Collaborative Review – Bladder Cancer

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

By: Michael Rinka lowast , Marko Babjukb, James W.F. Cattoc, Patrice Jichlinskid, Shahrokh F. Shariate, Arnulf Stenzlf, Herbert Steppg, Dirk Zaakh and J. Alfred Witjesi

European Urology, Volume 64 Issue 4, October 2013, Pages 624-638

Published online: 01 October 2013

Keywords: Non–muscle-invasive bladder cancer, Photodynamic diagnosis, Hexyl aminolevulinate, Tumour detection, Recurrence-free survival, Cost effectiveness, Urothelial cancer

Abstract Full Text Full Text PDF (703 KB)



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).


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.


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.

Take Home Message

Photodynamic diagnosis is a significant tool for improving tumour detection rates, particularly carcinoma in situ, and completeness of tumour resection during white-light cystoscopy/transurethral resection of bladder tumour for non–muscle-invasive bladder cancer treatment. Translation to reduced disease recurrence rates is confirmed by most but not all randomised controlled studies. Cost effectiveness needs to be proven.

Keywords: Non–muscle-invasive bladder cancer, Photodynamic diagnosis, Hexyl aminolevulinate, Tumour detection, Recurrence-free survival, Cost effectiveness, Urothelial cancer.

1. Introduction

Bladder cancer (BCa) is one of the most common cancers in the Western world, with an estimated 133 696 new cases each year in Europe [1]. Around three-quarters of patients present with non–muscle-invasive BCa (NMIBC) [2]. The natural history and treatment of this disease are highly variable. For example, whilst most patients with NMIBC develop intravesical recurrence (up to 70%) within 5 yr of initial treatment, in a minority, the disease progresses to muscle invasion (up to 20%) and metastases [3] and [4]. This risk of disease recurrence or progression means that most patients undergo prolonged bladder surveillance (cystoscopy) following initial diagnosis and treatment. Such surveillance, when combined with the use intravesical therapy, cytologic or molecular urinary tests, and the low mortality rate from NMIBC, makes NMIBC one of the most expensive human malignancies to manage [5].

Despite a better understanding of the disease's biology and the use of intravesical therapies, the outcomes from NMIBC have not improved over the past decades [6]. This outcome may be the result of many factors, including the misdiagnoses of BCa (false-negative investigations) or an inadequate transurethral resection of the bladder tumour (TURBT) leading to residual untreated disease or missed coexisting carcinoma in situ (CIS) when performed with white-light cystoscopy (WLC) [7]. Methods to improve these factors would improve the outcomes from NMIBC treatment and should be cost effective for both the patient and the health care provider [8].

The introduction of photosensitising drugs allowing photodynamic diagnosis (PDD) during cystoscopy and TURBT appeared to be the beginning of a new era in NMIBC diagnosis and treatment. PDD enhances the visual contrast between benign and malignant tissue by selective accumulation of red-fluorescent porphyrins, mainly protoporphyrin IX (PpIX), in cancerous cells [9]. Two drugs have been used to diagnose BCa: 5-aminolevulinic acid (5-ALA) and its derivate, hexyl aminolevulinate (HAL; Hexvix, Photocure, Oslo Norway). As these drugs are prodrugs, they lack of photoactivity themselves. After transportation into the urothelial cell, they are incorporated in the conventional cellular haemobiosynthesis metabolism. In BCa cells and precancerous tissue, altered enzyme activities lead to a significant accumulation of PpIX [10]. When the bladder wall is illuminated by blue light (<380–440 nm), the PpIX in malignant tissue emits red fluorescence (<635 nm) in contrast to normal or benign urothelial tissue (which appears blue-green) [11]. The different appearances of malignant and normal tissues can be visualised in real time during diagnostic cystoscopy or TURBT [9].

PDD offered improved tumour detection, reduced residual tumour rates (after TURBT), and prolonged recurrence-free survival (RFS) [12], [13], [14], and [15]. In particular, PDD-guided detection of CIS appeared superior to WLC alone (given that CIS in the presence of papillary disease is associated with a high risk of tumour progression, and the failure of CIS eradiation may worsen prognosis) [16]. However, recent prospective, randomised studies have challenged the benefits of PDD. In particular, these have not found that higher NMIBC detection rates affect RFS or progression-free survival (PFS) [17] and [18].

The aim of this review is to summarise current therapeutic and economic data regarding PDD use in NMIBC management and to identify areas of research that are needed.

2. Evidence acquisition

2.1. Search strategy

A systematic PubMed/Medline, Embase, and Cochrane Library search was conducted in October 2012. The complete free-text search terms and the search strategy are attached as supplementary material (Appendix). The only limit applied for searches was a publication date of 1 January 1974 or later. Cited references from selected studies were also retrieved.

2.2. Inclusion criteria

All authors participated in the design of the search strategy and inclusion criteria. Our procedure for evaluating records identified during the literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria (Fig. 1) [19]. Search results were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) [20] and Standards for the Reporting of Diagnostic Accuracy (STARD) [21] criteria to assess the articles with the highest level of evidence (LoE). The final list of included articles was selected with the consensus of all collaborating authors, verifying that they met the inclusion criteria.


Fig. 1

Flow diagram of evidence acquisition in a systematic review on hexyl aminolevulinate–guided fluorescence cystoscopy in the diagnosis and treatment of patients with non–muscle-invasive bladder cancer.

2.3. Study eligibility

We defined study eligibility using the patient population, intervention, comparator, outcome, and study design approach [19]. A study was considered relevant to this review if it assessed the following: a patient cohort treated for NMIBC (P); a cohort treated with transurethral rigid or flexible cystoscopy or TURBT (I) using WLC as the gold standard compared to PDD with either 5-ALA or its derivate, HAL (C); and outcomes including tumour detection (papillary tumours, CIS, or dysplastic lesions), residual tumour detection, disease recurrence, disease progression, and adverse events (O). All study designs were accepted except for case reports (S). We limited these criteria to studies published in the English language, original studies, and meta-analyses. Review articles, meeting abstracts, editorials, and commentaries were excluded. In addition, studies with ≤10 participants were not accepted for inclusion. If multiple studies reporting on the same or overlapping series met our inclusion criteria, the latest study was selected, unless different end points were investigated or different subgroup analyses were performed.

3. Evidence synthesis

Our search identified 396 manuscripts (24 October 2012). Of these, 44 original articles were selected for inclusion [12], [13], [14], [15], [16], [17], [18], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], and [58] (Fig. 1 and Table 1). The primary outcomes were tumour detection rate (n = 32), residual (post-TURBT) tumour rate (n = 10), change in treatment pattern (n = 5), RFS rate (n = 13), and time to disease recurrence (n = 4). PFS was a secondary end point in six reports. Of note, five publications were secondary reports of previously published studies, including three from the same study [32]. In addition, three meta-analyses were identified and included in this systematic review [7], [59], and [60].

Table 1

Descriptive baseline characteristics of selected original publications identified by systematic literature review

StudyYearOriginal trialStudy typeNo. of patients under analysisUni-/ multicentre study (no. of institutions)Study end pointsStudy particularitiesProdrug (5-ALA, HAL)Age, meanMale gender
Geavlete et al. [36]2012Prospective, randomised362181181UnicentreDetection rate, residual tumour rate, RFS, PFSHAL66.8267
Grossman et al. [39]2012Stenzl et al. [54]
Prospective, randomised516255261Multicentre (28)RFS, time to recurrenceHAL
Hermann et al. [40]2011Prospective, comparative randomised1456877Multicentre (2)Residual tumour rate, RFSHAL71693:1
Stenzl et al. [18]2011Prospective, randomised, double-blind, placebo-controlled359183176Multicentre (8)Detection rate, RFS, PFS5-ALA66259
Geavlete et al. [35]2010Prospective, randomised446223223UnicentreResidual tumour rateHAL64327
Ray et al. [51]2010Prospective, in-patient. comparison423210UnicentreDetection rate, treatment regimen changeAfter BCG treatmentHAL63.5219
Schumacher et al. [17]2010Prospective, randomised300153147Multicentre (5)Detection rate, RFS, PFS5-ALA7069103104
Stenzl et al. [56]2010Prospective, randomised551271280Multicentre (28)Detection rate, RFSHAL68.069.6212223
Burger et al. [23]2009Retrospective4195-ALA: 139142UnicentreResidual tumour rate, RFSComparison of HAL and 5-ALA5-ALA plus HAL68719993
HAL: 1456991
Ray et al. [52]2009Prospective, in-patient. comparison23UnicentreDetection rateUnconfirmed positive cytologyHAL6420
Ray et al. [53]2009Prospective, in-patient comparison18UnicentreDetection rate, treatment regimen changeMultifocal, recurrent NMIBCHAL7411
Denzinger et al. [29]2008Filbeck et al. [30]
Retrospective462125UnicentreResidual tumour rate, RFS, PFST1 tumours5-ALA69711519
Karl et al. [45]2008Retrospective348UnicentreDetection ratePositive cytology and negative WLC5-ALA plus HAL63.5252
Burger et al. [24]2007Filbeck et al. [30]
Prospective, randomised19188103UnicentreRFS, cost analysis5-ALA68706578
Colombo et al. [25]2007Prospective, in-patient comparison49UnicentreDetection rateOnly CIS5-ALA plus HAL68.5
Denzinger et al. [28]2007Filbeck et al. [30]
Retrospective19188103UnicentreResidual tumour rate, RFSLong-term results5-ALA68706568
Fradet et al. [16]2007Prospective, in-patient comparison196Multicentre (18)Detection rate, treatment regimen changeOnly CISHAL67148
Grossman et al. [38]2007Prospective, in-patient comparison196Multicentre (18)Detection rateHAL67148
Hungerhuber et al. [41]2007Retrospective875Multicentre (2)Detection rateLong-term results5-ALA65.3671
Babjuk et al. [22]2005Prospective, randomised1226062UnicentreRFS, time to recurrence5-ALA67.969.84339
Daniltchenko et al. [12]2005Riedl et al. [10]
Prospective, randomised1025151Multicentre (2)RFS, PFS, time to recurrence5-ALA70673736
Jocham et al. [44]2005Prospective, in-patient comparison146Multicentre (7)Detection rate, treatment regimen changeHAL67107
Loidl et al. [50]2005Prospective, in-patient comparison45UnicentreDetection rateComparison of rigid and flexible PDDHAL6834
Witjes et al. [57]2005Prospective, in-patient comparison20UnicentreDetection rateComparison of rigid and flexible PDDHAL7117
Schmidbauer et al. [55]2004Prospective, in-patient comparison211Multicentre (19)Detection rateCIS detection rateHAL70169
Grimbergen et al. [37]2003Prospective, in-patient comparison160UnicentreDetection rateAfter intravesical therapy5-ALA67
Jichlinski et al. [43]2003Prospective, in-patient comparison52Multicentre (4)Detection rateHAL7238
Filbeck et al. [31]2002Prospective, in-patient comparison279UnicentreDetection rate, treatment regimen change5-ALARange: 34–89
Filbeck et al. [32]2002Prospective, randomised19188103UnicentreResidual tumour rate, RFS5-ALA6870
Kriegmair et al. [49]2002Prospective, randomised1015249Multicentre (8)Residual tumour rate5-ALA70.170.74136
Zaak et al. [58]2002Prospective, in-patient comparison713Multicentre (5)Detection rateCIS and dysplasia5-ALA
De Dominicis et al. [27]2001Prospective, in-patient comparison49UnicentreDetection rate5-ALA6042
Ehsan et al. [30]2001Prospective, in-patient comparison30UnicentreDetection rate5-ALARange: 55–8919
Jeon et al. [42]2001Prospective, in-patient comparison62UnicentreDetection rate5-ALA
Riedl et al. [14]2001Prospective, randomised1025151Multicentre (2)Residual tumour rate, time to recurrence5-ALA70673736
Zaak et al. [15]2001Prospective, in-patient comparison605UnicentreDetection rate5-ALA65.6472
Filbeck et al. [33]1999Prospective, in-patient comparison120UnicentreDetection rate5-ALA64.5
Filbeck et al. [34]1999Prospective, in-patient comparison50UnicentreResidual tumour rate5-ALA63.436
Koenig et al. [46]1999Prospective, in-patient comparison55UnicentreDetection rate5-ALA6644
Kriegmair et al. [13]1999Prospective, in-patient comparison208UnicentreDetection rate5-ALA64.8170
Riedl et al. [54]1999Prospective, in-patient Comparison52UnicentreDetection rate5-ALARange: 44–79
D’Hallewin et al. [26]1998Prospective, in-patient Comparison16UnicentreDetection rate5-ALA
Kriegmair et al. [47]1996Prospective, in-patient comparison104UnicentreDetection rate5-ALA6880
Kriegmair et al. [48]1994Prospective, in-patient comparison68UnicentreDetection rate5-ALA66.251

5-ALA = 5-aminolevulinate acid; HAL = hexyl aminolevulinate; PDD = photodynamic diagnostic; WLC = white-light cystoscopy; RFS = recurrence-free survival; PFS = progression-free survival; BCG = bacillus Calmette-Guérin; NMIBC = non–muscle-invasive bladder cancer; CIS = carcinoma in situ.

3.1. Comparison of 5-aminolevulinic acid and hexyl aminolevulinate

The agent 5-ALA was initially developed for PDD and has therefore been evaluated in more studies than HAL, but HAL is the only drug with worldwide approval for PDD and has better pharmacology than 5-ALA (including a higher local bioavailability, better stability, exceeded fluorescence intensity, and more homogeneous PpIX enhancement and distribution) [61] and [62]. Independent prospective studies have demonstrated comparable sensitivities and specificities for 5-ALA and HAL [18], [37], [43], [44], and [55], and one retrospective study found no difference between 5-ALA and HAL in direct comparison [23]. A meta-analysis compared photosensitising agents (5-ALA in 18, HAL in five, and both in two reports) and found similar sensitivity and specificity rates for patients (5-ALA vs HAL: sensitivity 96% vs 90% and specificity 56% vs 80%, respectively) and biopsies (5-ALA vs HAL: sensitivity 95% vs 85% and specificity 57% vs 80%, respectively) [59]. As consensus exists that 5-ALA and HAL are transferable [8], we included studies using either drug in this review.

3.2. Tumour detection rates

Numerous prospective randomised studies have showed the superiority of PDD-guided cystoscopy over WLC alone in tumour detection (Table 2) [16], [31], [36], [37], [38], [43], [44], [55], [56], and [58]. Sensitivity for PDD ranges from 76% to 97% compared with 46–80% for WLC. A random effects meta-analysis using 900 patients from eight studies found a 20% (95% confidence interval [CI], 0.08–0.35) increase in tumour detection with PDD over WLC [7]. These findings were supported by a further meta-analysis of 2807 patients from 27 studies that identified higher sensitivity for PDD over WLC in the pooled estimates for patients (PDD vs WLC: 92% [95% CI, 0.80–1.00] vs 71% [95% CI, 0.49–0.93], respectively) and biopsies (PDD vs WLC: 93% [95% CI, 0.90–0.96] vs 81% [95% CI, 0.73–0.90], respectively) [59].

Table 2

Comparison of tumour detection rates between photodynamic diagnostic and white-light cystoscopy in selected prospective studies from the past 10 yr in patients with non–muscle-invasive bladder cancer

StudyYearProdrugOverall detection rate, %Detection rate pTa tumours, %Detection rate pT1 tumours, %Detection rate CIS %Detection rate dysplasia, %Tumours solely detected by PDD, %
Geavlete et al. [36] (n = 362)2012HAL9280928193899463All: 21
pTa: 17
pT1: 25
CIS: 33
Stenzl et al. [18] (n = 359)20115-ALAG1: 9684G1: 50501006510067pTa: 17
G2: 9181G2: 8696pT1: 11
G3: 100100G3: 10087CIS: 35
Dysplasia: 56
Stenzl et al. [56] (n = 551)2010HALpTa: 16
pT1: 13
CIS: 46
Schumacher et al. [17] (n = 300)20105-ALApTa: 7
pT1: 13
CIS: 33
Dysplasia: 52
Grossman et al. [38] (n = 108)2007HAL95839586pTa: 29
pT1: 0
Fradet et al. [16] (n = 58)2007HAL9268CIS: 16
Jocham et al. [44] (n = 146)2005HAL96779685969695689348All: 18
pTa: 12
pT1: 0
CIS: 34
Dysplasia: 41
Schmidbauer et al. [55] (n = 211)2004HAL97789788968897589453CIS: 28
Jichlinski et al. [43] (n = 52)2003HAL7646495All: 23
CIS: 69
Grimbergen [37] (n = 160)20035-ALA9769All: 24
pTa: 27
CIS: 76
Filbeck et al. [31] (n = 279)20025-ALApTaG1–2:
pTaG3: 0
pT1G2: 7
pT1G3: 12
CIS: 57
Dysplasia: 44
Zaak et al. [58] (n = 713)20025-ALA91.247.280.669.7CIS: 53
Dysplasia: 30

CIS = carcinoma in situ; PDD = photodynamic diagnostic; WLC = white-light cystoscopy; HAL = hexyl aminolevulinate; 5-ALA = 5-aminolevulinate acid

In contrast, two recent prospective randomised studies using 5-ALA did not find higher tumour detection rates with PDD compared to WLC [17] and [18], but intrapatient comparison of PDD with WLC in patients randomised to receive 5-ALA showed a higher tumour detection rate with fluorescent light than with WLC in both studies. Furthermore, a recent meta-analysis (of 2952 patients from nine studies) found similar tumour detection rates for PDD-guided cystoscopy (91.8%) and WLC alone (90.9%) [60], but this analysis has been criticised for the use of multiple reports from the same series, as the findings contrast with other meta-analyses using similar data.

3.2.1. Detection of papillary tumours (Ta/T1 tumours)

Detection rates for NMIBC tumours using PDD-guided cystoscopy range from 92% to 100% (pTa) and 93% to 100% (pT1), in contrast with those reported for WLC alone (81–100% [pTa] and 50–96% [pT1]; Table 2). Thus, PDD detects between 8.6% and 29% (pTa) and 7% and 25% (pT1) more tumours than WLC alone. There are no consistent data suggesting that detection rates vary for PDD and WLC with tumour grade. Several prospective studies have focused on patients with multiple papillary tumours and found PDD to be especially beneficial for these bladders [33], [36], [38], and [53]. The majority of studies included patients with primary and recurrent NMIBC. Only one study analysed the impact of PDD in patients with multiple, recurrent tumours [53]: It found a sensitivity of 97.8% (83% papillary lesions) for PDD-guided tumour detection, compared with 69.6% for WLC alone. Most evidence suggests that PDD-guided cystoscopy improves the detection of papillary NMIBC, and this improvement is greater in patients with multifocal disease.

3.2.2. Detection of flat lesions and carcinoma in situ

Several studies have proved the benefit of PDD in the detection of flat lesions, particularly CIS [16], [17], [18], [31], [36], [37], [43], [44], [55], [56], and [58]. CIS detection rates using PDD-guided cystoscopy range from 49% to 100%, while detection rates of 5–68% are reported for WLC alone (Table 2). The detection rates of CIS (Fig. 2), which were solely detected using the PDD approach and therefore would have been missed during WLC alone, range from 16% to 76%. Overall, the detection rate for CIS is approximately 25–30% higher under PDD guidance compared with WLC alone [14], [16], [36], [44], [49], [55], and [56]. Thus, PDD offers a clear advantage in CIS detection at the time of primary diagnosis, but in patients with multiple, small, and scattered lesions, a few additional CIS lesions might be missed during PDD cystoscopy. The meta-analysis by Kausch et al. found a random effect estimate of 39% (95% CI, 0.23–0.57) [7], and the meta-analysis of Mowatt et al. found a pooled sensitivity estimate advantage for PDD of 51% per patient-based detection and 36% per biopsy-based detection [59]. The meta-analysis by Shen et al. found a trend in relative risk (RR) reduction of 18% (RR: 0.82; 95% CI, 0.67–1.02; p = 0.07) [60]. Ultimately, PDD significantly improves the detection of CIS.


Fig. 2

Image showing (a) an inconspicuous left ureteral orifice in white-light cystoscopy, and (b) two spots of carcinoma in situ that were detected by hexyl aminolevulinate fluorescence cystoscopy. Reproduced with permission from Elsevier [15].

3.2.3. Detection of dysplastic lesions and tumours in patients with positive urinary cytology and negative white-light cystoscopy

Positive voided urinary cytology has a high sensitivity for high-grade urothelial carcinoma and can indicate a tumour in the upper or lower urinary tract [2]. WLC is considered the diagnostic gold standard in patients with positive urinary cytology. The combination of positive urinary cytology and negative WLC remains a clinical problem, especially because flat urothelial lesions without thickening of the epithelium, such as CIS, dysplasia, or small papillary tumours, are sometimes barely visible during WLC or TURBT [15]. PDD-guided cystoscopy enables superior detection of dysplastic lesions compared with WLC alone (detection rates: PDD: 80.6–100% vs WLC: 48–69.7%; Table 2) [18], [44], [55], and [58] (difference ranges from 30% to 56% [17], [18], [31], [44], and [58]). One prospective [52] and one retrospective study [45] investigated the effectiveness of PDD in patients with positive cytology and negative WLC. Both studies found that PDD detected additional malignant and premalignant lesions. Ray et al. reported additional pathologies in 32% of these patients solely detected by PDD [52], but it is important to note that in none of these studies were random biopsies of normal-appearing mucosa taken using either light source. The study design therefore was suboptimal for evaluating the true value of PDD, because guidelines recommend performance of random biopsies in patients with positive urinary cytology in the absence of visible bladder tumour [2]. PDD may help in the detection of premalignant lesions, but prospective randomised studies in which the comparison arm includes WLC with random bladder biopsies are needed to confirm these findings.

3.2.4. The impact of rigid and flexible cystoscopy

Two prospective studies have analysed the effectiveness of flexible PDD-guided cystoscopy compared with rigid PDD-guided cystoscopy and WLC alone [50] and [57]. Both found that flexible PDD cystoscopy outperformed WLC in tumour detection but was not as effective as rigid PDD cystoscopy (Table 2). A recent study found that flexible PDD-guided cystoscopy with bladder biopsy in an outpatient setting was reliable for the diagnosis of Ta, CIS, and T1a BCa but not as convenient as rigid cystoscopy [63]. Thus, rigid PDD cystoscopy is likely to remain the technique of choice until further improvements appear [8].

3.2.5. The impact on residual tumour

PDD-guided TURBT facilitates a more complete tumour resection, as suggested by a plethora of randomised studies, with re-resection intervals ranging from 10 d to 6 wk [14], [23], [28], [29], [32], [34], [35], and [49]. Comparative residual tumour rates ranged from 4.5% to 32.7% for PDD groups to 25.2% to 53.1% for WLC groups (average of 20% lower with PDD [14], [28], [29], [32], [35], and [49]). Improvements in residual tumour rates were present for both pTa [14], [32], and [35] and pT1 tumours [14], [29], and [35]. Although the majority of studies performed re-resection using WLC, Riedl et al. [14] used PDD-guided re-resection and found results comparable to other reports. All meta-analyses have found significantly reduced residual tumour rates with PDD [7], [59], and [60]. The odds ratio of residual tumour with PDD is 0.28 (95% CI, 0.15–0.52) compared to WLC [7], and the RR of residual tumour is 2.77-fold higher (95% CI, 1.47–5.02; p = 0.002) with WLC compared [60]. There is strong (level 1) evidence that PDD reduces the rate of residual tumour.

3.3. The impact on disease recurrence

3.3.1. Recurrence-free survival rates

The results of the 13 prospective randomised studies reporting on RFS rates are summarised in Table 3. The majority of studies reported RFS rates between 3 and 24 mo [12], [17], [18], [22], [23], [28], [32], [36], [40], and [56]. Five studies reported long-term RFS rates >48 mo (range: 48–96) [12], [24], [28], [29], and [39]. Eight studies found significantly fewer recurrences at any time point of analysis with PDD compared to WLC [12], [22], [23], [28], [32], [36], [40], and [56]. Recurrence-free rates at 12 and 24 mo were 10.9–27% and 13–24% higher with PDD than WLC. It is noteworthy that some studies found extended RFS rates after 7–8 yr [24], [28], and [29]. Patients with multifocal or recurrent tumours seem to benefit most from PDD-guided TURBT [22], [32], [36], and [56].

Table 3

Comparison of recurrence-free survival rates, time to disease recurrence, and progression-free survival rates between photodynamic diagnostic and white-light cystoscopy in selected prospective studies from the past 10 yr in patients with non–muscle-invasive bladder cancer

StudyYearProdrugInterval since resectionRFS, %PFS*, %Time to recurrence, mo
Grossman [39] (n = 516)2012HALMedian follow-up:38**32**16.49.4
PDD: 55 mo
WLC: 53 mo
Geavlete et al. [36] (n = 362)2012HAL3 mo92.884.2
12 mo78.467.597.6**95.6**
24 mo68.254.496.0**93.0**
Hermann et al. [40] (n = 145)2011HAL4 mo83.168.9
12 mo69.552.7
Stenzl et al. [18] (n = 359)20115-ALA12 mo68.9**74.4**89.4**89.9**
Stenzl et al. [56] (n = 551)2010HAL9 mo5344
Schumacher et al. [17] (n = 300)20105-ALA12 mo55.1**55.9**91.1**89.1**
Burger et al. [23] (n = 419)20095ALA12 mo9478
24 mo8771
36 mo8067
HAL12 mo92
24 mo84
36 mo82
Denzinger et al. [29] (n = 46)20085-ALA48 mo9169
96 mo805281**88**
Denzinger et al. [28] (n = 301)20075-ALA24 mo8873
48 mo8464
72 mo7954
96 mo7145
Burger et al. [24] (n = 101)20075-ALA85 mo714598**98**
Daniltchenko et al. [12] (n = 102)20055-ALA2 mo8459Overall: 92Overall: 82125
12 mo5739
36 mo4127
60 mo4125
Babjuk et al. [22] (n = 122)20055-ALA10–15 wk926817.058.05
12 mo6639
24 mo4028
Filbeck et al. [32] (n = 191)20025-ALA12 mo9074
24 mo9066

* Disease progression was defined as progression to muscle-invasive disease.

** No statistical significant difference between the PDD and WLC arms.

RFS = recurrence-free survival; PFS = progression-free survival; PDD = photodynamic diagnostic; WLC = white-light cystoscopy; HAL = hexyl aminolevulinate; 5-ALA = 5-aminolevulinate acid.

In contrast, three studies did not find a statistically significant difference in recurrence rates with PDD and WLC [17], [18], and [39]. However, two studies reported only short-term outcomes (at 9–12 mo) [17] and [18], but in the third, the median follow-up was 55 mo (PDD) and 53 mo (WLC) [39]. In one study, the recurrence rate with WLC was lower than for PDD (68.9% vs 74.4%), but this did not reach significance [18]. The difference in these findings (compared with other reports) may be the result of patient heterogeneity (proportion of patients with recurrent tumours [17]), high rates of low-grade disease [17] and low rates of CIS [18], differences in adjuvant intravesical therapy use, a more meticulous WLC within a randomised controlled trial (RCT) [18], or the underpowering of studies [39]. Furthermore, all three studies were relatively recent, and WLC practice within these studies may not reflect general practice outside of large teaching centres or RCTs [18].

Some authors analysed outcomes according to NMIBC risk group, with contrasting findings. Two reports observed durable long-term reductions in disease recurrence rates for intermediate- and high-risk NMIBC patients with PDD compared with WLC [28] and [32], whilst two other studies with short-term follow-up did not confirm these findings [17] and [18].

Only one meta-analysis analysed data for RFS at 3 mo (n = 291) and 12 mo (n = 1658) [60]. The authors found a nonsignificant (14%) reduction in the RR of recurrence with PDD-guided TURBT versus WLC (RR: 0.86; 95% CI, 0.70–1.06; p = 0.16). These results should be interpreted with care, as they are opposite to the findings by three separate studies at 12 mo [12], [22], and [23].

Administration of adjuvant intravesical chemotherapy or immunotherapy may reduce the risk of disease recurrence and progression and is recommended for patients with intermediate- and high-risk NMIBC [2] and [64], but the impact of PDD on the true natural history of BCa recurrence is difficult to assess, because no study sufficiently adjusted for the effects of intravesical therapy use. Only three studies [12], [14], and [49] reported patients without administration of adjuvant intravesical therapy, and in only one of these was RFS included [12]. In this report, patients received adjuvant intravesical therapy for repeated recurrences (which was not defined precisely), and PDD-guided TURBT significantly reduced disease recurrence rates (by an average of 18%) for up to 60 mo [12].

Although evidence exists that PDD reduces NMIBC recurrence, the true benefit needs to be better evaluated in studies adjusting for intravesical therapy use.

3.3.2. Time to recurrence

Four prospective, randomised studies analysed the length of the disease-free interval, of which one study re-reported previously published results [12], [14], [22], and [39]. In all studies, patients treated using PDD had significantly longer recurrence-free intervals (median: 7–9 mo) than for WLC.

3.4. The impact of disease progression on muscle-invasive bladder cancer

Six prospective studies analysed the impact of PDD on PFS (Table 3) [12], [17], [18], [24], [28], and [36], but none used time to disease progression. Only one study found a difference in PFS for PDD-guided TURBT compared with WLC. In this report, patients treated with PDD-guided TURBT had an overall increase in PFS (defined as the onset of muscle invasion or metastatic disease) compared with WLC TURBT (92% vs 82%, respectively) [12]. Of note, other studies have defined progression as invasion of the detrusor muscle [18], [24], [28], and [36], progression to a higher T stage, and/or presence of CIS [17]. The impact of PDD on disease progression remains unknown. In light of the ongoing discussion on the reduction of the progression rate by bacillus Calmette-Guérin (BCG), the most effective intravesical treatment, this lack of proof for a diagnostic tool is not surprising.

3.5. Limitations of the technique

The main limitation of PDD is the false-positive detection rate, which ranges from 1% to 26% (Table 4). There has been a reduction in this false-positive rate over time, as experience of PDD has increased and technology has improved. High false-positive rates are found with a recent TURBT, the use of BCG, and urinary tract infection [8]. These may lead to mucosal inflammation and possible scarring and consequently to an enhanced red illumination of the bladder wall under blue light. To mitigate this effect, it has been suggested that physicians defer PDD administration for 3–4 mo after TURBT or BCG instillation. Doing so may not be necessary in patients receiving a single BCG instillation within 4 mo and those receiving mitomycin C [8] and [65]. Ray et al. looked at BCG timing and false-positive rates and found that a 6-wk delay was sufficient [51]. Of note, there is little information regarding the false-positive rates for WLC.

Table 4

Overview of false-positive detection rates between photodynamic diagnostic and white-light cystoscopy in selected prospective studies from the past 10 yr

StudyYearProdrugFalse-positive rate, %
Jichlinski et al. [43]2003HAL217
Grimbergen et al. [37]20035-ALA2611
Schmidbauer et al. [55]2004HAL1310
Jocham et al. [44]2005HAL3726
Loidl et al. [50]2005HALFlexible: 139
Rigid: 119
Witjes et al. [57]2005HALFlexible: 1515
Rigid: 20
Fradet et al. [16]2007HAL3931
Grossman [38]2007HAL3931
Colombo et al. [25]2007HAL/5-ALA337
Burger et al. [23]2009HAL2917
Ray et al. [52]2009HAL6050
Ray et al. [53]2009HAL293
Stenzl et al. [56]2010HAL1211
Ray et al. [51]2010HAL6372
Hermann et al. [40]2011HAL2516

PDD = photodynamic diagnostic; WLC = white-light cystoscopy; HAL = hexyl aminolevulinate; 5-ALA = 5-aminolevulinate acid.

Results for false-negative PDD findings must be interpreted with caution, because the majority of studies did not perform random biopsies in every patient. Therefore, most “false-negative” findings were not completely missed by PDD but were identified during WLC. In addition, there was no consistent way of reporting this rate. For example, missed lesions may be reported per patient or per biopsy. The rates for lesions that PDD missed ranged from 1% to 11% [15], [34], [38], [43], [46], and [54]. Reported rates per patient were usually higher than per biopsy (mainly because of small patient numbers).

Finally, technical aspects may influence the results of PDD. HAL typically needs to be administered approximately 60 min prior to intervention. Patients with severe urge symptoms may pass out the drug earlier, and thus uptake into the mucosa would be reduced. Specific technical equipment is needed, and light cables, cystoscopes, and cameras might be mixed with standard components, which can cause erroneous findings. Moreover, correct maintenance of the equipment is essential for the quality of the information [9]. Available testing equipment can help reduce these technical limitations. Because TURBT is more challenging under blue light, several surgeons perform TURBT under white light and use PDD only for detection of residual tumour tissue or additional lesions. Of note, PpIX stability is dependent of the wavelength and intensity of light used during surgery, and its elimination (“photobleaching”) is accelerated during WLC. Therefore, tumours may be overlooked if TURBT under white light is of long duration (eg, large or multiple tumours, inexperienced surgeon).

The limitations of PDD are minor. The increased false-positive detection rates have decreased over time and with increasing experience. The generation of a complete bladder map in white light and PDD might reduce erroneous findings.

3.6. Safety

HAL and 5-ALA are safe and well tolerated. The overall adverse event rate in studies analysing PDD ranged from 22.5% to 80.5%, with only 0–2.4% of these events related to the drug [16], [17], [18], [38], [43], [49], and [56]. In general, most events were side-effects associated with standard cystoscopy and TURBT. There was no difference in the rates of adverse events between PDD-guided cystoscopy and WLC alone in different randomised studies [18], [38], and [56]. No phototoxicity was reported in any study. Adverse events potentially related to drug instillations are penile infection and pain, gross haematuria, bladder pain and spasm, and urinary frequency, without any of those having a proven relationship to the drug instillation. Anaphylactic reactions may become an issue because of repeated drug exposure during follow-up cystoscopies or further TURBTs, but to the authors’ knowledge, only one drug-associated allergic reaction has ever been reported, whereas repeated use of HAL has become more and more common in clinical practice.

3.7. Cost issues

Although patient outcomes are the main focus of medical research, the economic aspects of patient care are important for most health care providers. As stated in our introduction, for various reasons, BCa is one of the most expensive human cancers to manage [2], [5], [66], and [67]. It is complicated and difficult to gather BCa-related costs as well as the impact of PDD on these costs because of large differences in treatment reimbursement and practice patterns (eg, office fulguration or outpatient facilities) across the Western world.

In general, application of PDD is associated with additional costs compared to WLC, including the costs for the drug, a catheter for application, as well as acquisition and maintenance of specific equipment. Moreover, the additional amount of work necessary for drug application and a longer duration of surgery, at least during the learning period, have to be taken into account. Stenzl et al. [68] were the first to suggest the cost effectiveness of PDD in NMIBC treatment based on assumptions from a retrospective analysis of TURBTs performed in their institution. The assumptions that support the cost effectiveness of PDD are based on higher tumour diagnostic detection rates and a more complete TURBT with PDD compared with WLC. This should reduce recurrence rates and the need for further TURBTs, and a prolonged RFS should lead to a reduction in the frequency of follow-up cystoscopies. Two prospective studies investigated the cost effectiveness of PDD, and both postulated a benefit for PDD [12] and [24]. Daniltchenko and colleagues estimated a 25% reduction in additional TURBTs in the PDD arm because of fewer recurrences [12]. They calculated a savings of $425 per patient without adjustment for costs of adjuvant instillation therapies or surveillance cystoscopies. Burger et al. calculated savings of approximately 170€ per year because of PDD administration in a patient cohort with a 7.1-yr follow-up, including costs for adjuvant intravesical treatment, but not outpatient surveillance cystoscopies or costs for radical cystectomies [24].

As recent reports have challenged the reduction in recurrence rate with PDD [17] and [18], these cost-based analyses might not hold true in contemporary practice. Also, the savings were calculated using 5-ALA, which is less expensive than HAL. Moreover, cost analyses were based on an average patient, but they did not adjust for a specific risk group (eg, high- vs intermediate- vs low-risk NMIBC), which may influence the risk of disease recurrence or progression [2], nor did they adjust for variable clinical courses (eg, length of hospital stay, immediate postoperative or adjuvant instillation therapies). Finally, PDD has a limited benefit in large necrotic or invasive tumours, investigation of haematuria, presence of infection, or when surgical inflammation is a problem and therefore likely only to add costs in these scenarios.

Novel technologies need to demonstrate reasonable cost effectiveness, but economic models are complex, and the cost effectiveness of PDD is multifactorial, so current models cannot account for all variables. Therefore, cost analyses for each country and Europe as a whole are almost impossible. Although PDD may not be superior in costs compared with WLC alone for a single institution, especially with low caseloads, it is quite likely to be at least cost neutral for high-volume centres.

3.8. Discussion

An important question is whether there is a real advantage in NMIBC patients from the use of PDD. There are consistent data to suggest that PDD improves the detection and management of NMIBC compared with WLC alone. Several independent, prospective, randomised studies have provided level 1 evidence of PDD superiority over WLC in papillary tumour and CIS detection as well as residual tumour reduction [7], [12], [32], [38], [43], [44], [49], and [56]. Although recent studies have challenged these findings, these reports require longer follow-up to ensure their durability [17] and [18] compared with more established data [28] and [29]. These recent data may reflect improvements in WLC that have followed the introduction of PDD. Importantly, an analysis of the benefits from PDD needs adjustment for the use of intravesical chemotherapy or immunotherapy [2] and tumour risk group stratification. Without these, the true value of PDD for the improvement of outcomes remains to be definitively demonstrated. It can be speculated that improvements in topical photosensitisers with better biologic performance and implementation of new technical improvements, such as high-definition video devices, may further improve treatment and outcomes. Beyond these, PDD needs to demonstrate its superiority to other optical imaging technologies during WLC, such as narrow-band imaging (NBI). NBI has been reported to be an effective method for the identification of additional and abnormal lesions, including CIS, which may reduce the risk of NMIBC recurrence, while additional costs and effort resulting from drug application are nonexistent [69] and [70].

Three meta-analyses of prospective PDD studies analysed the data to provide the best LoE and reported partially contrasting findings [7], [59], and [60]. Therefore, it is important to mention that all meta-analyses included only a subset of those patients available for analyses, and none used the same selection of studies (differing inclusion criteria). Furthermore, one meta-analysis included re-reports of previously published studies, introducing a potential selection bias. No meta-analyses adjusted for the use of intravesical therapies, and none performed subgroup analyses using NMIBC risk groups. Indeed, few studies have analysed outcomes according to NMIBC risk [17], [18], [28], and [32]. Thus, additional studies, more distinct analyses, or meta-analyses that comprise all available studies without re-reporting are necessary.

Several questions remain unanswered to assess whether there is a real advantage to PDD-guided TURBT compared with WLC alone. For example, there is level 1 evidence that PDD-guided TURBT leads to more complete resections [7], [59], and [60], so that one might assume that a repeat TURBT could be avoided and the need for a single, immediate instillation may be reduced. Amongst others, this idea may affect the economical burden, but to date, no randomised study has evaluated these important clinical questions. Another problem is the number of patients in available studies, which is too low to analyse specific questions (eg, unconfirmed positive urinary cytology; recurrent, multiple tumours [52] and [53]). Consequently, the strength of these data is limited, although PDD application might be preferably used for biopsy guidance in patients with suspicion of high-grade tumours and high-risk constellations. Finally, the benefit of PDD in the general urologic community remains unanswered. All studies are coming from high-volume tertiary care centres with great experience in NMIBC treatment. It is likely that experienced surgeons also obtain good results with WLC. Nevertheless, PDD may help most surgeons improve their results, as it offers clear visualisation of tumours and their margins, thereby facilitating improved TURBT, which is of vital importance in the management of such a heterogeneous disease [8].

4. Conclusions

Level 1 and 2 evidence exists that PDD improves tumour detection and reduces residual tumour in NMIBC compared with WLC alone, especially in flat lesions such as CIS and dysplasia. A translation of these findings into reduced disease recurrence rates is confirmed by most but not all randomised controlled studies. PDD does not seem to reduce disease progression rates (Table 5). If PDD is used, it should be applied at initial resection or with an adequate interval to previous resections to avoid false-positive findings caused by previous treatments. In patients who did not receive PDD at initial treatment, PDD may be applied at least once for more accurate tumour detection and resection at the time of tumour recurrence or when NMIBC is suspected but not verified on WLC or when CIS was previously present. PDD cannot be recommended for surveillance and office-based procedures. Well-designed prospective, randomised future studies with long-term follow-up may shed more light on the true impact of PDD and its cost effectiveness.

Table 5

Recommendations from this collaborative systematic literature review and the expert panel of authors on use of and indications for photodynamic diagnostics in patients with non–muscle-invasive bladder cancer

Clinical question/scenarioUse of PDD recommendationCurrent available evidence/comment
1. In-hospital setting
a) Primary tumour
General use of PDDRecommended• Recommended for all patients based on the currently available evidence, as mentioned below.
• Patients with high-grade tumours and CIS benefit most from PDD.
• Not recommended in patients with suspicion of muscle-invasive BCa.
Detection of additional papillary tumoursRecommended• PDD-guided cystoscopy improves the detection of papillary NMIBC.
• This effect seems pronounced in patients with multifocal tumours.
Detection of CISHighly recommended• Level 1 evidence exists that PDD-guided cystoscopy improves CIS detection.
Completeness of TURBTHighly recommended• Level 1 evidence exists that PDD-guided cystoscopy reduces residual tumour rates.
Positive cytology but negative WLCPDD useful• PDD-guided cystoscopy may detect additional malignant and premalignant lesions.
• No study used random biopsies of normal-appearing mucosa as a gold-standard for comparison.
Reduction of disease recurrenceRecommended• PDD-guided cystoscopy may reduce disease recurrence.
• PDD-guided cystoscopy prolongs time to disease recurrence.
• Adjustment for the use of intravesical chemotherapy or immunotherapy and tumour risk group stratification is insufficient in most studies.
Reduction of disease progressionNot recommended• PDD-guided cystoscopy does not seem to influence disease progression.
b) Recurrent tumour/repeat TURBT
General use of PDDSee recommendations above with limitations.• Patients (particularly those with high-grade tumours) not having received PDD in the initial setting should undergo PDD treatment.
• False-positive rates may increase in patients who recently underwent TURBT.
• Previous BCG/MMC instillations may increase false-positive detection rates.
• Use of PDD may be deferred in these patients for at least 4–6 wk after the last intervention.
c) For surveillanceNot recommended• No data available to assess a firm recommendation for PDD in surveillance of NMIBC.
2. Outpatient setting
General use of PDDNot recommended• Insufficient data available.
• Cost–benefit calculations are missing.
Use of PDD during flexible cystoscopyNot recommended• Rigid PDD cystoscopy is more effective than flexible PDD cystoscopy.

PDD = photodynamic diagnostic; CIS = carcinoma in situ; BCa = bladder cancer; NMIBC = non–muscle-invasive BCa; TURBT = transurethral resection of bladder tumour; WLC = white-light cystoscopy; BCG = bacillus Calmette-Guérin; MMC = mitomycin C.

Author contributions: Michael Rink had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rink, Witjes.

Acquisition of data: Rink.

Analysis and interpretation of data: Rink, Babjuk, Catto, Jichlinski, Shariat, Stenzl, Stepp, Zaak, Witjes.

Drafting of the manuscript: Rink.

Critical revision of the manuscript for important intellectual content: Rink, Babjuk, Catto, Jichlinski, Shariat, Stenzl, Stepp, Zaak, Witjes.

Statistical analysis: Rink, Shariat.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Witjes.

Other (specify): None.

Financial disclosures: Michael Rink certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michael Rink received honoraria from Bayer and travel funding from GE Healthcare. Shahrokh F. Shariat is an advisory board member for Ferring Pharma. Arnulf Stenzl is a consultant for Ipsen Pharma, Novartis AG, Janssen, and Alere; he is speaker for GE Company, Novartis AG, Amgen, Janssen, and Ipsen Pharma as well as a researcher for Novartis AG, Johnson & Johnson, Amgen, Bayer AG, immatics biotechnologies GmbH, and Photocure ASA. He received a research grant from immatics biotechnologies GmbH. Herbert Stepp is co-inventor of a patent on the PDD light source characteristics, which is licensed to Karl Storz Company. Dirk Zaak received honoraria from GE Healthcare, Ipsen, and Photocure ASA; he is an advisory board member of GE Healthcare and Ipsen. J. Alfred Witjes has been an advisor to Sanofi Pasteur, Allergan, Ipsen, GE, and Photocure since 2011 and has received lecture honoraria from Ipsen.

Funding/Support and role of the sponsor: None.

Appendix. – Search terms and strategy for systematic literature review

  • #1 randomized controlled trial [pt]
  • #2 controlled clinical trial [pt]
  • #3 clinical trial [pt]
  • #4 comparative study [pt]
  • #5 #1 OR #2 OR #3 OR #4
  • #6 humans
  • #7 #5 AND #6
  • #8 bladder cancer
  • #9 bladder neoplasm
  • #10 bladder carcinoma
  • #11 bladder tumor
  • #12 bladder tumour
  • #13 bladder
  • #14 urothel*
  • #15 non-muscle invasive
  • #16 #8 OR #9 OR # 10 OR #11 OR #12 OR #13 OR #14 OR #15
  • #17 PDD
  • #18 Hexvix
  • #19 fluorescen*
  • #20 5-ALA
  • #21 HAL
  • #22 photodyn*
  • #23 hexyl aminolevilinate
  • #24 #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23
  • #25 #7 AND #16 AND #24
  • * PubMed/Medline format


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a Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

b Department of Urology, Hospital Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

c Institute for Cancer Studies and Academic Urology Unit, University of Sheffield, Sheffield, United Kingdom

d Department of Urology, CHUV-University Hospital, Lausanne, Switzerland

e Department of Urology, Medical University of Vienna, Vienna, Austria

f Department of Urology, University Hospital Tübingen, Tübingen, Germany

g LIFE-Centre, Laser-Forschungslabor, University Hospital of Munich, Munich, Germany

h Department of Urology, Hospital Traunstein, Traunstein, Germany

i Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Corresponding author. Department of Urology, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Tel. +49 40 7410 53442; Fax: +49 40 7410 42444.

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