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.     

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

Background

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.

Methods

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.

Results

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.

Conclusions

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.     

Photodynamic Diagnosis in Non-Muscle-Invasive Bladder Cancer

ObjectiveThis paper reviews the development and clinical validation of photodynamic diagnosis (PDD) of bladder cancer.MethodsThe authors reviewed the literature on the development of PDD, in particular the evidence for the clinical efficacy of hexaminolevulinate PDD in the diagnosis of bladder cancer.ResultsAfter initial work on ultraviolet cystoscopy following oral tetracycline, the focus of PDD research shifted to the use of synthetic porphyrins. First, the prodrug delta-aminolevulinic acid (ALA) was shown to cause a transient but significant accumulation of protoporphyrin IX (PpIX) in malignant or premalignant bladder tissue. Excitation by blue light leads to PpIX fluorescence (red), which distinguishes tumour from normal tissue (blue). Hexaminolevulinate (HAL, Hexvix), an ester of ALA, was then developed and has greater bioavailability and stability than the parent compound. It has been approved for clinical use in the diagnosis of bladder cancer. Clinical studies have shown that HAL PDD detects tumours, including carcinoma in situ (CIS), that are missed by conventional white-light cystoscopy.ConclusionsHAL PDD is a valuable aid to the detection of bladder tumours, including CIS.     

Value of Fluorescence Cystoscopy in High Risk Non-muscle Invasive Bladder Cancer

Photodynamic Diagnosis (PDD), an adjunct to white light cystoscopy, has been shown to improve detection and thoroughness of resection of bladder cancer by enhancing visualisation of malign lesions during transurethral resection of bladder tumours (TURBT) compared to the sole use of standard white light cystoscopy. The PDD also has been shown to improve recurrence of free survival in non-muscle invasive bladder cancer. Little data on its impact on outcome in non-muscle invasive bladder cancer of high risk of progression is available however. The few trials and studies available demonstrate improved accuracy of diagnosis especially of flat malign lesions. In addition, improved recurrence rates have been suggested without an impact on progression rates in early invasive bladder cancer indicating little influence of thoroughness of resection on the tumour biology in those tumour stages. While no specific and larger data on impact of PDD on cancer specific survival exist to date and the few long-term data suggest little impact, improved accuracy of diagnosis is suggested to be beneficial for clinical decision making and thus a value of PDD is postulated in the management of high-risk non-muscle invasive bladder cancer.     

Photodynamic Diagnosis in Non–Muscle-Invasive Bladder Cancer: A Systematic Review and Cumulative Analysis of Prospective Studies

Context

The clinical benefit of photodynamic diagnosis (PDD) with 5-aminolevulinic acid or hexaminolevulinate in addition to white-light cystoscopy (WLC) in bladder cancer has been discussed controversially.

Objective

To assess in a systematic review the effect of PDD in addition to WLC on (1) the diagnosis and (2) the therapeutic outcome of primary or recurrent non–muscle-invasive bladder cancer investigated by cystoscopy or transurethral resection.

Evidence acquisition

An electronic database search of Medline, Embase, the Cochrane Library, and CancerLit was undertaken, plus hand searching of relevant congress abstracts and urologic journals. Trials were included if they prospectively compared WLC with PDD in bladder cancer. The review process followed the guidelines of the Cochrane Collaboration. Two reviewers evaluated independently both trial eligibility and methodological quality and data extraction.

Evidence synthesis

The primary end point of diagnostic accuracy was additional detection rate. The primary end points of therapeutic outcome were residual tumour at second resection and recurrence-free survival (RFS). Seventeen trials were identified. Twelve diagnostic trials used WLC and PDD with the same patients. Seven reported results for the subgroup of patients with carcinoma in situ (CIS). Five randomised trials studied therapeutic outcome. The results were combined in random effects meta-analyses if end points, designs, and populations were comparable. Twenty percent (95% confidence interval [CI], 8–35) more tumour-positive patients were detected with PDD in all patients with non–muscle-invasive tumours and 39% (CI, 23–57) more when only CIS was analysed. Heterogeneity was present among diagnostic studies even when the subgroup of patients with CIS was investigated. Residual tumour was significantly less often found after PDD (odds ratio: 0.28; 95% CI, 0.15–0.52; p < 0.0001). RFS was higher at 12 and 24 mo in the PDD groups than in the WLC-only groups. The combined p value of log-rank tests of RFS was statistically significant (0.00002).

Conclusions

PDD detects more bladder tumour–positive patients, especially more with CIS, than WLC. More patients have a complete resection and a longer RFS when diagnosed with PDD.     

Photodynamic Diagnosis in Non–Muscle-Invasive Bladder Cancer

ContextAlthough crucial to optimal management, transurethral resection of the bladder (TURB) techniques and results are highly heterogeneous in Europe, due in part to site-specific variations in the detection of cancer foci.Optimizing detection is of tantamount importance. Techniques were designed that took advantage of the ubiquitous observation that cancer cells exhibit abnormal heme metabolism resulting in increased intracellular concentrations of protoporphyrin IX (PPIX) after topical or systemic application of heme precursors. In the bladder, the excitation of PPIX by blue light (380–450 nm) induced a faint red (640-nm) fluorescence of cancer cells that gave rise to the concept of photodynamic diagnosis (PDD) in non–muscle-invasive bladder cancer (NMIBC).Evidence acquisitionThis paper is based on a presentation at the 2010 meeting of the European Society of Oncological Urology. A structured comprehensive literature review was performed. The latest version of the European Association of Urology (EAU) guidelines on NMIBC was also accessed.Evidence synthesisCurrent diagnosis of NMIBC is based on white light (WL) cystoscopy. The current literature on NMIBC suggests that there is significant room for improvement in that setting. One solution was to augment the signal-to-noise ratio of suspicious lesions versus normal mucosa by highlighting cancer cells either indirectly, through the alteration in their stromal support such as in narrow-band imaging, or directly, as in Hexvix-based PDD. Hexvix is now available in most European countries and use is steadily increasing.Recent evidence at the molecular level has confirmed clinicians’ suspicions that NMIBC is a very heterogeneous condition. Sylvester et al identified six independent risk factors (number of tumors, tumor size, prior recurrence rate, T category, carcinoma in situ [CIS], and grade), the combination of which was predictive of progression to muscle-invasive state and of recurrence. As recommended by the EAU guidelines, these factors are used to stratify patients into risk groups that drive treatment and follow-up modalities.In the setting of low-risk NMIBC, three objectives can be addressed by Hexvix PDD—detection, quality control of resection, confirmation of the absence of CIS—with the ultimate objective of reducing the recurrence rate and related costs. Hexvix PDD increases the rate of detection of NMIBC by 20%. It is a valuable tool in controlling the quality of resection at the end of TURB and was recently shown to reduce the recurrence rate at 9 mo by 21%, which is anticipated to offset the supplementary costs for equipment and Hexvix within the first year of follow-up.Regarding high-risk NMIBC, Hexvix PDD facilitates the detection of CIS and might improve treatment results by reallocating the case to a higher level of risk, requesting more intensive treatment (eg, bacillus Calmette-Guérin), and by improving the quality of resection. Mixed results were observed in control resection, where Hexvix PDD can be used to detect additional lesions such as associated CIS when the first TURB was conducted under WL.Five endoscopic criteria (smooth of slightly raised appearance, intensity [mild or intense], homogeneous or irregular fluorescence, well-delineated or indistinct limits, detachment of the fluorescent mucosa by the loop) were prospectively recorded to assess their respective value in detecting CIS among the wide array of flat PDD-positive lesions. We showed that a slightly raised appearance and detachment of fluorescence by gentle stroking with the loop were associated with the diagnostic of CIS. This new semiology could refine the level of suspicion of PDD-positive flat lesions to reduce the number of false-positive results.ConclusionsIn low-risk NMIBC, Hexvix PDD helps to avoid overlooking small preexisting papillary lesions and to optimize resection. It was recently shown to reduce 9-mo recurrence rates by 20%, which is anticipated to be sufficient to offset the supplementary costs in equipment and drugs. In high-risk NMIBC, Hexvix PDD can be of value in restaging TURB to detect additional lesions such as associated CIS when the first TURB was conducted under WL. Finally, the high rate of false-positive results for flat PDD-positive lesions can be controlled by implementing simple semiotic analysis and focusing on CIS-associated characters such as slightly raised appearance and detachment of fluorescence by gentle stroking with the loop (pink veil sign).     

Hexaminolevulinate-guided transurethral resection of non-muscle-invasive bladder cancer does not reduce the recurrence rates after a 2-year follow-up: a prospective randomized trial

Purpose

To assess the impact of hexaminolevulinate (HAL) on the long-term recurrence rate of NMIBC.

Methods

A total of 130 patients with bladder tumour were randomized into two groups. The patients in one group had a HAL instillation before surgery, and they first had a white-light and after that a blue-light cystoscopy (BL group) and resection. The second group had only white-light cystoscopy (WL group) and resection. They have been followed up with cystoscopy every 3 months for a period of up to 40 months.

Results

The recurrence-free period was not significantly different between the two groups (BL and WL groups) (long-rank test p = 0.202). The use of HAL helped detect four flat lesions and 28 papillary lesions with cancer that would have been missed under WL only, on 16 out of the 54 patients (29.6 % CI 95 % 11.1–33.3). The use of HAL changed the proposed postoperative treatment and follow-up for one out of the five patients.

Conclusions

Although the use of HAL cystoscopy identified at least one cancer lesion more than WL cystoscopy on one out of the three patients, the recurrence-free period was not significantly different.     

Urothelial carcinoma in situ response to cisplatin-based neoadjuvant chemotherapy,or lack thereof: Impact on patient selection for organ preservation in muscle-invasive disease?

IntroductionNeoadjuvant cisplatin-based chemotherapy (NACT) followed by radical cystectomy improves urothelial bladder cancer survival [1]. Complete pathological response on cystectomy pathology (pT0N0) is associated with the best survival outcomes [2]. Rates of complete response have increased with improved adoption of NACT calling into question the need for radical cystectomy or perhaps use of organ preservation protocols. In patients with papillary bladder tumors, carcinoma in situ (CIS) has been shown to influence progression and develop into invasive urothelial carcinoma [3]. Furthermore, in patients with invasive urothelial carcinoma, concurrent CIS has been reported in roughly 45% to 65% of cases [4]. Thus, we sought to determine the response rate of CIS to NACT to determine if the presence of CIS should factor into excluding patients from organ preservation.MethodsA review of our prospectively maintained bladder cancer database was performed among patients undergoing preoperative cisplatin-based chemotherapy followed by cystectomy between 2007 and 2017. Presence of CIS before and after radical cystectomy was assessed. Random bladder biopsies or transurethral resection (TUR) with enhanced imaging for CIS (Cysview) were not routinely utilized in the preoperative setting.ResultsOne-hundred eighty-three patients were identified that underwent preoperative cisplatin chemotherapy. A total of 96 (52.4%) unique patients had documented CIS in the entire cohort. Forty-eight (50%) patients were noted to have CIS on TUR. Of these 48 patients, 26 (54.1%) were noted to have residual CIS on final pathology. An additional 48 patients were found to have CIS on final pathology that was not diagnosed on TUR, making a total of 74 (77.1%) patients with CIS refractory to NACT on cystectomy pathology.ConclusionsCIS seems to respond poorly to cisplatin-based neoadjuvant chemotherapy. If organ preservation protocols are considered, a thorough assessment for CIS with enhanced photodynamic detection cystoscopy or random bladder biopsies should be considered. Residual cisplatin-refractory disease, even if noninvasive CIS, may lead to poor outcomes. Future molecular classifiers may assist in disease signatures to help guide treatment protocols.     

Transurethral Resection of Non–Muscle-Invasive Bladder Transitional Cell Cancers With or Without 5-Aminolevulinic Acid Under Visible and Fluorescent Light: Results of a Prospective,Randomised, Multicentre Study

Background

Fluorescent light (FL)–guided cystoscopy induced by 5-aminolevulinic acid (5-ALA) has been reported to detect more tumours compared with standard white-light (WL) cystoscopy. Most reports are from single centres with relatively few patients.

Objective

To evaluate whether 5-ALA–induced FL and WL cystoscopy at transurethral resection (TUR) is superior compared with standard procedures under WL only with respect to tumour recurrence and progression in patients with non–muscle-invasive bladder cancer.

Design, setting, and participants

This randomised, multicentre, observer- and pathologist-blinded, prospective phase 3 clinical trial enrolled 300 patients, and of those patients, 153 were randomised to FL cystoscopy and 147 were randomised to standard WL cystoscopy.

Intervention

All patients were first inspected under WL and all lesions were recorded. Patients randomised to FL underwent a second inspection. TUR was carried out in both groups.

Measurements

Control cystoscopy under WL was performed in all patients every 3 mo during the first year after randomisation and biannually thereafter.

Results and limitations

At the first TUR, the mean number of resection specimens per patient was 2.5 (FL: 2.5; WL: 2.4; p = 0.37) and the resulting mean number of resected tumours was 1.7 with FL and 1.8 with WL (p = 0.85). More patients were diagnosed with carcinoma in situ (CIS) in the WL group (13%) than in the FL group (4.2%). Within-patient comparison of FL patients only showed that FL detected more lesions than WL. Tumour lesions solely detected by FL cystoscopy that would not otherwise be detected by WL cystoscopy included 52% dysplasia, 33% CIS, 18% papillary neoplasms, 13% pT1, and 7% pTa. Outcome at 12 mo did not show any difference between groups with regard to recurrence-free and progression-free survival rates.

Conclusions

In this prospective, randomised, multi-institutional study, we found no clinical advantage of FL cystoscopy compared with WL cystoscopy and TUR.     

Early recurrence of non-muscle invasive bladder cancer as a clinical marker of a poor prognosis and cancer-specific survival

ObjectiveTo determine whether early recurrence of non-muscle invasive bladder cancer confers prognostic value with respect to bladder cancer-specific survival.Patients and methodsFollowing local ethics committee approval, all patients that underwent TURBT for a bladder tumour within the Oxford Radcliffe Trust between 1997 and 2007 were entered into the local Cancer Research Uro-Oncology Database (CRUD^©). The rate of positive histological recurrence of non-muscle invasive bladder cancer at first cystoscopy (<4 months) following the index TURBT was calculated and the cancer-specific survival calculated using data from the National Cancer Intelligence Network.ResultsMedian positive early recurrence of (NMIBC) non-muscle invasive bladder cancer was 18.9% for the period of 1997 to 2007 (mean 20.3%; range 13.9–28.3%). Positive early recurrence was associated with significantly worse survival, with 5-year cancer specific survival falling from 82.3% (first cystoscopy negative) to 69.4%, (first cystoscopy positive), Log Rank p = 0.02.ConclusionsOur results suggest that if histological recurrence is present at first cystoscopy then the patient is more likely to die from bladder cancer, with 5-year cancer specific mortality of 18% if first cystoscopy clear, compared to 31% if histological recurrence (relative risk 1.7). With the growing demand for surgical outcome measures, our study suggests that ‘positive recurrence at first cystoscopy’ is both simple to measure and a valid predictor of patient outcome.     

Assessment of diagnostic gain with hexaminolevulinate (HAL) in the setting of newly diagnosed non–muscle-invasive bladder cancer with positive results on urine cytology

ObjectiveIn accordance with the European Association of Urology guidelines, a second transurethral resection of the bladder (TURB) is recommended for high-grade or T1-category tumors. This practice brings into question the benefit of photodynamic diagnosis (PDD) in reducing the residual disease after TURB in patients with positive results on urine cytology showing high-grade cancer cells.Methods and materialsA prospective, bicentric, randomized study comparing white light cystoscopy (WLC)+PDD with hexaminolevulinate arm with WLC alone (control arm) during the first TURB in patients with primary non–muscle-invasive bladder cancer and with positive results on urine cytology showing high-grade cancer cells. Patients underwent a first TURB with WLC and PDD or WLC alone, and then a second TURB with WLC and PDD, after 4 to 6 weeks. The number of tumors visualized in WLC and PDD and histology of the TURB specimen was recorded to perform a statistical analysis comparing both the 2 arms.ResultsA total of 151 patients were enrolled (hexaminolevulinate, n = 72; control, n = 79). The number of visualized tumors did not increase with PDD in the first or second TURB. During the second TURB, the residual tumor rate was not reduced in patients who had PDD during the first TURB. No significant difference was observed regarding the pattern of category and grade, the size, and the recurrence and progression risks during either the first or the second TURB.ConclusionsIn the setting of primary non–muscle-invasive bladder cancer with positive results on urine cytology, performing a second TURB allows to diagnose residual tumor in approximately half of the cases. This rate was not significantly reduced by the use of the PDD during the first TURB.     

Promises and challenges of fluorescence cystoscopy

IntroductionFluorescence based photodynamic diagnostic (PDD) techniques have been developed to improve detection and treatment of non-muscle invasive bladder cancer. The goal of this article is to evaluate the promises and challenges of blue light cystoscopy.MethodsThe literature was reviewed regarding articles pertaining to fluorescent cystoscopy and blue light cystoscopy (BLC).ResultsBlue light cystoscopy improves detection of bladder cancer tumors especially CIS. Randomized trials have demonstrated a reduction of recurrences. BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The main obstacle to BLC will be adoption by urologists. Purchase cost of capital equipment may impact usage especially if adopted for outpatient clinics.ConclusionsBLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The reduction of recurrences and yet unproven but potential reduction in progression should be viewed favorably by urologists and patients. The main obstacle to BLC will be adoption by urologists who can put pressure on hospitals to acquire the capital equipment and who will seek the training to become proficient in using the technology. Patient demand for the technology may also help increase availability. Finally, the companies involved with BLC need to support trials that will demonstrate reduction in progression and that will answer the practical issues regarding usage in proximity to BCG and repeated usage.     

Phase II multi-center trial of optical coherence tomography as an adjunct to white light cystoscopy for intravesical real time imaging and staging of bladder cancer

BackgroundOptical coherence tomography (OCT) is a novel imaging modality that provides microstructural information of different tissue layers using near-infrared light. This prospective, multicenter phase II trial aimed to assess the accuracy of OCT-assisted cystoscopy for bladder tumor staging.MethodsPatients with primary or recurrent bladder tumors (Ta,T1) identified by outpatient cystoscopy were included. The primary objective was to assess the accuracy and positive predictive value of for determining tumor stage ≥T1 correlated by histopathology. 72 suspicious lesions from 63 patients were eligible to analyze in the study. All suspected lesions were evaluated with conventional cystoscopy, interpreted in real-time using OCT, and then resected. All results were compared to pathology. A total of 363 OCT images of tumor and normal mucosa in 25 patients were obtained to evaluate diagnostic efficacy of the computer-aided texture analysis algorithm.ResultsSensitivity and specificity for predicting invasive tumors (≥ T1, n = 17) were 58.8% and 92.7% for cystoscopy, 64.7% and 100% for OCT-assisted cystoscopy, respectively. Accuracy of cystoscopy and OCT-assisted cystoscopy for predicting invasive tumor was 84.7% and 91.7% (P = 0.063), respectively. Cystoscopy and OCT-assisted cystoscopy correctly predicted T stage in 52/72 and 59/72 cases, respectively (P = 0.016). Cystoscopy missed 2 more invasive tumors than OCT-assisted cystoscopy. Cystoscopy (14.3%, 1/7) and OCT-assisted cystoscopy (28.6%, 2/7) showed relatively low sensitivity in detecting muscle invasion. Computer aided texture analysis demonstrated 75.1% sensitivity, 64.0% specificity, and 74.4% accuracy for differentiating tumor and normal urothelium.ConclusionOCT-assisted cystoscopy is a real time noninvasive and simple procedure that enhanced the accuracy of staging bladder tumors and prediction of any tumor invasion. Though the study did not meet the prespecified primary endpoint, OCT imaging is a promising adjunct to cystoscopy that may supplement intraoperative decision-making during transurethral resection of bladder tumors and additional prospective studies are warranted.     

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

PURPOSE: We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

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.     

The bladder epicheck test and cytology in the follow-up of patients with non-muscle-invasive high grade bladder carcinoma.

BackgroundThe management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection of a bladder tumor consists of adjuvant intravesical therapy and strict and long surveillance with urine cytology and cystoscopy. The Bladder EpiCheck test (Nucleix Ltd) (BE) is a newly developed urinary markers based on DNA methylation changes in a panel of 15 genomic biomarkers, with a promising performance in term of non-invasive NMIBC detection.MethodsIn this study we prospectively enrolled 151 consecutive patients with high grade NMIBC, treated with intravesical BCG and mitomycin C therapy and evaluated during the follow-up by voided urine cytology and white-light cystoscopy, according to the European Association of Urology Guidelines. The Bladder EpiCheck test was performed at the same time of urine cytology in voided specimen. In all cases with positive cytology the diagnosis was confirmed by histology and a diagnosis was made according to the 2017 tumor, node, metastasis (TNM) classification and graded using both the 1973 and the 2004 World Health Organization (WHO) classifications.ResultsAt three months of follow-up, we reported similar overall specificity rates for BE and urine cytology (85,1% vs 86,3%). In the group of patients with carcinoma in situ (CIS), we found the same specificity for BE and urine cytology (81,4%), while in the groups of patients with papillary high grade NMIBC, the specificity of BE was higher compared to cytology (96,3% vs 90,4%). The sensitivity of BE was always higher compared to cytology during all the follow-up both for papillary NMIBC and CIS.ConclusionIn the early follow-up of NMIBC the EpiCheck test might replace urinary cytology.     

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

Background

The 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.

Objective

To 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 participants

In 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.

Intervention

Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied.

Measurements

We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT.

Results and limitations

In 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.

Conclusions

Combining 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.     

Comparison of the bladder tumour antigen test with photodynamic diagnosis in patients with pathologically confirmed recurrent superficial urinary bladder tumours

OBJECTIVE: To verify the sensitivity of the bladder tumour antigen (BTAstat, Bard Urological, Covington, GA) test against the sensitive procedure of photodynamic diagnosis (PDD), in which 5-aminolaevulinic acid (5-ALA, a precursor of fluorescent porphyrins) is absorbed by the tumour and detected by ultraviolet cystoscopy, in the early diagnosis of urinary bladder tumours. PATIENTS AND METHODS: Forty-three patients (31 men and 12 women, age range 21-87 years) were assessed after transurethral resection of their bladder tumour using the BTAstat test and PDD. Sixty-nine biopsies from suspect areas of bladder mucosa were taken during cystoscopy under ultraviolet light and all suspect lesions electrocoagulated. RESULTS: Thirty-five patients (81%) had a positive BTAstat test; in these patients PDD detected malignant lesions (17 Ta1G1-2, two T1G2, two T1G3 and 14 Tis). In eight patients (19%) the BTAstat was negative but PDD detected three malignant lesions (two Tis and one TaG1). CONCLUSIONS: PDD is valuable for detecting bladder malignancy and can identify small lesions not detected by the BTAstat test.     

Evaluating the need for transurethral bladder biopsy at first follow up after intravesical BCG therapy for superficial bladder cancer: Preliminary data

IntroductionPatients with high-risk superficial transitional cell carcinoma (TCC) of the bladder have a lifelong risk of progression and require particular attention. Intravesical Bacillus Calmette-Guerin (BCG) is recommended as a first-choice adjuvant treatment to reduce the risk of progression of high-grade tumors and carcinoma in situ (CIS).ObjectivesTo evaluate the need for routine transurethral bladder biopsy from the site of previously resected tumor three months following intravesical BCG therapy, even if the urine cytology and cystoscopy were both negative.Subjects and methodsA prospective study was carried out on 45 patients of both genders presenting with superficial bladder cancer. All patients received a six-week course of intravesical BCG. The mean age of the patients was 59 (range 33–80) years. Three months following resection, urine cytology was negative in all patients. Cystoscopy was then performed and although it was negative for any suspicious lesions, a routine biopsy from the previous resection site was taken.ResultsThe indication for BCG instillation was T1G1 in 20 patients (44%), T1G2 in 12 patients (27%) and TaG2 in eight patients (18%). Three patients (7%) had a positive bladder biopsy for malignancy at follow-up despite the negative cystoscopy and cytology. There were no statistically significant differences between patients with positive and those with negative biopsies with regard to the stage and grade of the tumor before resection or the number of resected lesions. The original pathology of the three positive patients was T1G1 (two patients) and T1G2 (one patient). The pathology after BCG treatment was the same as before instillation, T1G1 (two patients) and T1G2 (one patient).ConclusionUntil more studies on larger numbers of patients are done, a routine biopsy from the site of previously resected tumor at the time of check cystoscopy may improve the detection of tumor recurrence.     

Long-term efficacy of hyperthermic intravesical chemotherapy for BCG-unresponsive non-muscle invasive bladder cancer

BackgroundThe recommended treatment for patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy (RC). However, many patients refuse, or are unfit for RC. Therefore, alternative bladder-sparing treatment modalities are needed for BCG-unresponsive NMIBC. In this study we sought to assess the long-term efficacy of hyperthermic intravesical chemotherapy (HIVEC) as alternative to radical cystectomy in BCG-unresponsive non-muscle invasive bladder cancer patients.Methods and materialsRetrospectively collected data from 56 patients with BCG-unresponsive NMIBC who received ≥5 HIVEC instillations between October 2014 and March 2020 was analyzed. All patients met the BCG-unresponsive criteria according to the current EAU guideline on NMIBC 2020. Patients were followed-up with cystoscopy and/or bladder biopsies, urine cytology and annually CT-urography. The Primary outcome was the high grade (HG) recurrence-free survival (RFS), defined as the time from the first HIVEC instillation until histologically confirmed intravesical recurrence or last follow-up. The Kaplan Meier method was used to estimate survival outcomes. Secondary outcomes were: complete response rate (CR), adverse events (AE), assessed by the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) and tumor progression to muscle invasive disease or distant metastases.ResultsThe median follow-up was 32.2 months (IQR 13.7–44.8). The 1- and 2-year HG-RFS was 53% (SE:6.8) and 35% (SE:6.9), respectively. The CR for patients with CIS was 70% (21/30) at 6 months. Overall, 80% of the population developed an AE, only 1 was classified as CTCAE ≥3. Limitation of this study was the small sample size.ConclusionHIVEC resulted in a 2-year HG-RFS of 35% for BCG-unresponsive NMIBC patients without severe side-effects and therefore HIVEC seems to be an alternative treatment option for patients who refuse or are unfit for RC.