Non-muscle-invasive bladder cancer: a vision for the future.

The management of non-muscle-invasive bladder cancer (NMIBC) has evolved from the first reports on bladder endoscopy and transurethral resection to the introduction of adjuvant intravesical treatment. However, disease recurrence and progression remain an ongoing risk, placing a heavy burden on healthcare resources and on patients' quality of life. Deeper understanding of the molecular basis of the disease and developments in optics, lasers and computer science are already offering opportunities to revolutionize care and improve long-term prognosis. This article discusses developments likely to cause a paradigm shift towards the delivery of personalized care and reduced burden of disease in NMIBC.

Clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: evidence review and updated expert recommendations.

CONTEXT: Non-muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence risk, partly because of the persistence of lesions following transurethral resection of bladder tumour (TURBT) due to the presence of multiple lesions and the difficulty in identifying the exact extent and location of tumours using standard white-light cystoscopy (WLC). Hexaminolevulinate (HAL) is an optical-imaging agent used with blue-light cystoscopy (BLC) in NMIBC diagnosis. Increasing evidence from long-term follow-up confirms the benefits of BLC over WLC in terms of increased detection and reduced recurrence rates. OBJECTIVE: To provide updated expert guidance on the optimal use of HAL-guided cystoscopy in clinical practice to improve management of patients with NMIBC, based on a review of the most recent data on clinical and cost effectiveness and expert input. EVIDENCE ACQUISITION: PubMed and conference searches, supplemented by personal experience. EVIDENCE SYNTHESIS: Based on published data, it is recommended that BLC be used for all patients at initial TURBT to increase lesion detection and improve resection quality, thereby reducing recurrence and improving outcomes for patients. BLC is particularly useful in patients with abnormal urine cytology but no evidence of lesions on WLC, as it can detect carcinoma in situ that is difficult to visualise on WLC. In addition, personal experience of the authors indicates that HAL-guided BLC can be used as part of routine inpatient cystoscopic assessment following initial TURBT to confirm the efficacy of treatment and to identify any previously missed or recurrent tumours. Health economic modelling indicates that the use of HAL to assist primary TURBT is no more expensive than WLC alone and will result in improved quality-adjusted life-years and reduced costs over time. CONCLUSIONS: HAL-guided BLC is a clinically effective and cost-effective tool for improving NMIBC detection and management, thereby reducing the burden of disease for patients and the health care system. PATIENT SUMMARY: Blue-light cystoscopy (BLC) helps the urologist identify bladder tumours that may be difficult to see using standard white-light cystoscopy (WLC). As a result, the amount of tumour that is surgically removed is increased, and the risk of tumour recurrence is reduced. Although use of BLC means that the initial operation costs more than it would if only WLC were used, over time the total costs of managing bladder cancer are reduced because patients do not need as many additional operations for recurrent tumours.

Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. A combined analysis of the trials used for registration and postmarketing data.

OBJECTIVE: To detail and put into perspective, safety of hexaminolevulinate blue light cystoscopy (HAL-BLC), including repeated use, based on combined data of controlled trials used for registration of HAL and postmarketing experience. METHODS: Safety data of 2 randomized comparative studies (group 1) and 4 within patient control studies (group 2) were combined. Postmarketing data from >200,000 patients were analyzed. RESULTS: In group 1, 533 patients were examined with HAL-BLC and 499 with white light (WL) cystoscopy. In group 2, 791 patients were examined with both WL and HAL-BLC. Between 73% and 93% of these patients had concomitant diseases. Between 41% and 58% of the patients had at least 1 adverse event (AE), although predominantly mild to moderate. The majority was considered as not related to HAL-BLC and reported in the urinary tract. No serious adverse events (SAEs) were considered definitely related to HAL-BLC, but in 6 patients serious AEs were of an uncertain relationship. Four possibly related hypersensitivity reactions have been reported. Repeated use did not reveal additional toxicity, also supported by data from 3 European centers. CONCLUSION: This combined and detailed analysis of patients from 6 HAL-BLC studies with very comparable criteria shows that HAL-BLC is safe and poses very little additional risks other than expected for WL cystoscopy for bladder tumor resection in this specific patient population. This is supported by 9 years of postmarketing experience. Repeated use also seems safe.

Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature.

CONTEXT: Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. CONCLUSIONS: Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required.

Photodynamic therapy of bladder cancer - a phase I study using hexaminolevulinate (HAL).

OBJECTIVES: To assess the safety and feasibility of hexaminolevulinate (HAL) based photodynamic therapy (PDT) as adjuvant treatment after transurethral resection of the bladder (TURB) in patients with intermediate or high-risk urothelial cell carcinoma (UCC) of the bladder. MATERIALS AND METHODS: Seventeen patients received 50 ml of either a 16 mM (4 patients) or 8 mM HAL (13 patients) solution instilled intravesically. Bladder wall irradiation was performed using an incoherent white light source coupled via a quartz fiber assembled into a flexible transurethral irrigation catheter. Each patient received 3 treatments with HAL-PDT 6 weeks apart. After PDT, patients were followed by regular cystoscopy for up to 21 months to assess time to recurrence. Reported adverse events (AEs) were coded according the World Health Organization Adverse Reaction Terminology (WHO-ART). Efficacy was assessed by cystoscopy, cytology, and histology, and was defined as the number of patients who were tumor-free at 6 or 21 months after initial PDT treatment. Transient bladder irritability was reported by 15 of the 17 patients and resolved completely in all patients. No evidence of a cumulative effect of treatment on the incidence of AEs could be detected. PDT treatment was performed without any technical complications. Furthermore preliminary assessment of efficacy showed that of the 17 patients included, 9 (52.9%; 95% CI: 27.8-77.0) were tumor-free at 6 months, 4 (23.5%; 95% CI: 6.8-49.9) were tumor-free at 9 months, and 2 (11.8%, 95% CI: 1.5-36.4) were tumor-free after 21 months. CONCLUSIONS: PDT using hexaminolevulinate and an incoherent white light system with the special flexible irradiation catheter system is technically feasible and safe and may offer an alternative in the treatment of non-muscle-invasive intermediate and high-risk bladder cancer.

Urine colour after radical prostatectomy predicts urinary leakage at the vesicourethral anastomosis.

OBJECTIVE: The aim of this investigation was to determine whether postoperative urine colour could be used as a predictor for the presence or absence of a urinary leakage at the vesicourethral anastomosis after open radical prostatectomy. MATERIAL AND METHODS: In this prospective study, the urine colour of 223 patients who underwent open radical prostatectomy due to histologically proven localized prostate cancer was assessed macroscopically and microscopically on postoperative day (POD) 6, 7 and 8. All patients underwent evaluation of perianastomotic extravasation by retrograde cystography on POD 8. Baseline characteristics included age; prostate-specific antigen; prostate volume; tumour, node, metastasis classification; and Gleason score. RESULTS: The urine colour was a highly significant predictor for perianastomotic extravasation in cystography when it was red on POD 6, 7 and 8. The sensitivity and specificity of urine colour as a predictor for extravasation were 71.4% and 83.2% on POD 6, 71.4% and 85.8% on POD 7, and 81.8% and 90.9% on POD 8, respectively, with a clear or slightly ensanguined urine colour. The negative and positive predictive values were 98.6% and 81.8%, respectively. CONCLUSION: A cystography can be omitted if the patient demonstrates a clear urine colour on POD 8, without an increased risk of missing a perianastomotic extravasation.

The impact of bladder neck mucosal eversion during open radical prostatectomy on bladder neck stricture and urinary extravasation.

PURPOSE: To determine whether the bladder neck mucosal eversion (BNM-eversion) during radical retropubic prostatectomy (RRP) reduces the risk of bladder neck stricture (BNS) and of peri-anastomotic extravasation (PAE) in postoperative cystography. METHODS: Two hundred and eleven patients with clinically localized prostate cancer underwent RRP and were prospectively randomized into patients with BNM-eversion (group I) and without BNM-eversion (group II). All patients underwent an evaluation of PAE by retrograde cystography on postoperative day 8. We assessed BNS after 6 months. RESULTS: Ninety-two patients with and 113 patients without BNM-eversion were included. There was no significant difference in baseline characteristics, including age, TNM-classification, Gleason score, PSA, prostate volume, and blood loss in both groups. A complete follow-up of 6 months for BNS was available for 188 patients (89.1 %). Sixteen BNS out of 188 patients were recorded, 4.7 % (n = 4) in group I and 11.7 % (n = 12) in group II (p = 0.09). Data from 205 out of 211 patients were available for the evaluation of the extravasation by cystography. Peri-anastomotic extravasation was detectable in 11.96 %, (11/205) in group I and in 21.24 % (24/205) in group II (p = 0.08). CONCLUSION: BNM-eversion does not have a positive influence on the prevention of bladder neck strictures. Peri-anastomotic extravasation detected by cystography does not correlate with a formation of bladder neck stricture.

Individual learning curve reduces the clinical value of urinary cytology.

UNLABELLED: The aim of the study was to define the learning curve of a single cytologist as a limitation of urinary cytology. A total of 1034 cytologic and histologic findings of patients undergoing transurethral resection of the bladder for suspicion of bladder cancer were reviewed, and cytologic evaluations of a single cytologist from the beginning of his learning period were compared with the results of a cytologist at a national reference center. Our results showed that the individual learning curve has a significant impact on the quality of urine cytology. BACKGROUND: To define the learning curve of a single cytologist as a limitation of urinary cytology and to compare his results with a reference center for urinary cytology. PATIENTS AND METHODS: Cytologic and histologic findings of patients undergoing transurethral resection of the bladder for suspicion of bladder cancer were reviewed. Cytologic evaluations from a single local cytologist during his learning period and of a cytologist of a national reference center were compared. Changes of sensitivity and specificity of cytology from the local cytologist over the time period were assessed. Differences were estimated by using kappa statistics. RESULTS: The local cytologist evaluated 1034 cytologic findings. Sensitivity and specificity of cytology estimated by the local cytologist were 86% and 66% at the beginning of the learning period, but 68% and 84% at the end of it (P ≤ .05). In high-grade carcinomas, sensitivity did not decrease over the years (P > .05). In contrast, the sensitivity in the diagnosis of low-grade tumors decreased from 86% to 56% (P ≤ .05). The reference center estimated a constant sensitivity and specificity of 59% and 97%, respectively. Agreement of findings between local and national cytologists increased significantly over the learning period (P < .05). CONCLUSION: The individual learning curve has a significant impact on the quality of urinary cytology. Both specificity of cytology and sensitivity for low-grade tumors changed significantly when done by a local cytologist at the beginning of learning period. These findings emphasize the impact of the individual learning curve on the clinical value of urinary cytology in diagnosis of bladder cancer.

Detection of urinary leakage after radical retropubic prostatectomy by contrast enhanced ultrasound - do we still need conventional retrograde cystography?

INTRODUCTION: To prospectively evaluate the accuracy of transvesical contrast-enhanced ultrasound (CEUS) as an alternative method for the detection of anastomotic leakage after radical retropubic prostatectomy (RRP) in comparison with the current standard method of conventional retrograde cystography (CG). PATIENTS AND METHODS: Forty-three patients underwent RRP for histologically proven localized prostate cancer. The vesico-urethral anastomosis was evaluated 8 days after RRP by CG and CEUS. Any peri-anastomotic leakage was assessed and determined in CG and CEUS as follows: no extravasation (EV), small leakage (≤0.5 cm), moderate leakage (>0.5 cm to ≤2 cm), large leakage (>2 cm diameter of EV seen). RESULTS: In total, 21 (49%) patients showed a watertight anastomosis. Ten (23%), two (4.7%) and ten (23%) patients showed a small, intermediate and large EV, respectively. In 31 cases (72%) there was 100% agreement of CG and CEUS for detection of no, moderate and large EV, respectively. In nine cases a small and in two cases a moderate EV was categorized as watertight anastomosis by CEUS. Only in one case did CG detect a small EV where a large EV was detected in CEUS. The agreement between both methods was 95% for detecting absence or large leakages. CONCLUSION: CEUS is a promising imaging modality that seems to be equivalent to CG for detecting the presence of a large anastomotic leakage that is clinically relevant for postoperative persistence of the indwelling catheter. CEUS could be a cheap and time-saving alternative to the CG without exposure of the patient to radiation.

Photodynamic diagnosis in patients with T1G3 bladder cancer: influence on recurrence rate.

INTRODUCTION: Therapeutic strategies on treatment of T1G3 urothelial cancer of the urinary bladder are controversial. The objective of this study was to investigate the impact of photodynamic diagnosis (PDD) on the recurrence-free survival rate of patients with the initial diagnosis of T1G3 bladder cancer. PATIENTS AND METHODS: Between 1995 and 2007, 153 patients were treated for T1G3 bladder cancer at our institution. In 77 patients, initial TUR-BT was performed under PDD condition at our hospital, and 76 patients underwent TUR-BT in a standard white light setting at other institutions. PDD was performed either using 5-aminolevulinate or hexaminolevulinate for induction of fluorescence. Average follow-up was 53.9 months. Fisher's exact test and Kaplan-Meier method were used to test data for significance. RESULTS: Of the 77 patients who were treated using PDD at initial TUR-BT, recurrence was observed in 23 (29.9%) cases, whereas 43 of 76 (56.6%) patients treated without PDD showed recurrence (P < 0.001). The detection rate of additional carcinoma in situ was 35.4% in the PDD group versus 21.8% in the white light group (P = 0.077). A limitation of the present study is the retrospective, monocentre setting, which is more likely to be biased. CONCLUSION: PDD during initial TUR-BT in T1G3 bladder cancer seems to reduce significantly the rate of recurrence in our study population. Therefore, PDD seems to be associated with superior initial tumour control and more effective tumour treatment even in patients with highly aggressive tumours like T1G3 bladder cancer.

Fluorescence in situ hybridisation in the diagnosis of upper urinary tract tumours.

BACKGROUND: Upper urinary tract (UUT) tumours are often a diagnostic challenge. Because of delayed diagnosis at an advanced stage, prognosis is less qualitative when compared to bladder tumours. There is, therefore, a need for reliable markers to improve diagnosis. OBJECTIVE: Because of the difficulty in interpreting washing cytologies of the UUT, we evaluated the reliability of fluorescence in situ hybridisation (FISH) in the detection of upper tract urothelial cancer. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicentre cohort study was carried out on 55 consecutive patients with a suspected UUT tumour. MEASUREMENTS: Between May 2007 and May 2009, 55 consecutive patients (mean age 71.7 yr; range: 52-93) with a suspected urinary tract tumour were studied with intravenous pyelography, cytology, washing cytology, ureterorenoscopy, and endoscopic biopsies. The patients were followed for a mean observation time of 12.21 mo (range: 0.5-20; standard deviation: 6.12). A multicolour-FISH approach was performed on a liquid-based washing urinary cytology in all cases. RESULTS AND LIMITATIONS: Twenty-one out of 55 patients had a histologically proven urothelial carcinoma, of which 10 had stage pTa disease, 6 had pT1 disease, 2 had pT2 disease, 2 had pTis disease, and 1 had pTx disease (6 G1, 6 G2, and 9 G3). Three patients had a papilloma, 2 had renal cell carcinoma, 27 had a negative histologic report, and 2 had a nondiagnostic histology. In total, 68 analyses were performed. The cytology was negative or doubtful in 60 out of a total 68 specimens (88.2%) and was suspicious or positive for malignancy in 7 (10.3%) specimens. One specimen was not diagnostic. FISH was negative in 37 of 68 analyses (54.4%) and positive in the other 30 analyses (44.1%). One FISH analysis was not diagnostic as a result of insufficient cellular material. The overall sensitivity of the cytology was 20.8% and of FISH 100%. The specificity was 97.4% for cytology and 89.5% for FISH. Even though this is the largest UUT cohort studied with FISH, the sample size is relatively small. CONCLUSIONS: The UroVysion FISH test is a reliable method in the diagnosis of UUT tumours in cases with clinical suspicion but negative or doubtful cytology and no diagnostic histology.

Urinary cytology in era of fluorescence endoscopy: redefining the role of an established method with a new reference standard.

OBJECTIVES: To assess whether the use of fluorescence endoscopy (FE) decreases the clinical value of urinary cytology compared with the use of white light endoscopy (WLE). METHODS: The endoscopic, cytologic, and histologic findings of patients who had undergone transurethral resection of the bladder with or without FE were reviewed. The number and characteristics of the tumors that had been overlooked by WLE or FE but detected by cytology were analyzed. An assessment of whether the sensitivity and specificity of urinary cytology changed according to the use of FE or WLE was conducted. RESULTS: The data from 1705 patients were included. Histologic findings were obtained from 238 patients using WLE and from 1467 patients using FE. Histologically confirmed malignancy was found in 641 patients, and the disease of 1064 was classified as benign. FE was superior to WLE in sensitivity in the detection of bladder cancer (94.3% vs 86.3%, P <.05). Cytology detected 53 of 88 tumors that were not detected by WLE (47 high-grade tumors); 31 tumors were overlooked by FE, of which 20 were detected by cytology (12 were high-grade tumors). The sensitivity and specificity of cytology was 66.0% and 78.4%, respectively. The specificity of cytology using WLE and FE was 75% and 79.1% (P >.05) and the sensitivity was 61.4% and 67.4% (P >.05), respectively. CONCLUSIONS: Although FE demonstrated a great sensitivity, cytology still has a role even when using FE, because a small group of patients with high-grade tumors were detected by urinary cytology only.

Influence of clinical information on the interpretation of urinary cytology in bladder cancer: how suggestible is a cytologist?

OBJECTIVE: to determine the influence of the knowledge of the endoscopic findings and the influence of the patient's history on the cytologist's judgement, as urinary cytology is known to be subjective and has several limitations, in particular a high inter- and intra-observer variability. PATIENTS AND METHODS: we analysed the cytological and histological findings of patients who underwent transurethral resection of a bladder tumour, and determined whether the cytologist was aware of the endoscopic findings or not. The sensitivity and specificity of cytology were calculated with or without this knowledge, and that of the patients' bladder cancer history. RESULTS: the findings of 1705 patients were reviewed; in 641 the histological examination confirmed a malignant tumour and 1046 were classified as benign. The sensitivity of cytology was 66.0% and the specificity was 78.4%. The cytologist was aware of the endoscopic finding and patient history in 742 cases, and unaware of the endoscopic findings in 963. The specificity was higher in the latter group (80.2% vs 73.0%; P= 0.006). The specificity in patients with the endoscopic findings described as 'negative', 'inflammation', 'scar tissue', 'flat lesion', 'suspicious for tumour', and 'exophytic tumour' was 89.8%, 89.9%, 85.0%, 77.1%, 63.2% and 48.6%, respectively (P < 0.001). In 898 patients the history was negative for bladder tumours. Among these patients the sensitivity and specificity of cytology was 67.3% and 79.7%; the sensitivity and specificity was 65.4% and 74.8% for the 807 patients with a positive history of bladder cancer (P= 0.054). CONCLUSION: both being aware of the endoscopic findings and a positive patient history for bladder cancer lowers the specificity of cytology. Consequently, the cytologist should be unaware of the endoscopic findings.

Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations.

CONTEXT: Compared with standard white-light cystoscopy, photodynamic diagnosis with blue light and the photosensitiser hexaminolevulinate has been shown to improve the visualisation of bladder tumours, reduce residual tumour rates by at least 20%, and improve recurrence-free survival. There is currently no overall European consensus outlining specifically where hexaminolevulinate is or is not indicated. OBJECTIVE: Our aim was to define specific indications for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). EVIDENCE ACQUISITION: A European expert panel was convened to review the evidence for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of NMIBC (identified through a PubMed MESH search) and available guidelines from across Europe. On the basis of this information and drawing on the extensive clinical experience of the panel, specific indications for the technique were then identified through discussion. EVIDENCE SYNTHESIS: The panel recommends that hexaminolevulinate-guided fluorescence cystoscopy be used to aid diagnosis at initial transurethral resection following suspicion of bladder cancer and in patients with positive urine cytology but negative white-light cystoscopy for the assessment of tumour recurrences in patients not previously assessed with hexaminolevulinate, in the initial follow-up of patients with carcinoma in situ (CIS) or multifocal tumours, and as a teaching tool. The panel does not currently recommend the use of hexaminolevulinate-guided fluorescence cystoscopy in patients for whom cystectomy is indicated or for use in the outpatient setting with flexible cystoscopy. CONCLUSIONS: Evidence is available to support the use of hexaminolevulinate-guided fluorescence cystoscopy in a range of indications, as endorsed by an expert panel.

Radical cystectomy in the elderly patient: a contemporary comparison of perioperative complications in a single institution series.

PURPOSE: To report on our recent experience with peri- and postoperative morbidity of radical cystectomy in patients 75 years and older compared to younger patients. PATIENTS AND METHODS: Medical records of 326 consecutive patients undergoing radical cystectomy from May 2004 through April 2008 were reviewed. RESULTS: Eighty-five of 326 patients (26%) were > or =75 years (75-95) old. ASA score was equal 3 or greater in 51% of patients > or =75 years and 32% of patients <75 years. Ileal conduit was performed in 83% of patients > or =75, 16% received an ileal neobladder compared to 46 and 51%, respectively, in patients <75. A total of 33 patients (39%) in the older patient group received blood transfusions intraoperatively compared to 76 patients (32%) in the younger age group. In 6 patients > or =75 years (7.1%) and 17 patients <75 (7.1%) open surgical revision was necessary, perioperative complication rate was 22 and 21%, respectively. The most common complications were wound dehiscence (5.9 vs. 7.5%), infections (4.7 vs. 4.6%), and pulmonary embolism (3.5 vs. 2.1%). Perioperative mortality was 1.2% (1 patient) in the elderly versus 0.4% (1 patient) in the younger age group. CONCLUSION: Our data show that radical cystectomy can be offered to the elderly patient with acceptable morbidity. Because of higher comorbidity rate in the elderly, therapeutic decision for radical cystectomy in elderly patients should be made carefully and individually. Nevertheless our results demonstrate that age itself is not a main criterion which has to be considered strongly in decision making for radical cystectomy.

Predicting individual outcomes after radical cystectomy: an external validation of current nomograms.

OBJECTIVE: To determine whether published nomograms, i.e. The International Bladder Cancer Nomogram Consortium (IBCNC) and the Bladder Cancer Research Consortium (BCRC) statistical models for predicting disease recurrence and survival of patients after radical cystectomy, are feasible for routine use in intermediate-volume institutions in Europe, as although these nomograms had high accuracy by internal validation tests, they stem from high-volume centres and have not been validated elsewhere and thus their general applicability remains unproven. PATIENTS AND METHODS: We externally validated the published nomograms. Information about treatments, pathological details, and recurrence and survival status was retrospectively collected from 246 patients. The expected survival according to the nomograms was calculated. The predictive accuracy of the proposed models was calculated by Harrell's concordance indices. To assess the independent prognostic value of the variables proposed by IBCNC and BCRC, stepwise multivariable Cox regressions based on Akaike's Information Criterion (AIC) for the different endpoints were used. A best model for prediction was created on the basis of our data. RESULTS: The IBCNC and the BCRC nomograms showed an improvement in the predictive accuracy of recurrence, all-cause and bladder-cancer-specific survival after radical cystectomy of up to 4% compared to Tumour-Node-Metastasis stage-based predictions. According to the calculated AIC values for the different models, all nomograms performed better than the TNM classification. CONCLUSIONS: The BCRC and IBCNC nomograms provided accurate predictions when they were applied to an external cohort of patients from low- to intermediate-volume centres. The prediction of recurrence and survival based on the addressed nomograms is better than TNM stage-based prediction. The application of such nomograms can be supported on a sound basis, but further amendments are warranted.

Hexaminolevulinate is equal to 5-aminolevulinic acid concerning residual tumor and recurrence rate following photodynamic diagnostic assisted transurethral resection of bladder tumors.

OBJECTIVES: To compare the outcomes of 5-aminolaevulinic acid (ALA) vs hexaminolaevulinate (HEX) vs white light (WL) transurethral resection of bladder tumors (TURB) to assess transferability of ALA findings to HEX. Extending WL-TURB with photodynamic diagnostic improves outcome. Two fluorescent agents have been commonly used for this. Although numerous and specific data exist on the older substance ALA, considerably less are available on hex, the only agent approved however. To date no such report has been published. METHODS: By random generator, each 200 patients with non-muscle-invasive bladder cancer having undergone TURB with WL, ALA or HEX were selected from our institutional data bank. Residual tumor in control TURB (RT) and recurrence-free survival (RFS) were assessed. RESULTS: Complete follow-up data were available on 142 WL, 139 ALA, and 135 HEX patients. Median duration of follow-up was 24 months. RT was 33% in WL, 15% in ALA, and 9% in hex, respectively. RFS at 3 years was 67% in WL, 80% in ALA, and 82% in hex, respectively. RT was significantly reduced in ALA and HEX vs WL (P < .001) and RFS prolonged (P < .01). There were no significant differences between ALA and HEX in RT and RFS, respectively (RT: P = .37; RFS: P = .72). CONCLUSIONS: In the present retrospective series, ALA and HEX were found to be significantly superior to WL. No differences between ALA and HEX were demonstrated. Even from a careful perspective both fluorescent agents seem to be comparable. Thus, ALA-based findings seem to be transferable on the approved agent HEX.

Intraoperative photodynamic evaluation of surgical margins during endoscopic extraperitoneal radical prostatectomy with the use of 5-aminolevulinic acid.

PURPOSE: Today there are no established techniques to image positive surgical margins (PSM) intraoperatively in endoscopic extraperitoneal radical prostatectomy (EERPE). The intention of this study was to describe the specific technique of photodynamic diagnosis (PDD) in patients undergoing EERPE and report on the potential to detect PSM under PDD. MATERIALS AND METHODS: Twenty-four patients with clinically organ-confined prostate cancer received 5-aminolevulinic acid 20 mg/kg body weight orally 3 hours prior to nonnerve-sparing EERPE. An endoscopic PDD system (Karl Storz, Tuttlingen, Germany) including a Tricam PDD 3-chip camera head linked with a straight 10-mm telescope and a D-light C system was used. During EERPE, visualization of the surgical margins was performed by means of both white light and PDD at specific steps during standardized prostatectomy in all patients. Positive PDD areas on the prostate specimen were marked with white ink and consequently processed in pathology. RESULTS: In white light endoscopy, no suspicion of a PSM was raised. Six out of the eight PSM were detected by PDD. In two cases, areas of positive PDD findings were free of prostate cancer and two PSM were not detected by PDD ( one bladder neck, one lateral). The overall sensitivity and specificity were 75% and 88.2%, respectively. CONCLUSIONS: Laparoscopy offers an appropriate setting for the use of PDD in prostate cancer to visualize possible PSM. Although imaging of PSM by PDD is promising with the technique being feasible and safe, larger series are needed to prove the reproducibility of our results.

Photodynamic diagnosis using 5-aminolevulinic acid for the detection of positive surgical margins during radical prostatectomy in patients with carcinoma of the prostate: a multicentre, prospective, phase 2 trial of a diagnostic procedure.

BACKGROUND: Surgical margin status after radical prostatectomy (RP) is a significant risk factor for tumour recurrence. It is an intriguing concept to find a fluorescence marker for photodynamic diagnosis (PDD) to make tumour margins visible during surgery. OBJECTIVE: To investigate the feasibility of identification of positive surgical margins (PSM) during open retropubic or endoscopic extraperitoneal RP by 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) to enhance surgical radicality. DESIGN, SETTING, AND PARTICIPANTS: Thirty-nine patients (Gleason score 6-10, prostate-specific antigen [PSA] 2.3-120 ng/ml) received 20 mg/kg of body weight of 5-ALA orally and underwent RP (24 endoscopic extraperitoneal, 15 open retropubic). MEASUREMENTS: A PDD-suitable laparoscopy optic (Karl-Storz GmbH, Tuttlingen, Germany) with a yellow long-pass filter was coupled to a fibre-optic light cord with an excitation light source (380-420 nm, D-Light, Karl-Storz GmbH, Tuttlingen, Germany) for fluorescence excitation of PpIX and to a PDD-suitable camera for video and photo documentation by the AIDA DVD system (Karl-Storz GmbH, Tuttlingen, Germany). RESULTS AND LIMITATIONS: There were more false-negative cases in the open group (four vs two) than in the endoscopic group but more false-positive cases in the endoscopic group (two vs none) than in the open group. The overall sensitivity and specificity were 56% and 91.6%, respectively. The sensitivity of the endoscopic cases was much higher (75% vs 38%) than for the open cases, while the specificity was higher for the open group (88.2% vs 100%). CONCLUSIONS: PDD with 5-ALA-induced PpIX during RP might be a feasible and effective method for reducing the rate of PSM. The technique seems to be more practicable during endoscopic RP rather than open RP. Further clinical studies with higher patient volumes and further development of the technique seem justified. TRIAL REGISTRATION: EudraCT: 2005-004406-93.