Hexaminolevulinate Fluorescence Research Articles

Efficacy of Hexaminolevulinate Photodynamic Diagnosis of Non-Muscle Invasive Bladder Cancer

Objective: This study evaluated the efficacy of hexaminolevulinate fluorescence cystoscopy as a diagnostic tool for bladder cancer. The study was a case series in the Department of Urology in Hippokratio General Hospital of Athens between October 2008 and May 2012. Methods: Fifty patients (43 males and 7 females) who were investigated for hematuria were included in the study. White light cystoscopy (WLC) was first performed in all patients and after was performed a fluorescence cystoscopy (BLC-blue light cystoscopy). Biopsies were collected from any suspicious area and resection of the tumors identified (TUR).Whenever no suspicious areas could be seen, a standard random mapping including 8 biopsies overall was completed. Results: Patients demographic data and clinical history are presented in Table 1. Two-hundred twenty specimens were extracted and bladder cancer was diagnosed in 137. There were 17 CIS lesions all diagnosed with BLC whereas only 11 with WLC. WLC correctly diagnosed 109/140 specimens and the positive and negative predictive values were 77.9% and 65% respectively. The sensitivity and specificity were 79.6% and 62.6% respectively. BLC diagnosed 125/169 specimens and the positive and negative predictive values were 73.9% and 76.5% respectively. The sensitivity of BLC was 91.2% and the specificity 46.9%. Conclusion: Hexaminolevulinate-guided cystoscopy is a valuable diagnostic method, with considerably improved accuracy and improvement in diagnosis of non-muscle-invasive bladder cancer and especially CIS.

Editorial Comment

After resection of a primary non–muscle-invasive bladder cancer (NMIBC), about two-thirds of patients will develop recurrences. Kompier 1 Kompier L.C. van der Aa M.N. Lurkin I. et al. The development of multiple bladder tumour recurrences in relation to the FGFR3 mutation status of the primary tumour. J Pathol. 2009; 218: 104-112 Crossref PubMed Scopus (47) Google Scholar followed 118 patients with NMIBC. During a median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. The 38 patients who did not develop any recurrences underwent on average 14 cystoscopies. For these patients, surveillance by cystoscopy can be considered as overtreatment. Cystoscopy is an invasive technology that is associated with anxiety and pain. 2 van der Aa M.N. Steyerberg E.W. Sen E.F. et al. Patients' perceived burden of cystoscopic and urinary surveillance of bladder cancer: a randomized comparison. BJU Int. 2008; 101: 1106-1110 Crossref PubMed Scopus (88) Google Scholar Although the gold standard, its sensitivity is estimated to be between 46% and 86% and specificity between 31% and 93%. 3 Witjes J.A. Douglass J. The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer. Nat Clin Pract Urol. 2007; 4: 542-549 Crossref PubMed Scopus (107) Google Scholar The limited sensitivity is often ignored, and this oversight is one of the reasons that urine tests have not been introduced in the clinic. We and others have demonstrated that molecular assays can detect recurrences in cells obtained from voided urine with a sensitivity that allows implementation of urine diagnostics especially for patients who are at low risk of progression and which is also cost-effective. 4 Zuiverloon T.C. Tjin S.S. Busstra M. et al. Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay. J Urol. 2011; 186: 707-712 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar , 5 Zuiverloon T.C. Beukers W. van der Keur K.A. et al. Combinations of urinary biomarkers for surveillance of patients with incident nonmuscle invasive bladder cancer: the European FP7 UROMOL project. J Urol. 2013; 189: 1945-1951 Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar , 6 van Kessel K.E. Kompier L.C. de Bekker-Grob E.W. et al. FGFR3 mutation analysis in voided urine samples to decrease cystoscopies and cost in nonmuscle invasive bladder cancer surveillance: a comparison of 3 strategies. J Urol. 2013; 189: 1676-1681 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The Diagnostic and Prognostic Performance of Urinary FGFR3 Mutation Analysis in Bladder Cancer Surveillance: A Prospective Multicenter StudyUrologyVol. 86Issue 6PreviewTo assess the diagnostic and prognostic performance of a noninvasive FGFR3 mutation analysis. After transurethral resection (TUR) of noninvasive bladder transitional cell carcinoma (B-TCC), recurrence occurs in 70% of patients, thus justifying cystoscopic surveillance. Full-Text PDF

Hexaminolevulinate hydrochloride in the detection of nonmuscle invasive cancer of the bladder.

Clinical trials have shown that hexaminolevulinate (HAL) fluorescence cystoscopy improves the detection of bladder tumors compared with standard white-light cystoscopy, resulting in more efficacious treatment. However, some recent meta-analyses report controversially on recurrence-free rates with this procedure. A systematic review of literature was performed from December 2014 to January 2015 using the PubMed, Embase and Cochrane databases for controlled trials on photodynamic diagnosis (PDD) with HAL. A total of 154 publications were found up to January 2015. Three of the authors separately reviewed the records to evaluate eligibility and methodological quality of clinical trials. A total of 16 publications were considered eligible for analysis. HAL-PDD-guided cystoscopy increased overall tumor detection rate (proportion difference 19%, 95% confidence interval [CI] 0.152-0.236) although the benefit was particularly significant in patients with carcinoma in situ (CIS) lesion (proportion difference 15.7%, 95% CI 0.069-0.245) and was reduced in papillary lesions (Ta proportion difference 5.9%, 95% CI 0.014-0.103 and T1 proportion difference 1.2%, 95% CI 0.033-0.057). Moreover, there were 15% of patients (95% CI 0.098-0.211) with at least one additional tumor seen with PDD. With regard to recurrence rates, the data sample was insufficient for a statistical analysis, although the evaluation of raw data showed a trend in favor of HAL-PDD. This meta-analysis confirms the increased tumor detection rate by HAL-PDD with a most pronounced benefit for CIS lesion.

Fluorescence cystoscopy: the end of biopsies for carcinoma in situ detection?

The present prospective study by Palou et al. 1, conducted in eight Spanish centres, documents the use of hexaminolevulinate fluorescence cystoscopy (FC)-guided bladder tumour resection and biopsies in 283 patients with non-muscle-invasive bladder cancer (NMIBC). It is an inpatient comparison between white-light cystoscopy and FC. The study presents data from routine practice in Spain and the results show an improvement in diagnosis of NMIBC, especially Ta tumours and carcinoma in situ (CIS) with FC-guided resections. These results are confirmation of reports in the literature, including a number of randomized controlled trials and a recent large meta analysis 2. Although the magnitude of the difference between FC and white-light cystoscopy was somewhat lower in the present study, apparently even in normal daily practice the difference was significant. Moreover, as the rate of CIS in Spain is very high, up to 19% in a large Spanish series 3, I can imagine that the use of FC is of specific interest in this country. Apart from the confirmation of the better detection rate (75.5 and 93.2% for white-light cystoscopy and FC, respectively, figures similar to those in the recent literature) and confirmation of safety of hexaminolevulinate FC, there are two particular points regarding the present study that I would like to highlight. The first item that deserves some discussion is mucosal biopsies. In this study the number of false-positive results (948/1569; 60.4%) was very high. This was predominantly explained by the inclusion or mucosal biopsies from ‘normal appearing urothelium’ in these calculations. Only 36 lesions were detected with biopsies, which suggests a very low detection rate. Assuming that >800 random biopsies were taken (apparently six biopsies were taken per patient, and biopsies were taken in 49.1% of the 283 patients), the detection rate was <4%, and one might ask whether it was still worthwhile to take these biopsies. Even though 26.7% of patients with CIS were only diagnosed by biopsies in this study, the number was small. The authors also indicate that it was surprising that CIS was not found more often with FC, but they blame it on the learning curve for FC. The value of mucosal biopsies was also questioned by some reviewers, and in fact by the present authors too. In their introduction they explain the biopsy policy by the high rate of CIS in Spain; however, they also indicate that this incidence seems to be decreasing. Taking together the disappointing detection rate of mucosal biopsies and the high detection rate of CIS with FC, the message should be clear: stop taking mucosal biopsies from normal-looking urothelium. As a matter of fact, this had already been suggested before the era of FC by the authors of other large studies, such as an analysis by the European Organisation for the Research and Treatment of Cancer 4 and a large Dutch study 5. The false-positive rate for FC was not very high (15.7%, similar to the more recent studies with hexaminolevulinate FC). And I assume that these figures would even be much lower if biopsies of normal urothelium were to be excluded from these calculations. The second point that deserves attention is the learning curve for FC and its impact on the results. The authors indeed mention as an important limitation of this study ‘the investigators’ lack of experience’ with FC. They point out that this might be the reason that the advantage of FC for the detection of CIS seemed to be less pronounced than in published series, although still significantly better than with white light. In their cohort, 27 of 36 patients with CIS (75%) were detected with FC. The impact of the learning curve and the limited experience of some of the centres is also illustrated by the wide range between centres in, for example, the false-positive rates. Indeed, some training with this FC technique is mandatory. Unfortunately, however, the authors were not able to provide details of the relationship between experience and detection of CIS or false-positive rates. In conclusion, even in routine practice, FC significantly improves the detection of NMIBC. The advantage is seen especially in Ta tumours and CIS, similarly to recent publications. The use of FC can, in my view, replace the use of random mucosal biopsies of normal-looking urothelium with white light because the detection rate of these biopsies is only a few percent. Finally, the present study also shows that a learning curve significantly improves the detection rate of NMIBC with FC and decreases the rate of false-positives. This should probably be somewhere between 5 (the number used in some of the registration studies for hexaminolevulinate) and 20 as suggested by a recent Canadian study 6. J.A.W. has been an investigator for Photocure and has been an advisor for and has received honoraria from Photocure and Ipsen.

Effectiveness of hexaminolevulinate fluorescence cystoscopy for the diagnosis of non-muscle-invasive bladder cancer in daily clinical practice: a Spanish multicentre observational study.

To assess the sensitivity and specificity of blue-light cystoscopy (BLC) with hexaminolevulinate as an adjunct to white-light cystoscopy (WLC) vs WLC alone for the detection of non-muscle-invasive bladder cancer (NMIBC), in routine clinical practice in Spain. An intra-patient comparative, multicentre, prospective, observational study. Adults with suspected or documented primary or recurrent NMIBC at eight Spanish centres were included in the study. All patients were examined with WLC followed by BLC with hexaminolevulinate. We evaluated the detection rate of bladder cancer lesions by WLC and BLC with hexaminolevulinate, overall and by tumour stage and compared with histological examination of the biopsied lesions. Sensitivity and specificity was calculated. In all, 1,569 lesions were identified from 283 patients: 621 were tumour lesions according to histology and 948 were false-positives. Of the 621 tumour lesions, 475 were detected by WLC (sensitivity 76.5%, 95% confidence interval [CI] 73.2-79.8) and 579 were detected by BLC (sensitivity 93.2%, 95% CI 91.0-95.1; P < 0.001). There was a significant improvement in the sensitivity in the detection of all types of NMIBC lesions with BLC compared with WLC. Of 219 patients with tumours, 188 had NMIBC [highest grade: carcinoma in situ (CIS), n = 36; Ta, n = 87; T1, n = 65). CIS lesions were identified more with BLC (n = 27) than with WLC [n = 19; sensitivity: BLC 75.0% (95% CI 57.8-87.9) vs WLC 52.8% (95% CI 35.5-69.6); P = 0.021]. Results varied across centres. This study shows that improvement in diagnosis of NMIBC, mainly CIS and Ta tumours, obtained with BLC with hexaminolevulinate as an adjunct to WLC vs WLC alone can be shown in routine clinical practice.

Would the benefits of hexaminolevulinate fluorescence cystoscopy be eliminated if every patient received postoperative installation of intravesical chemotherapy?

Would the benefits of hexaminolevulinate fluorescence cystoscopy be eliminated if every patient received postoperative installation of intravesical chemotherapy?

1771 RANDOMISED PROSPECTIVE EVALUATION OF FLUORESCENCE FOR TRANSURETHRAL RESECTION OF THE BLADDER: WHAT IS THE REAL GAIN FOR DIAGNOSIS?

You have accessJournal of UrologyBladder Cancer: Superficial (II)1 Apr 20131771 RANDOMISED PROSPECTIVE EVALUATION OF FLUORESCENCE FOR TRANSURETHRAL RESECTION OF THE BLADDER: WHAT IS THE REAL GAIN FOR DIAGNOSIS? Yann NEUZILLET, Charlotte METHORST, Marc SCHNEIDER, Mathieu ROUANNE, Thierry LEBRET, and Henry BOTTO Yann NEUZILLETYann NEUZILLET Suresnes, France More articles by this author , Charlotte METHORSTCharlotte METHORST Suresnes, France More articles by this author , Marc SCHNEIDERMarc SCHNEIDER Colmar, France More articles by this author , Mathieu ROUANNEMathieu ROUANNE Suresnes, France More articles by this author , Thierry LEBRETThierry LEBRET Suresnes, France More articles by this author , and Henry BOTTOHenry BOTTO Suresnes, France More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2861AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To evaluate the gain provided by fluorescence for diagnostic cystoscopy during transurethral resection of bladder (TURB) in patients with at least one bladder tumor diagnosed by endoscopy, a priori non-muscle invasive, and high grade urine cytology. METHODS Randomised prospective study. From November 2009 to September 2012, 151 patients were randomised in two centres for the first TURB with or without fluorescence using Hexaminolevulinate (HAL) instilled at least 1 hour before TURB. A second TURB with fluorescence was systematically programmed 6 weeks afterwards. The number of tumours detected using white (WL) and fluorescent (FL) light and their pathological features were recorded and compared between the two arms. RESULTS One hundred and thirty-three men and 18 women (11.9%) aged 74 ± 14 years had a first TURB, including 72 (47.7%) with HAL. The number of tumours visualised in WL and FL in patients with HAL was 2.66 ± 2.26 and 3.04 ± 2.54 respectively. In the 79 patients without HAL, 2.42 ± 1.72 tumours were seen in WL. Twenty-two patients and 6 patients who had a cystectomy, respectively, for a muscle-invasive tumour or a T1G3 + CIS tumour diagnosed by the first TURB, 5 patients T0, 15 patients refusing the 2nd TURB (including 5 for Ta tumours of low grade and 5 due to worsening of their general condition), 2 intercurrent deaths from cardiac causes and 8 patients lost to follow-up have not had a 2nd TURB. Ninety-three patients (62%) had a 2nd REV. The number of tumours visualised in WL and FL in 43 patients who underwent the first TURB with HAL was 2.02 ± 1.66 and 2.56 ± 2.10 respectively. For the 50 patients who had the first TURB without HAL, the number of tumours visualised in WL and FL was 1.90 ± 2.29 and 2.06 ± 2.45 respectively. CONCLUSIONS TURB with HAL fluorescence in patients with high grade urine cytology provides a gain in the number of tumours diagnosed compared to WL alone. This gain was observed during the first and 2nd with TURB with HAL. However, the differences observed in this prospective randomised study were not significant. With HAL when 1st TURB Without HAL when 1st TURB p = Age 74 ± 14 years 74 ± 14 years 0.93 women 11.1% 12.7% 0.77 Tumours (WL) 1st TURB 2.66 ± 2.26 2.42 ± 1.72 0.65 n (%) T2 diagnosed by 1st TURB 10 (14.3%) 15 (19.2%) 0.69 n (%) T2 diagnosed by 2nd TURB 1 (2.3%) 2 (4.0%) 0.54 n (%) cis diagnosed by 1st TURB 15 (21.7%) 13 (16.9%) 0.84 n (%) cis diagnosed by 2nd TURB 9 (20.9%) 14 (29.8%) 0.47 Tumours (WL) 2nd TURB 1,97 ± 1,79 2,20 ± 2,26 0.63 n (%) T0 diagnosed by 1st TURB 3 (4.6%) 5 (6.8%) 0.72 n (%) T0 diagnosed by 2nd TURB 23 (53.5%) 25 (48.0%) 0.25 © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e728 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yann NEUZILLET Suresnes, France More articles by this author Charlotte METHORST Suresnes, France More articles by this author Marc SCHNEIDER Colmar, France More articles by this author Mathieu ROUANNE Suresnes, France More articles by this author Thierry LEBRET Suresnes, France More articles by this author Henry BOTTO Suresnes, France More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Combinations of Urinary Biomarkers for Surveillance of Patients with Incident Nonmuscle Invasive Bladder Cancer: The European FP7 UROMOL Project

We determined a combination of markers with optimal sensitivity to detect recurrence in voided urine after resection of an incident low grade, nonmuscle invasive bladder tumor. A total of 136 patients with G1/G2 nonmuscle invasive bladder tumor were included in the study at transurethral resection of the incident tumor. At least 3 followup urine samples were required for patient selection. DNA was extracted from the incident tumor and cell pellets of subsequently collected urine samples. We performed FGFR3, PIK3CA and RAS mutation analysis, and microsatellite and methylation analysis on tissue and urine DNA samples. We obtained 716 urine samples. The 136 patients experienced a total of 552 recurrences during a median 3-year followup. Sensitivity for detecting a recurrent tumor varied between 66% and 68% for the molecular tests after patient stratification based on tumor DNA analysis. A combination of markers increased sensitivity but decreased the number of patients eligible for a certain test combination. Combining urine cytology with FGFR3 analysis without stratifying for FGFR3 status of the incident tumor increased sensitivity from 56% to 76%. A combination of markers increased the percentage of patients eligible for urine based followup and the sensitivity of recurrence detection. Adding FGFR3 analysis to urine cytology could be valuable for noninvasive followup of patients with nonmuscle invasive bladder cancer.

A comparison of hexaminolevulinate (Hexvix®) fluorescence cystoscopy and white-light cystoscopy for detection of bladder cancer: results of the HeRo observational study

To date, no study has presented results of photodynamic diagnosis (PDD) cystoscopy compared with white-light cystoscopy (WLC) in daily practice. The aim of the present study is to evaluate the diagnostic accuracy of hexylaminolevulinate hydrochloride (Hexvix(®)) PDD cystoscopy compared with standard WLC used in daily practice. An observational, open-label, comparative, controlled (within patient), multicenter study was carried out on 96 consecutive patients with suspected or confirmed bladder cancer. All patients had standard WLC followed by blue-light cystoscopy (BLC). Positive lesions detected using WLC and BLC were recorded. Biopsies/resection of each positive lesion were taken after the bladder was inspected. Sensitivity, specificity, positive predictive value, and negative predictive value with each method were calculated. Overall, 234 suspicious lesions were detected; 108 (46.2%) were histologically confirmed to be bladder tumors/carcinoma in situ (CIS). The sensitivity of BLC biopsies was significantly higher than for WLC technique (99.1 vs 76.8%; p < 0.00001). The relative sensitivity of BLC versus WLC was 1.289, showing superiority of BLC of 28.9%. The specificity of BLC biopsies was not significantly different compared with WLC (36.5 vs 30.2%). Positive predictive value for BLC- and WLC-guided biopsies was 54.9 and 50.9%, respectively. Negative predictive value per biopsy for BLC- and WLC-guided biopsies was 97.4 and 64.8%, respectively. BLC and WLC reached the correct diagnosis in 97.9 and 88.5% of patients, respectively. This difference was statistically significant (p = 0.0265). The lack of a random biopsy protocol was the major limitation of the study. Hexvix(®) PDD cystoscopy used in daily practice enhances the diagnostic accuracy of standard cystoscopy with higher negative predictive value, potentially permitting an improvement in patient prognosis.

Long-Term Decrease in Bladder Cancer Recurrence with Hexaminolevulinate Enabled Fluorescence Cystoscopy

We assessed the impact of hexaminolevulinate fluorescence cystoscopic detection of papillary, nonmuscle invasive bladder cancer on the long-term recurrence rate. Long-term followup was assessed in 551 participants enrolled in a prospective, randomized study of fluorescence cystoscopy for Ta or T1 urothelial bladder cancer. In the original study 280 patients in the white light cystoscopy group and 271 in the fluorescence cystoscopy group were followed with cystoscopy for 3, 6 and 9 months after initial resection or until recurrence. A study extension protocol was done for long-term followup of these patients. Followup information was obtained for 261 of the 280 patients (93%) in the white light group and 255 of the 271 (94%) in the fluorescence group. Median followup in the white light and fluorescence groups was 53.0 and 55.1 months, and 83 (31.8%) and 97 patients (38%) remained tumor free, respectively. Median time to recurrence was 9.4 months in the white light group and 16.4 months in the fluorescence group (p = 0.04). The intravesical therapy rate was similar in the 2 groups (46% and 45%, respectively). Cystectomy was done in 22 of 280 cases (7.9%) in the white light group and in 13 of the 271 (4.8%) in the fluorescence group (p = 0.16). Hexaminolevulinate fluorescence cystoscopy significantly improves long-term bladder cancer time to recurrence with a trend toward improved bladder preservation.

Early Detection of Carcinoma In Situ of the Bladder: A Comparative Study of White Light Cystoscopy, Narrow Band Imaging, 5-ALA Fluorescence Cystoscopy and 3-Dimensional Optical Coherence Tomography

We compared the efficacy and potential limitations of white light cystoscopy, narrow band imaging, 5-ALA fluorescence cystoscopy and 3-dimensional optical coherence tomography for early diagnosis of bladder carcinoma in situ. By expressing simian virus 40T antigen in the urothelium carcinoma in situ typically develops in SV40T transgenic mice in about 8 to 20 weeks and then frank high grade papillary urothelial carcinoma starts to emerge. A total of 18 control and 29 SV40T mice were examined during weeks 8 to 22 by white light cystoscopy, fluorescence cystoscopy, narrow band imaging and 3-dimensional optical coherence tomography. Results were validated by histology. Newly improved algorithms for computer aided detection were applied to acquired 3-dimensional optical coherence tomography images to enhance the quantitative diagnosis of carcinoma in situ in near real time. Of 29 carcinoma in situ samples 27 were detected by 3-dimensional optical coherence tomography, 1 by white light cystoscopy, 26 by narrow band imaging and 13 by fluorescence cystoscopy. Of the 18 histologically confirmed benign cases 17 were detected by 3-dimensional optical coherence tomography, 14 by white light cystoscopy, 5 by narrow band imaging and 18 by fluorescence cystoscopy. The diagnostic sensitivity of white light cystoscopy (3.4%) and fluorescence cystoscopy (44.8%), and the specificity of narrow band imaging (27.8%) were significantly enhanced by 3-dimensional optical coherence tomography to 93.1% and 94.4%, respectively (p <0.01). Three-dimensional optical coherence tomography with quantitative computer aided detection can significantly enhance the sensitivity of white light cystoscopy and fluorescence cystoscopy, and the specificity of narrow band imaging for early diagnosis of carcinoma in situ. This suggests the potential of narrow band imaging guided 3-dimensional optical coherence tomography for future clinical detection of carcinoma in situ when effective image guidance is desirable.

Efficacy and Safety of Hexaminolevulinate Fluorescence Cystoscopy in the Diagnosis of Bladder Cancer

PurposeThe aim of this study was to evaluate the efficacy and safety of hexaminolevulinate fluorescence cystoscopy in the diagnosis of bladder cancer.Materials and MethodsIn a prospective design, we included patients who had a bladder lesion suggesting bladder cancer. Patients with massive hematuria, urethral Foley catheter insertion, chronic retention state, or urinary tract infection were excluded. After the bladder was emptied, hexaminolevulinate was gently administered into the bladder. One hour later, cystoscopy under white light and blue light was performed. After marking the lesions confirmed with white light or blue light, transurethral resection of the bladder lesion and pathologic confirmation were done. Transurethral resection of the lesions that were negative in both white and blue light was also performed.ResultsFrom April 2010 to September 2010, 30 patients were enrolled. From the total of 30 patients (25 men and 5 women; mean age, 60.4±9.22 years), 134 specimens were extracted. Among these, 101 specimens showed positive results by blue light cystoscopy (BLC). The sensitivity of BLC and white light cystoscopy (WLC) was 92.3% and 80.8%, respectively (p=0.021). The specificity of BLC and WLC was 48% and 49.1%, respectively (p>0.05). The positive and negative predictive values of BLC were 71.2% and 81.8%, respectively, whereas those of WLC were 72.0% and 68.6%, respectively. With WLC, 48 specimens showed negative findings, but of that group, 15 specimens (31.2%) were revealed to be malignant with BLC. There were no significant side effects in the 24 hours after the instillation of hexaminolevulinate.ConclusionsPhotodynamic diagnosis with hexaminolevulinate helps to find tumors that could be missed by use of WLC only. Photodynamic diagnosis might be valuable in complete resection as well as for more accurate diagnosis of bladder tumor.

Treatment changes and long‐term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non‐muscle‐invasive bladder cancer (NMIBC)?

• To evaluate in a prospective, randomized study the impact of hexaminolevulinate blue-light cystoscopy (HAL-BLC) on the diagnostic accuracy and treatment changes in cases of non-muscle invasive bladder cancer (NMIBC) compared with standard white-light cystoscopy (WLC). • To compare the long-term recurrence rates in the two study arms. • In all, 362 patients suspected of NMIBC were included in the trial based on positive urinary cytology and/or ultrasonographic suspicion of bladder tumours and underwent transurethral resection of bladder tumours. • A single postoperative mytomicin-C instillation was performed in all cases, intravesical chemotherapy for intermediate-risk patients and BCG instillations for high-risk cases. • The follow-up protocol consisted of urinary cytology and WLC every 3 months for 2 years. • Only first-time recurrences after the initial diagnosis were considered. • In the 142 patients with NMIBC in the HAL-BLC series, tumour detection rates significantly improved for carcinoma in situ, pTa andoverall cases. • In 35.2% of the cases, additional malignant lesions were found by HAL-BLC and consequently, the recurrence- and progression-risk categories of patients and subsequent treatment improved in 19% of the cases due to fluorescence cystoscopy. • In all, 125 patients in the HAL-BLC group and 114 of the WLC group completed the follow-up. • The recurrence rate at 3 months was lower in the HAL-BLC series (7.2% vs 15.8%) due to fewer 'other site' recurrences when compared with the WLC series (0.8% vs 6.1%). • The 1 and 2 years recurrence rates were significantly decreased in the HAL-BLC group compared with the WLC group (21.6% vs 32.5% and 31.2% vs 45.6%, respectively). • HAL-BLC was better than WLC for detecting NMIBC cases and improved tumour detection rates. • HAL-BLC significantly modified the postoperative treatment of cases. • The 3 months, 1 and 2 years recurrence rates were significantly improved in the HAL-BLC arm.

Fluorescence and white light cystoscopy for detection of carcinoma in situ of the urinary bladder

ObjectivesTo understand the additional benefits of HAL compared with conventional cystoscopy at the patient level and to explore relationships of urine cytology and CIS. MethodsWe reanalyzed pooled data from 3 phase III studies comparing hexaminolevulinate (HAL, Hexvix) fluorescence cystoscopy with white light (WL) cystoscopy for detecting CIS. ResultsOf 551 patients, 174 had at least one CIS lesion detected by HAL, WL, or random biopsy. The CIS detection rate of HAL was 0.87 vs. 0.75 for WL (P = 0.006). By multivariate Poisson regression, female patients had fewer CIS lesions (P < 0.0001) while older patients (≥65) had a higher number of CIS lesions detected by HAL (P = 0.04). HAL was less likely to detect CIS in patients previously treated with chemotherapy or BCG (P = 0.01 and 0.03, respectively), after adjusting for age. CIS was unifocal in 44% and multifocal in 56%. Multifocal CIS was associated with positive cytology more frequently than unifocal (65% vs. 45%; P = 0.016) whereas a negative cytology was more frequently associated with unifocal CIS. Patients with positive urine cytology had twice as many CIS lesions detected by HAL as patients with negative urine cytology (P = 0.02). ConclusionsHAL cystoscopy had a higher CIS detection rate than WL cystoscopy. The average number of CIS lesions detected was associated with baseline clinical characteristics. Cytology was positive more frequently in multifocal CIS suggesting that HAL may be particularly useful in this setting to optimize detection of the extent of CIS.

Early detection of urothelial premalignant lesions using hexaminolevulinate fluorescence cystoscopy in high risk patients

BackgroundTo evaluate fluorescence cystoscopy with hexaminolevulinate (HAL) in the early detection of dysplasia (DYS) and carcinoma in situ (CIS) in select high risk patients.MethodsWe selected 30 consecutive bladder cancer patients at high risk for progression. After endoscopic resection, all patients received (a) induction BCG schedule when needed, and (b) white light and fluorescence cystoscopy after 3 months. HAL at doses of 85 mg (GE Healthcare, Buckinghamshire, United Kingdom) dissolved in 50 ml of solvent to obtain an 8 mmol/L solution was instilled intravesically with a 12 Fr catheter into an empty bladder and left for 90 minutes. The solution was freshly prepared immediately before instillation. Cystoscopy was performed within 120 minutes of bladder emptying. Standard and fluorescence cystoscopy was performed using a double light system (Combilight PDD light source 5133, Wolf, Germany) which allowed an inspection under both white and blue light.ResultsThe overall incidence was 43.3% dysplasia, 23.3% CIS, and 13.3% superficial transitional cell cancer. In 21 patients, HAL cystoscopy was positive with one or more fluorescent flat lesions. Of the positive cases, there were 4 CIS, 10 DYS, 2 association of CIS and DYS, 4 well-differentiated non-infiltrating bladder cancers, and 1 chronic cystitis. In 9 patients with negative HAL results, random biopsies showed 1 CIS and 1 DYS. HAL cystoscopy showed 90.1% sensitivity and 87.5% specificity with 95.2% positive predictive value and 77.8% negative predictive value.ConclusionPhotodynamic diagnosis should be considered a very important tool in the diagnosis of potentially evolving flat lesions on the bladder mucosa such as DYS and CIS. Moreover, detection of dysplasic lesions that are considered precursors of CIS may play an important role in preventing disease progression. In our opinion, HAL cystoscopy should be recommended in the early follow-up of high risk patients.

Fluorescence Cystoscopy with High-Resolution Optical Coherence Tomography Imaging as an Adjunct Reduces False-Positive Findings in the Diagnosis of Urothelial Carcinoma of the Bladder

BackgroundThe advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure. ObjectiveTo evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC. Design, setting, and participantsIn this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning. InterventionSuspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied. MeasurementsWe measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT. Results and limitationsIn 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure. ConclusionsCombining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies.

Hexaminolevulinate Fluorescence Cystoscopy and Transurethral Resection of the Bladder in Noninvasive Bladder Tumors

We compared hexaminolevulinate (HAL) blue light cystoscopy (BLC) with standard white light cystoscopy (WLC) in the diagnosis of noninvasive bladder tumors (NIBT) and analyzed the efficiency of blue light transurethral resection of the bladder (BL-TURB). WLC and BLC were performed in 64 cases. BL-TURB was applied for lesions that were detected only by BLC. Patients who received a diagnosis of NIBT were followed up after 18 weeks by WLC and BLC. The control group included the same number of consecutive patients with NIBT, diagnosed only by WLC and treated by WL-TURB. WLC correctly diagnosed 66.4%, with a 9.7% rate of false-positive results, while BLC diagnosed 95.7%, but had a 13.5% rate of false-positive results. The study group had a recurrence rate of 5.3% vs 23.2% in the control group. HAL fluorescence cystoscopy is a valuable diagnostic method, with considerably improved accuracy. BL-TURB represents a superior treatment modality, with significant impact on the recurrence rate.

Experiencia inicial en el diagnóstico y tratamiento del tumor vesical superficial con Hexvix®

White light cystoscopy is the current standard for the diagnosis of bladder cancer and monitorization for recurrence. Recent studies suggest that porphyrin based fluorescence cystoscopy may improve endoscopic detection of bladder tumors. We aimed to evaluate the improvement that hexaminolevulinate fluorescence cystoscopy could lead in bladder cancer detection and treatment at one single centre. Between September 2006 and September 2007 a total of 39 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate (HAL) for 1 hour. The bladder was inspected using white light cystoscopy (WLC), followed by blue light (fluorescence) cystoscopy (BLC). Papillary and suspicious lesions were resected for histological examination. Mean age was 70.1 years (50-86). Thirty patients were male (76.9%) and 9 female (23.1%). The tumor characteristics were: 18% primary tumors, 51% recurrences and 30% control cystoscopies. 24 patients had previously received some treatment (9 MMC and 15 BCG). Only 7 patients had previous positive urine cytology. All papillary lesions visualized with WLC were confirmed by BLC (18 patients). From these, 17 have positive biopsies (6 pTaG1, 9 pT1G1-3, 1 pT2, 1 CIS). In 15 patients (38.4%) we found at least 1 lesion more with BLC. In this group 8 cases (20.5%) had positive histological diagnosis (3 pTaG1, 2 pT1G3, 3 CIS). In five patients (13%) post-TUR therapeutic management has changed by using BLC (BCG vs MMC). All four patients with CIS were diagnosed by BLC. There was no evidence of local or systemic side effects due to HAL in the postoperative time. Our results suggest there is an improvement in the diagnosis of papillary and flat lesions in bladder cancer by using HAL fluorescence cystoscopy. This has changed the management in the postoperative period (MMC vs BCG) in 13% of the patients. Obviously, we need more patients to assess our data and long-term follow-up to analyze the impact in terms of tumor recurrence and progression.

The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer

Non-muscle-invasive bladder cancer is labor intensive and costly to manage. Owing to long-term survival rates and life-long monitoring and treatment, it is the most expensive cancer to manage in per-patient terms. Significant costs are attributable to the treatment of recurrences and complications. Fluorescence-guided cystoscopy, using 5-aminolevulinic acid (ALA) or its hexyl ester, hexaminolevulinate 5-ALA (Hexvix [HAL], Photocure, Oslo, Norway), improves the detection of bladder tumors, particularly carcinoma in situ, compared with standard white-light cystoscopy. The quality of transurethral resection of the bladder tumor is also improved. It has been shown that improved tumor detection leads to better patient management and, in the case of ALA, reduced long-term recurrence rates and costs. Long-term studies in this area with HAL are ongoing. The technique is well tolerated and is a useful adjunct to white-light cystoscopy.

A Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Carcinoma In Situ in Patients With Bladder Cancer: A Phase III, Multicenter Study

We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p=0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer.