Neoadjuvant Chemotherapy with Gemcitabine plus Cisplatin in Patients with Locally Advanced Bladder Cancer.

BACKGROUND: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) is the standard of care for muscle-invasive urothelial bladder cancer. Gemcitabine plus cisplatin (GC) shows similar efficacy with less toxicity in the metastatic setting and has therefore often been used interchangeably with MVAC. We report on the efficacy and safety of neoadjuvant GC in patients with locally advanced urothelial cancer. MATERIALS AND METHODS: We prospectively evaluated 87 patients in 2 centers. Their median age was 68 years. Treatment consisted of 3× GC prior to radical cystectomy. The primary endpoint was pathologic response. The secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). RESULTS: In all, 83 patients finished chemotherapy; 80 patients were evaluable for the primary endpoint. Pathologic complete response (pCR) was achieved in 22.5% and near pCR was seen in 33.7% of the patients. The 1-year PFS rate was 79.5% among those patients achieving ≤pT2 versus 100% among those patients achieving pCR or near pCR (p = 0.041). Five-year OS was 61.8% (95% CI 67.6 to NA). GC was well tolerated. Grade 3/4 toxicities occurred in 38% of the patients. There was no grade 3/4 renal toxicity, febrile neutropenia, or death. CONCLUSION: Neoadjuvant GC is a well-tolerated regimen. Although the pathologic response is lower than that reported with MVAC, our data support GC as a feasible option in the absence of a prospective randomized comparison, particularly for older patients, since its toxicity is lower than that of MVAC.

The Use of Neoadjuvant Chemotherapy in Patients With Urothelial Carcinoma of the Bladder: Current Practice Among Clinicians.

INTRODUCTION: Guidelines recommend neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in patients with urothelial carcinoma of the bladder in clinical stages T2-T4a, cN0M0. We examined the frequency and current practice of NAC and sought to identify predictors for the use of NAC in a prospective contemporary cohort. MATERIALS AND METHODS: We analyzed prospective data from 679 patients in the PROMETRICS (PROspective MulticEnTer RadIcal Cystectomy Series 2011) database. All patients underwent RC in 2011. Uni- and multivariable regression analyses identified predictors of NAC application. Furthermore, a questionnaire was used to evaluate the practice patterns of NAC at the PROMETRICS centers. RESULTS: A total of 235 patients (35%) were included in the analysis. Only 15 patients (2.2%) received NAC before RC. Younger age (< 70 years; P = .035), lower case volume of the center (< 30 RC/year; P < .001), and advanced tumor stage (≥ cT3; P = .038) were identified as predictors for NAC. Of the 200 urologists who replied to the questionnaire, 69% (n = 125) declared tumor stage cT3-4 a/o N1M0 to be the best indication for NAC application, although 45% of the urologists stated that they would not perform NAC despite recommendations. The decision for NAC was made by the individual urologist in 69% of cases, and only 29% reported that all cases were discussed in an interdisciplinary tumor board. CONCLUSION: NAC was rarely applied in the present cohort. We observed a discrepancy between guideline recommendations and practice patterns, despite medical indication and pre-therapeutic interdisciplinary discussion. The potential benefit of NAC within a multimodal approach seems to be neglected by many urologists.

[The Clavien-Dindo classification of complications used for radical prostatectomy]. / Die Komplikationsklassifikation nach Clavien-Dindo am Beispiel der radikalen Prostatektomie.

The objective of the present study was to evaluate perioperative complications between retropubic, endoscopic and robot-assisted radical prostatectomy on basis of a prospective maintained database using the Clavien-Dindo classification of complications. According to our results, implementation of the radical robot-assisted laparoscopic prostatectomy shows a trend to a decrease of minor complications compared to retropubic and endoscopic radical prostatectomy. Major complications are comparable between all three procedures.

Prostate cancer at the peripheral end of prostate biopsy specimen predicts increased risk of positive resection margin after radical prostatectomy: results of a prospective multi-institutional study.

PURPOSE: To test a novel technique of processing prostate biopsy specimen by marking the peripheral end (PE) as a predictive tool for positive resection margin after radical prostatectomy (RP) or for locally advanced carcinoma of the prostate (PC). METHODS: Prospective, multi-institutional study of a consecutive cohort of men who underwent prostate biopsy with marking the peripheral biopsy end and subsequent RP at the same institution. RESULTS: The study cohort comprised 445 men with a mean age of 63 years (40-77 years). Overall, PE-positive cores were found in 174 men (39.1 %) and R1 status was diagnosed in 132 men after RP (29.7 %). In the multivariate analysis, the presence of at least one PE-positive core was correlated with an increased risk of R1 status (OR 2.29, 95 % CI 1.31-4.00, p = 0.003) and was the strongest predictor followed by Gleason score, PSA and percentage of positive cores. Including all predictive parameters, a nomogram with a concordance index of 72.1 % was calculated. In the pT3/pT4 subgroup, PE positivity was the only predictive factor for R1 status (OR 3.03, 95 % CI 1.36-6.75, p = 0.006). In pT2 stage, no single factor was predictive for R1 status. PE-positive biopsies were not predictive for pT3/pT4 stages. CONCLUSIONS: PC at the peripheral end of prostate biopsy specimen predicts an increased risk of R1 status in subsequent RP. This simple and cheap technique may contribute to an increased accuracy of risk stratification for curative treatment for PC.

Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer.

PURPOSE: The impact of diabetes mellitus (DM) and metformin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6,863 patients who underwent RP for clinically localized PC between 2000 and 2011. Univariable and multivariable Cox regression models addressed the association of DM and metformin use with BCR. RESULTS: Overall, 664 patients had a diagnosis of DM from which 287 (43 %) were on metformin and 377 (57 %) were on anti-diabetics other than metformin. DM and metformin were not associated with any clinicopathologic features (p values >0.05). Within a median follow-up of 25 months (interquartile range 35 months), 774 (11.3 %) patients experienced BCR. Actuarial 5-year biochemical-free survival was 83 % for non-diabetic, 79 % for diabetic patients without metformin use, and 85 % for diabetic patients with metformin use (log rank p = 0.17). In uni- and multivariable Cox regression analyses with the non-diabetic group as referent, DM without metformin use (HR = 0.99; 95 % CI 0.75-1.30, p = 0.65) and DM with metformin use (HR = 0.84, 95 % CI 0.58-1.22, p = 0.36) were not associated with BCR after RP. A subgroup analysis stratified by nodal status, surgical margins, tumor stage, and Gleason sum did not reveal any significant association between DM, use of metformin and risk of BCR. CONCLUSIONS: We found no association between DM or metformin use and cancer-specific features or BCR in patients treated with RP. The effect of DM and metformin on complications, wound healing and overall survival needs to be assessed in similar cohorts.

Prognosis of patients with pelvic lymph node (LN) metastasis after radical prostatectomy: value of extranodal extension and size of the largest LN metastasis.

OBJECTIVE: To assess the prognostic role of extranodal extension (ENE) and the size of the largest lymph node (LN) metastasis in predicting early biochemical relapse (eBCR) in patients with LN metastasis after radical prostatectomy (RP). PATIENTS AND METHODS: We evaluated BCR-free survival in men with LN metastases after RP and pelvic LN dissection performed in six high-volume centres. Multivariable Cox regression tested the role of ENE and diameter of largest LN metastasis in predicting eBCR after adjusting for clinicopathological variables. We compared the discrimination of multivariable models including ENE, the size of largest LN metastasis and the number of positive LNs. RESULTS: Overall, 484 patients were included. The median (interquartile range, IQR) follow-up was 16.1 (6-27.5) months. The median (IQR) number of removed LNs was 10 (4-14), and the median (IQR) number of positive LNs was 1 (1-2). ENE was present in 280 (58%) patients, and 211 (44%) had their largest metastasis >10 mm. Patients with ENE and/or largest metastasis of >10 mm had significantly worse eBCR-free survival (all P < 0.01). On multivariable analysis, number of positive LNs (≤2 vs >2) and the diameter of LN metastasis (≤10 vs >10 mm), but not ENE, were significant predictors of eBCR (all P < 0.003). ENE and diameter of LN metastasis increased the area under the curve of a baseline multivariable model (0.663) by 0.016 points. CONCLUSIONS: The diameter of the largest LN metastasis and the number of positive LNs are independent predictors of eBCR. Considered together, ENE and the diameter of the largest LN metastasis have less discrimination than the number of positive LNs.

Does increasing the nodal yield improve outcomes in contemporary patients without nodal metastasis undergoing radical prostatectomy?

OBJECTIVES: To determine if the number of lymph nodes (LNs) removed is an independent predictor of biochemical recurrence (BCR) in patients without LN metastases undergoing radical prostatectomy (RP). MATERIAL AND METHODS: Retrospective analysis of 7,310 patients treated at 7 centers with RP and pelvic LN dissection for clinically localized prostate cancer between 2000 and 2011. Patients with LN metastases (n = 398) and other reasons (stated later in the article) (n = 372) were excluded, which left 6,540 patients for the final analyses. RESULTS: Overall, median biopsy and RP Gleason score were both 7; median prostate specific antigen level was 6 ng/ml (interquartile range [IQR]: 5); and median number of LNs removed was 6 (IQR: 8). A total of 3,698 (57%), 2,064 (32%), and 508 (8%) patients had ≥ 6, ≥ 10, and ≥ 20 LNs removed, respectively. Patients with more LNs removed were older, had a higher prostate specific antigen level, had higher clinical and pathologic T stage, and had higher RP Gleason score (all P<0.002). Within a median follow-up of 21 (IQR: 16) months, more LNs removed was associated with an increased risk of BCR (continuous: P = 0.021; categorical: P = 0.014). In multivariable analyses that adjusted for the effects of standard clinicopathologic factors, none of the nodal stratifications predicted BCR. CONCLUSIONS: The number of LNs did not have any prognostic significance in our contemporary cohort of patients with LN-negative prostate cancer. This suggests that the risk of missed clinically significant micrometastasis may be minimal in patients currently treated with RP and having a lower LN yield.

A multinational, multi-institutional study comparing positive surgical margin rates among 22393 open, laparoscopic, and robot-assisted radical prostatectomy patients.

BACKGROUND: Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume. OBJECTIVE: To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates. DESIGN, SETTING, AND PARTICIPANTS: Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort. RESULTS AND LIMITATIONS: Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload. CONCLUSIONS: This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases. PATIENT SUMMARY: In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures.

Pathologic nodal staging scores in patients treated with radical prostatectomy: a postoperative decision tool.

BACKGROUND: Nodal metastasis is the strongest risk factor of disease recurrence in patients with localized prostate cancer (PCa) treated with radical prostatectomy (RP). OBJECTIVE: To develop a model that allows quantification of the likelihood that a pathologically node-negative patient is indeed free of nodal metastasis. DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with RP and pelvic lymph node dissection (PLND; n=7135) for PCa between 2000 and 2011 were analyzed. For external validation, we used data from patients (n=4209) who underwent an anatomically defined extended PLND. INTERVENTION: RP and PLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We developed a novel pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative based on the number of examined nodes and the patient's characteristics. RESULTS AND LIMITATIONS: In the development and validation cohorts, the probability of missing a positive node decreases with an increasing number of nodes examined. Whereas in pT2 patients, a 90% pNSS was achieved with one single examined node in both the development and validation cohort, a similar level of nodal staging accuracy was achieved in pT3a patients by examining five and nine nodes, respectively. The pT3b/T4 patients achieved a pNSS of 80% and 70% when 17 and 20 nodes in the development and validation cohort were examined, respectively. This study is limited by its retrospective design and multicenter nature. The number of nodes removed was not directly correlated with the extent/template of PLND. CONCLUSIONS: Every patient needs PLND for accurate nodal staging. However, a one-size-fits-all approach is too inaccurate. We developed a tool that indicates a node-negative patient is indeed free of lymph node metastasis by evaluating the number of examined nodes, pT stage, RP Gleason score, surgical margins, and prostate-specific antigen. This tool may help in postoperative decision making.

Sentinel lymphadenectomy compared to extended lymphadenectomy in men with prostate cancer undergoing prostatectomy.

BACKGROUND: To evaluate the reliability of sentinel lymphadenectomy compared to extended lymphadenectomy in men undergoing radical prostatectomy (RP). PATIENTS AND METHODS: A consecutive cohort of men with intermediate- to high-risk prostate cancer underwent RP with sentinel LA with intraoperative frozen section. In addition, extended LA was carried out in all cases. The endpoint was lymph node-positivity. RESULTS: In total, 54 men with a mean age of 65.3 (50.9-75.6) years were analyzed. The mean preoperative prostate-specific antigen was 10.6 (2.8-66.5) ng/ml, mean number of disease-positive cores was 5.8 (1-13), digital rectal examination was positive in 29 men (53.7%). In 12 men (22.2%), a positive lymph node was found (pN1). sLA was positive in 11 cases. One patient had a positive lymph node in eLA not found with sLA. The positive predictive value of frozen section was 50%; the respective figure for sLA compared to eLA was 91.6%. CONCLUSION: In this cohort, revealing a high prevalence of disease-positive lymph nodes, sLA was a reliable technique with a low rate of false negativity.

Initial experience and results with a new adjustable transobturator male system for the treatment of stress urinary incontinence.

PURPOSE: We report on our initial experience in terms of efficacy and safety with a new, self-anchoring adjustable transobturator male system (A.M.I.® ATOMS System) for the treatment of male stress urinary incontinence after prostate surgery. MATERIALS AND METHODS: In this prospective, nonrandomized single center study conducted between March and December 2009, patients with stress urinary incontinence secondary to prostatic surgery were treated with the ATOMS device. Urethroscopy, filling and voiding cystometry were performed preoperatively for all patients. In addition, incontinence symptoms were assessed, and a physical examination, 24-hour pad test and 24-hour pad count were performed before and after surgery. RESULTS: A total of 38 patients were included in the study (36 after radical prostatectomy, 2 after benign prostatic hyperplasia surgery). No intraoperative complications occurred. Mean number of adjustments during followup was 3.97 (range 0 to 9). At a mean followup of 16.9 months (range 13 to 21) the overall success rate was 84.2%. Of the successful cases 60.5% were considered dry (0 to 1 pad and less than 15 ml/24-hour pad test) and 23.7% improved (more than 1 pad per 24 hours but more than 50% decrease in pad use and less than 100 ml per 24-hour pad test). In 15.8% of the patients the treatment was considered to have failed (more than 2 pads daily and greater than 100 ml on 24-hour pad test). CONCLUSIONS: The treatment of male stress urinary incontinence with the ATOMS is safe and effective. It is an excellent first or second line treatment for mild to moderate male stress urinary incontinence, even after external irradiation. The option of long-term, minimally invasive adjustment to respond to patient needs is a significant advantage of this new implant.

[Urothelial carcinoma of the upper urinary tract: clinical and pathological criteria and their predictive implications after radical nephroureterectomy]. / Urothelkarzinom des oberen Harntraktes: klinische und pathologische Kriterien und deren Implikationen für den Verlauf nach Nephroureterektomie.

Recent multicentric studies contributed significantly to the understanding of clinical and pathological criteria and their implications as prognosticators of the upper urinary tract urothelial carcinoma. They demonstrated a large variety of prognosticators influencing the course of this rare disease. The influence of gender and age and the presence of symptoms and renal obstruction in addition to pathologic criteria such as staging, tumor architecture, lymphnode invasion, localization and the presence of CIS or tumor necrosis on prognosis and disease recurrence after radical nephroureterectomy were investigated. Additional multicentric, ideally prospective studies are warranted to validate current findings.

[Neoadjuvant therapy before radical prostatectomy - indications and protocols]. / Neoadjuvante Therapie vor radikaler Prostatektomie - Indikationen und Protokolle.

As neoadjuvant chemotherapy is established for a variety of nonorgan confined malignancies, neoadjuvant hormone ablation for hormone sensitive prostate cancer has demonstrated encouraging results. Neoadjuvant therapy not only provides possible early systemic treatment for subclinical distant disease, but also aims to improve local disease control and to increase the number of patients eligible for definitive local therapy via downstaging. However, only limited, heterogenous studies are available. Therefore, prospective high quality studies are urgently needed to assess the future role of neoadjuvant hormone ablation.

[Current treatment of locally advanced and metastatic prostate cancer]. / Aktuelle Therapie des fortgeschrittenen Prostatakarzinoms.

Despite the broad use of PSA-testing in western medicine, still an estimated 1/3 of carcinomas of the prostate (PC) are diagnosed in a locally advanced or metastatic stage. In the current treatment-algorithm for locally advanced PC, radical prostatectomy, external beam radiation therapy (with and without hormonal therapy) and primary androgen deprivation are available. In fact, in a majority of patients treatment of this tumor stage will be a multimodal approach, which has to be discussed individually. For metastatic PC hormonal deprivation therapy is still the gold standard. Beside LHRH-agonists, surgical castration and complete androgen deprivation today LHRH-antagonists represent the different therapeutic options in this tumor stage. Effects on natural course of this disease have to be balanced to the side effects of long-term therapy. Castration-resistant PC is not the object of this overview even though there are a variety of new medical interventions emerging for the treatment of this stage of PC.

Proposal for a standardized PSA doubling-time calculation.

PURPOSE: Prostate-specific antigen (PSA) doubling-time (PSA-DT) is an important indicator of progression and survival in men with prostate cancer. Three major limitations regarding PSA-DT determination may lead to inconsistent results: the variety of mathematical methods currently applied, the non-standardized handling of input variables and the potential lack of accuracy due to PSA variability. The aim of this project was to develop a reproducible PSA-DT determination tool which simultaneously provides a PSA-DT error estimation. MATERIALS AND METHODS: An internet-based PSA-DT calculation tool via nonlinear optimization implementing the least squares error method using the most recent three PSA values was developed. PSA-DT calculation error is estimated via randomly disturbed measurement data streams (n=65) based on a variable (5-25%) PSA variability. RESULTS: According to a simulation in five men, PSA-DT was calculated to be between 1.7 and 15 month (mean: 6.3 month) and determined with another standard tool between 1.3 and 14.5 month (mean: 4.2 month). CONCLUSION: We present a defined, open and reproducible PSA-DT calculation and PSA-DT error estimation tool based on a standardized PSA data input. This tool is not better compared to other methods but is scientifically standardized and freely accessible via the following internet address: http://adam.drahtwarenhandlung.at/webapp/mg2008/chapter_prostata4/example_psa.

[How to use PSA in 2009]. / Aktueller Einsatz von PSA.

PSA is without any doubt the most frequently used marker in urology due to its helpful information regarding various aspects of diagnosis, therapy and prognosis in men with prostate cancer. On the other hand, many controversies still exist about the various indications for PSA-determination. The following overview is aimed to analyse the current status of PSA in the management of men undergoing screening, therapy or follow-up of prostate cancer. Anyhow, a detailed knowledge of how to use and interpret PSA and PSA-kinetics is considered to play a crucial role in prostate cancer patients. Current strategies are aimed to start and stop PSA-use earlier.

[First experience with the laparoscopic radical cystectomy]. / Erste Erfahrungen mit der laparoskopischen radikalen Zystektomie.

In muscle-invasive bladder cancer, radical cystectomy is the treatment of choice. Pioneers of laparoscopy have tried to remove the bladder in the early 90s. In the year 2000 Gill et al. managed to remove the bladder and reconstruct the urinary diversion completely laparoscopically for the first time. Since the implementation of the technique of laparoscopic radical prostatectomy in many American and European institutes, the development of technical instruments for laparoscopy is a milestone. With these instruments and with the knowledge of laparoscopic radical prostatectomy, the step to perform a laparoscopic radical cystectomy is not very far.

[Multimodal therapy of prostate cancer - 2 case reports]. / Multimodale Therapie des Prostatakarzinoms - 2 Fallberichte.

The importance of the carcinoma of the prostate is still increasing. It is important to have options such as multimodal therapy. In this article two selected case reports are presented. Treatment options such as surgery, hormonal and irradiation therapy as well as chemotherapy will be discussed. Each patient suffering from carcinoma of prostate should receive individual best therapy.