PCM compared with RP (hazard ratio [HR]: 1.66; 95% confidence interval [CI], 1.05–2.63), while there was no statistically significant increase with BT (HR: 1.83; 95% CI, 0.88–3.82). Using competing risks analysis, the benefit of RP remained but was no longer statistically significant for EBRT (HR: 1.55; 95% CI, 0.92–2.60) or BT (HR: 1.66; 95% CI, 0.79–3.46). In comparison with RP, both EBRT (HR: 1.71; 95% CI, 1.40–2.08) and BT (HR: 1.78; 95% CI, 1.37–2.31) were associated with increased OM.
Conclusions
In a large multicenter series of men without recorded comorbidity, both forms of radiation therapy were associated with an increase in OM compared with surgery, but there were no differences in PCM when evaluated by competing risks analysis. These findings may result from an imbalance of confounders or differences in mortality related to primary or salvage therapy.
doi:10.1016/j.eururo.2013.03.005
PMCID: PMC3930076  PMID: 23506834
Prostatic neoplasms; Prostatectomy; Radiation therapy; Comorbidity; Comparative effectiveness research
16.  Analytical and Clinical Validation of a Prostate Cancer-Enhanced messenger RNA Detection Assay in Whole Blood as a Prognostic Biomarker for Survival 
European urology  2013;65(6):1191-1197.
Background
Biomarkers based on detecting prostate cancer-specific transcripts are associated with inferior outcomes, but their validation in a clinical context is lacking.
Objective
To determine whether detecting prostate cancer enhanced transcripts in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration.
Design, Setting, and Participants
The predictive value for overall survival of the detection in whole blood by reverse transcription real-time polymerase chain reaction (RT-PCR) of KLK3, KLK2, HOXB13, GRHL2, and FOXA1 was studied in 97 men with metastatic castration-resistant prostate cancer (mCRPC).
Intervention
2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5 ml for CTC enumeration from patients with progressive mCRPC.
Outcome Measurements and Statistical Analysis
Prostate cancer enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch® in an independent data set and survival associations were explored by concordance probability estimate (CPE).
Results and Limitations
Two or more genes were detected by PCR in 53% (51 of 97, 95% CI 43–63%) of patients, and unfavorable CTC counts (≥5cells) were seen in 46% (45 of 97, 95% CI 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%, 95% CI 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (SE=0.038), although limited by the number of patients.
Conclusions
This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival, and may assess patient risk complimentary with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.
doi:10.1016/j.eururo.2013.07.006
PMCID: PMC4113474  PMID: 23954088
biomarker; circulating tumor cells; prostate cancer; prostate-specific markers
17.  Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study 
Bancroft, Elizabeth K. | Page, Elizabeth C. | Castro, Elena | Lilja, Hans | Vickers, Andrew | Sjoberg, Daniel | Assel, Melissa | Foster, Christopher S. | Mitchell, Gillian | Drew, Kate | Mæhle, Lovise | Axcrona, Karol | Evans, D. Gareth | Bulman, Barbara | Eccles, Diana | McBride, Donna | van Asperen, Christi | Vasen, Hans | Kiemeney, Lambertus A. | Ringelberg, Janneke | Cybulski, Cezary | Wokolorczyk, Dominika | Selkirk, Christina | Hulick, Peter J. | Bojesen, Anders | Skytte, Anne-Bine | Lam, Jimmy | Taylor, Louise | Oldenburg, Rogier | Cremers, Ruben | Verhaegh, Gerald | van Zelst-Stams, Wendy A. | Oosterwijk, Jan C. | Blanco, Ignacio | Salinas, Monica | Cook, Jackie | Rosario, Derek J. | Buys, Saundra | Conner, Tom | Ausems, Margreet G. | Ong, Kai-ren | Hoffman, Jonathan | Domchek, Susan | Powers, Jacquelyn | Teixeira, Manuel R. | Maia, Sofia | Foulkes, William D. | Taherian, Nassim | Ruijs, Marielle | den Enden, Apollonia T. Helderman-van | Izatt, Louise | Davidson, Rosemarie | Adank, Muriel A. | Walker, Lisa | Schmutzler, Rita | Tucker, Kathy | Kirk, Judy | Hodgson, Shirley | Harris, Marion | Douglas, Fiona | Lindeman, Geoffrey J. | Zgajnar, Janez | Tischkowitz, Marc | Clowes, Virginia E. | Susman, Rachel | Ramón y Cajal, Teresa | Patcher, Nicholas | Gadea, Neus | Spigelman, Allan | van Os, Theo | Liljegren, Annelie | Side, Lucy | Brewer, Carole | Brady, Angela F. | Donaldson, Alan | Stefansdottir, Vigdis | Friedman, Eitan | Chen-Shtoyerman, Rakefet | Amor, David J. | Copakova, Lucia | Barwell, Julian | Giri, Veda N. | Murthy, Vedang | Nicolai, Nicola | Teo, Soo-Hwang | Greenhalgh, Lynn | Strom, Sara | Henderson, Alex | McGrath, John | Gallagher, David | Aaronson, Neil | Ardern-Jones, Audrey | Bangma, Chris | Dearnaley, David | Costello, Philandra | Eyfjord, Jorunn | Rothwell, Jeanette | Falconer, Alison | Gronberg, Henrik | Hamdy, Freddie C. | Johannsson, Oskar | Khoo, Vincent | Kote-Jarai, Zsofia | Lubinski, Jan | Axcrona, Ulrika | Melia, Jane | McKinley, Joanne | Mitra, Anita V. | Moynihan, Clare | Rennert, Gad | Suri, Mohnish | Wilson, Penny | Killick, Emma | Moss, Sue | Eeles, Rosalind A.
European Urology  2014;66(3):489-499.
Background
Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.
Objective
To report the first year's screening results for all men at enrolment in the study.
Design, setting and participants
We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy.
Outcome measurements and statistical analysis
PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.
Results and limitations
We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.
Conclusions
The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.
Patient summary
In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
Take Home Message
This report demonstrates that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these higher-risk men resulted in the identification of tumours that were more likely to require treatment.
doi:10.1016/j.eururo.2014.01.003
PMCID: PMC4105321  PMID: 24484606
BRCA1; BRCA2; Prostate cancer; Prostate-specific antigen; Targeted screening
18.  Words of Wisdom 
European urology  2011;59(4):657-658.
doi:10.1016/j.eururo.2011.01.020
PMCID: PMC4149802  PMID: 21414885
19.  Efficacy and Safety of Everolimus in Elderly Patients With Metastatic Renal Cell Carcinoma: An Exploratory Analysis of the Outcomes of Elderly Patients in the RECORD-1 Trial 
European urology  2012;61(4):826-833.
Background
Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.
Objective
To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.
Design, setting, and participants
The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).
Intervention
Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.
Measurements
Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.
Results and limitations
In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.
Conclusions
Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.
doi:10.1016/j.eururo.2011.12.057
PMCID: PMC4142675  PMID: 22297244
Adverse events; Kidney cancer; mTOR inhibitor; Pneumonitis
20.  Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials 
European urology  2012;63(4):717-723.
Background
Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM).
Objectives
The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352).
Outcome measurements and statistical analysis
Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures.
Results and limitations
ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable.
Conclusions
Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
doi:10.1016/j.eururo.2012.11.042
PMCID: PMC4127896  PMID: 23206856
Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status
21.  Comparative effectiveness of external beam radiation approaches for prostate cancer 
European urology  2012;65(1):162-168.
Background
Intensity-modulated radiotherapy (IMRT) is increasingly used for treating localized prostate cancer. While allowing for the delivery of higher doses of radiation to the prostate, its effectiveness compared to the prior standard, 3-dimensional conformal therapy (3D-CRT), is uncertain.
Objective
To examine the comparative effectiveness of IMRT relative to 3D-CRT.
Design, setting, and participants
We performed a population-based cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify men diagnosed with prostate cancer between 2001 and 2007 who underwent either 3D-CRT (n=6,976) or IMRT (n=11,039).
Measurements
We assessed our main outcomes (i.e., the adjusted use of salvage therapy with androgen deprivation therapy (ADT) and risk of a complication requiring an intervention) using Cox proportional-hazards models.
Results and limitations
The percentage of men receiving IMRT increased from 9% in 2001 to 93% in 2007. Compared to those treated with 3D-CRT, low-risk patients treated with IMRT had similar likelihoods of using salvage therapy with ADT and similar risks of having a complication requiring an intervention (all p>0.05). Conversely, a subset of higher-risk patients treated with IMRT who did not receive concurrent ADT were less likely to use salvage therapy (p=0.02), while maintaining similar complication rates. Since our cohort includes Medicare beneficiaries, our findings may not be generalizable to younger patients.
Conclusions
For a subset of higher-risk patients, IMRT appears to show a benefit in terms of reduced salvage therapy without an increase in complications. For other patients, the risks of salvage therapy and complications are comparable between the two modalities.
doi:10.1016/j.eururo.2012.06.055
PMCID: PMC4128498  PMID: 22790288
complications; intensity-modulated radiotherapy; prostate cancer; radiation; salvage therapy
22.  Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy 
European urology  2013;65(3):577-584.
Background
The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).
Objective
The purpose of this study was to analyze outcomes based on the presence of bone metastases (BM) and/or liver metastases (LM) in patients with RCC treated with targeted therapy.
Design, Setting and Participants
We conducted a review from the International Metastatic RCC Database Consortium (IMDC) of 2,027 patients with metastatic RCC.
Outcome Measurements and Statistical Analysis
We analyzed the impact of site of metastasis on overall survival (OS) and time-to-treatment failure (TTF). Statistical analyses were performed using multivariable Cox regression.
Results and Limitations
Presence of BM was 34% overall and when stratified by IMDC risk groups was 27%, 33%, and 43% in favorable, intermediate, and poor-risk groups, respectively (pitalic>0.001). Presence of LM was 19% overall and higher in the poor-risk patients (23%) compared to the favorable or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BM and/or LM the hazard ratio (HR), adjusted for IMDC risk factors, was 1.4 (95% Confidence Interval (CI) 1.22–1.62) for BM, 1.42 (95% CI 1.17–1.73) for LM, and 1.82 (95% CI 1.47–2.26) for both BM and LM compared to other metastatic sites (pbold>0.0001). The prediction model performance for OS was significantly improved when BM and LM were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis was collected retrospectively.
Conclusions
The presence of BM and LM in patients treated with targeted agents has a negative impact on survival. Patients with BM and/or LM may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
doi:10.1016/j.eururo.2013.08.012
PMCID: PMC4123121  PMID: 23962746
Bone metastases; Liver metastases; mTOR inhibitors; Outcome; Renal cell carcinoma; VEGF therapy
23.  Predictive and Prognostic Models in Radical Prostatectomy Candidates: A Critical Analysis of the Literature 
European urology  2010;58(5):687-700.
Context
Numerous predictive and prognostic tools have recently been developed for risk stratification of prostate cancer (PCa) patients who are candidates for or have been treated with radical prostatectomy (RP).
Objective
To critically review the currently available predictive and prognostic tools for RP patients and to describe the criteria that should be applied in selecting the most accurate and appropriate tool for a given clinical scenario.
Evidence acquisition
A review of the literature was performed using the Medline, Scopus, and Web of Science databases. Relevant reports published between 1996 and January 2010 identified using the keywords prostate cancer, radical prostatectomy, predictive tools, predictive models, and nomograms were critically reviewed and summarised.
Evidence synthesis
We identified 16 predictive and 22 prognostic validated tools that address a variety of end points related to RP. The majority of tools are prediction models, while a few consist of risk-stratification schemes. Regardless of their format, the tools can be distinguished as preoperative or postoperative. Preoperative tools focus on either predicting pathologic tumour characteristics or assessing the probability of biochemical recurrence (BCR) after RP. Postoperative tools focus on cancer control outcomes (BCR, metastatic progression, PCa-specific mortality [PCSM], overall mortality). Finally, a novel category of tools focuses on functional outcomes. Prediction tools have shown better performance in outcome prediction than the opinions of expert clinicians. The use of these tools in clinical decision-making provides more accurate and highly reproducible estimates of the outcome of interest. Efforts are still needed to improve the available tools’ accuracy and to provide more evidence to further justify their routine use in clinical practice. In addition, prediction tools should be externally validated in independent cohorts before they are applied to different patient populations.
Conclusions
Predictive and prognostic tools represent valuable aids that are meant to consistently and accurately provide most evidence-based estimates of the end points of interest. More accurate, flexible, and easily accessible tools are needed to simplify the practical task of prediction.
doi:10.1016/j.eururo.2010.07.034
PMCID: PMC4119802  PMID: 20727668
Prostate cancer; Radical prostatectomy; Prediction tools; Nomograms
24.  Timing of Curative Treatment for Prostate Cancer: A Systematic Review 
European urology  2013;64(2):204-215.
Context
Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).
Objective
To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.
Evidence acquisition
A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.
Evidence synthesis
Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.
Conclusions
Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.
doi:10.1016/j.eururo.2013.02.024
PMCID: PMC3784981  PMID: 23453419
Active surveillance; Delay; Expectant management; Outcomes; Prostate cancer; Radiation therapy; Radical prostatectomy
25.  Neoadjuvant Chemotherapy in Small Cell Urothelial Cancer Improves Pathologic Downstaging and Long-term Outcomes: Results from a Retrospective Study at the MD Anderson Cancer Center 
European urology  2012;64(2):10.1016/j.eururo.2012.04.020.
Background
Small cell urothelial carcinoma (SCUC) is a rare, aggressive malignancy with a propensity for early microscopic metastases. Data suggest that neoadjuvant chemotherapy may lead to improved survival compared with initial surgery.
Objective
To determine the influence of neoadjuvant chemotherapy on survival of SCUC patients in a large single-institution cohort.
Design, setting, and participants
Between 1985 and 2010, 172 patients were treated for SCUC at MD Anderson Cancer Center (MDACC). Clinical, pathologic, and surgical data were collected and analyzed.
Outcome measurements and statistical analysis
Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to evaluate the effects of neoadjuvant chemotherapy on survival.
Results and limitations
Of 125 patients with resectable disease (≤cT4aN0M0), 95 were surgical candidates. Forty-eight received neoadjuvant chemotherapy, and 47 underwent initial surgery. Neoadjuvant treatment was associated with improved OS and DSS compared with initial cystectomy (median OS: 159.5 mo vs 18.3 mo, p < 0.001; 5-yr DSS: 79% vs 20%, p < 0.001). Neoadjuvant chemotherapy resulted in pathologic downstaging to ≤pT1N0 in 62% of tumors compared with only 9% treated with initial surgery (odds ratio: 44.55; 95% confidence interval, 10.39–191). Eight patients with clinically node-positive disease had surgical consolidation with cystectomy and extended lymph node dissection after clinical complete response to chemotherapy. Median OS and DSS in this group of patients were 23.3 mo and 21.8 mo, respectively, with 5-yr OS and DSS of 38%.
Conclusions
Neoadjuvant chemotherapy is associated with a high rate of pathologic downstaging and correlates with significantly higher survival compared with historical expectations. Although limited by a small sample size and retrospective analysis, in the context of a rare disease, this experience suggests neoadjuvant chemotherapy as a standard approach in treating SCUC.
doi:10.1016/j.eururo.2012.04.020
PMCID: PMC3815632  PMID: 22564397
Small cell urothelial cancer; Bladder cancer; Neoadjuvant; Surgery; Chemotherapy

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