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.
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.
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.
Keywords: Non–muscle-invasive bladder cancer, Photodynamic diagnosis, Hexyl aminolevulinate, Tumour detection, Recurrence-free survival, Cost effectiveness, Urothelial cancer.
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 . Around three-quarters of patients present with non–muscle-invasive BCa (NMIBC) . 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  and . 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 .
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 . 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) . 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 .
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 . 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 . 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) . The different appearances of malignant and normal tissues can be visualised in real time during diagnostic cystoscopy or TURBT .
PDD offered improved tumour detection, reduced residual tumour rates (after TURBT), and prolonged recurrence-free survival (RFS) , , , and . 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) . 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)  and .
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) . Search results were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT)  and Standards for the Reporting of Diagnostic Accuracy (STARD)  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.
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 . 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 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and  (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 . In addition, three meta-analyses were identified and included in this systematic review , , and .
Descriptive baseline characteristics of selected original publications identified by systematic literature review
|Study||Year||Original trial||Study type||No. of patients under analysis||Uni-/ multicentre study (no. of institutions)||Study end points||Study particularities||Prodrug (5-ALA, HAL)||Age, mean||Male gender|
|Geavlete et al. ||2012||–||Prospective, randomised||362||181||181||Unicentre||Detection rate, residual tumour rate, RFS, PFS||–||HAL||66.8||–||267||–|
|Grossman et al. ||2012||Stenzl et al. |
|Prospective, randomised||516||255||261||Multicentre (28)||RFS, time to recurrence||–||HAL||–||–||–||–|
|Hermann et al. ||2011||–||Prospective, comparative randomised||145||68||77||Multicentre (2)||Residual tumour rate, RFS||–||HAL||71||69||3:1||–|
|Stenzl et al. ||2011||–||Prospective, randomised, double-blind, placebo-controlled||359||183||176||Multicentre (8)||Detection rate, RFS, PFS||–||5-ALA||66||–||259||–|
|Geavlete et al. ||2010||–||Prospective, randomised||446||223||223||Unicentre||Residual tumour rate||–||HAL||64||–||327||–|
|Ray et al. ||2010||–||Prospective, in-patient. comparison||42||32||10||Unicentre||Detection rate, treatment regimen change||After BCG treatment||HAL||63.5||–||21||9|
|Schumacher et al. ||2010||–||Prospective, randomised||300||153||147||Multicentre (5)||Detection rate, RFS, PFS||–||5-ALA||70||69||103||104|
|Stenzl et al. ||2010||–||Prospective, randomised||551||271||280||Multicentre (28)||Detection rate, RFS||–||HAL||68.0||69.6||212||223|
|Burger et al. ||2009||–||Retrospective||419||5-ALA: 139||142||Unicentre||Residual tumour rate, RFS||Comparison of HAL and 5-ALA||5-ALA plus HAL||68||71||99||93|
|Ray et al. ||2009||–||Prospective, in-patient. comparison||23||–||–||Unicentre||Detection rate||Unconfirmed positive cytology||HAL||64||–||20||–|
|Ray et al. ||2009||–||Prospective, in-patient comparison||18||–||–||Unicentre||Detection rate, treatment regimen change||Multifocal, recurrent NMIBC||HAL||74||–||11||–|
|Denzinger et al. ||2008||Filbeck et al. |
|Retrospective||46||21||25||Unicentre||Residual tumour rate, RFS, PFS||T1 tumours||5-ALA||69||71||15||19|
|Karl et al. ||2008||–||Retrospective||348||–||–||Unicentre||Detection rate||Positive cytology and negative WLC||5-ALA plus HAL||63.5||–||252||–|
|Burger et al. ||2007||Filbeck et al. |
|Prospective, randomised||191||88||103||Unicentre||RFS, cost analysis||–||5-ALA||68||70||65||78|
|Colombo et al. ||2007||–||Prospective, in-patient comparison||49||–||–||Unicentre||Detection rate||Only CIS||5-ALA plus HAL||68.5||–||–||–|
|Denzinger et al. ||2007||Filbeck et al. |
|Retrospective||191||88||103||Unicentre||Residual tumour rate, RFS||Long-term results||5-ALA||68||70||65||68|
|Fradet et al. ||2007||–||Prospective, in-patient comparison||196||–||–||Multicentre (18)||Detection rate, treatment regimen change||Only CIS||HAL||67||–||148||–|
|Grossman et al. ||2007||–||Prospective, in-patient comparison||196||–||–||Multicentre (18)||Detection rate||–||HAL||67||–||148||–|
|Hungerhuber et al. ||2007||–||Retrospective||875||–||–||Multicentre (2)||Detection rate||Long-term results||5-ALA||65.3||–||671||–|
|Babjuk et al. ||2005||–||Prospective, randomised||122||60||62||Unicentre||RFS, time to recurrence||–||5-ALA||67.9||69.8||43||39|
|Daniltchenko et al. ||2005||Riedl et al. |
|Prospective, randomised||102||51||51||Multicentre (2)||RFS, PFS, time to recurrence||–||5-ALA||70||67||37||36|
|Jocham et al. ||2005||–||Prospective, in-patient comparison||146||–||–||Multicentre (7)||Detection rate, treatment regimen change||–||HAL||67||–||107||–|
|Loidl et al. ||2005||–||Prospective, in-patient comparison||45||–||–||Unicentre||Detection rate||Comparison of rigid and flexible PDD||HAL||68||–||34||–|
|Witjes et al. ||2005||–||Prospective, in-patient comparison||20||–||–||Unicentre||Detection rate||Comparison of rigid and flexible PDD||HAL||71||–||17||–|
|Schmidbauer et al. ||2004||–||Prospective, in-patient comparison||211||–||–||Multicentre (19)||Detection rate||CIS detection rate||HAL||70||–||169||–|
|Grimbergen et al. ||2003||–||Prospective, in-patient comparison||160||–||–||Unicentre||Detection rate||After intravesical therapy||5-ALA||67||–||–||–|
|Jichlinski et al. ||2003||–||Prospective, in-patient comparison||52||–||–||Multicentre (4)||Detection rate||–||HAL||72||–||38||–|
|Filbeck et al. ||2002||–||Prospective, in-patient comparison||279||–||–||Unicentre||Detection rate, treatment regimen change||–||5-ALA||Range: 34–89||–||–||–|
|Filbeck et al. ||2002||–||Prospective, randomised||191||88||103||Unicentre||Residual tumour rate, RFS||–||5-ALA||68||70||–||–|
|Kriegmair et al. ||2002||–||Prospective, randomised||101||52||49||Multicentre (8)||Residual tumour rate||–||5-ALA||70.1||70.7||41||36|
|Zaak et al. ||2002||–||Prospective, in-patient comparison||713||–||–||Multicentre (5)||Detection rate||CIS and dysplasia||5-ALA||–||–||–||–|
|De Dominicis et al. ||2001||–||Prospective, in-patient comparison||49||–||–||Unicentre||Detection rate||–||5-ALA||60||–||42||–|
|Ehsan et al. ||2001||–||Prospective, in-patient comparison||30||–||–||Unicentre||Detection rate||–||5-ALA||Range: 55–89||–||19||–|
|Jeon et al. ||2001||–||Prospective, in-patient comparison||62||–||–||Unicentre||Detection rate||–||5-ALA||–||–||–||–|
|Riedl et al. ||2001||–||Prospective, randomised||102||51||51||Multicentre (2)||Residual tumour rate, time to recurrence||–||5-ALA||70||67||37||36|
|Zaak et al. ||2001||–||Prospective, in-patient comparison||605||–||–||Unicentre||Detection rate||–||5-ALA||65.6||–||472||–|
|Filbeck et al. ||1999||–||Prospective, in-patient comparison||120||–||–||Unicentre||Detection rate||–||5-ALA||64.5||–||–||–|
|Filbeck et al. ||1999||–||Prospective, in-patient comparison||50||–||–||Unicentre||Residual tumour rate||–||5-ALA||63.4||–||36||–|
|Koenig et al. ||1999||–||Prospective, in-patient comparison||55||–||–||Unicentre||Detection rate||–||5-ALA||66||–||44||–|
|Kriegmair et al. ||1999||–||Prospective, in-patient comparison||208||–||–||Unicentre||Detection rate||–||5-ALA||64.8||–||170||–|
|Riedl et al. ||1999||–||Prospective, in-patient Comparison||52||–||–||Unicentre||Detection rate||–||5-ALA||Range: 44–79||–||–||–|
|D’Hallewin et al. ||1998||–||Prospective, in-patient Comparison||16||–||–||Unicentre||Detection rate||–||5-ALA||–||–||–||–|
|Kriegmair et al. ||1996||–||Prospective, in-patient comparison||104||–||–||Unicentre||Detection rate||–||5-ALA||68||–||80||–|
|Kriegmair et al. ||1994||–||Prospective, in-patient comparison||68||–||–||Unicentre||Detection rate||–||5-ALA||66.2||–||51||–|
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)  and . Independent prospective studies have demonstrated comparable sensitivities and specificities for 5-ALA and HAL , , , , and , and one retrospective study found no difference between 5-ALA and HAL in direct comparison . 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) . As consensus exists that 5-ALA and HAL are transferable , 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) , , , , , , , , , and . 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 . 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) .
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
|Study||Year||Prodrug||Overall detection rate, %||Detection rate pTa tumours, %||Detection rate pT1 tumours, %||Detection rate CIS %||Detection rate dysplasia, %||Tumours solely detected by PDD, %|
|Geavlete et al.  (n = 362)||2012||HAL||92||80||92||81||93||89||94||63||–||–||All: 21|
|Stenzl et al.  (n = 359)||2011||5-ALA||–||–||G1: 96||84||G1: 50||50||100||65||100||67||pTa: 17|
|G2: 91||81||G2: 86||96||pT1: 11|
|G3: 100||100||G3: 100||87||CIS: 35|
|Stenzl et al.  (n = 551)||2010||HAL||–||–||–||–||–||–||–||–||–||–||pTa: 16|
|Schumacher et al.  (n = 300)||2010||5-ALA||–||–||–||–||–||–||–||–||–||–||pTa: 7|
|Grossman et al.  (n = 108)||2007||HAL||–||–||95||83||95||86||–||–||–||–||pTa: 29|
|Fradet et al.  (n = 58)||2007||HAL||–||–||–||–||–||–||92||68||–||–||CIS: 16|
|Jocham et al.  (n = 146)||2005||HAL||96||77||96||85||96||96||95||68||93||48||All: 18|
|Schmidbauer et al.  (n = 211)||2004||HAL||97||78||97||88||96||88||97||58||94||53||CIS: 28|
|Jichlinski et al.  (n = 52)||2003||HAL||76||46||–||–||–||–||49||5||–||–||All: 23|
|Grimbergen  (n = 160)||2003||5-ALA||97||69||–||–||–||–||–||–||–||–||All: 24|
|Filbeck et al.  (n = 279)||2002||5-ALA||–||–||–||–||–||–||–||–||–||–||pTaG1–2:|
|Zaak et al.  (n = 713)||2002||5-ALA||–||–||–||–||–||–||91.2||47.2||80.6||69.7||CIS: 53|
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  and , 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%) , 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 , , , and . 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 : 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 , , , , , , , , , , and . 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 , , , , , , and . 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) , 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 . 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) . Ultimately, PDD significantly improves the detection of CIS.
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 .
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 . 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 . 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) , , , and  (difference ranges from 30% to 56% , , , , and ). One prospective  and one retrospective study  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 , 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 . 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  and . 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 . Thus, rigid PDD cystoscopy is likely to remain the technique of choice until further improvements appear .
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 , , , , , , , and . 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 , , , , , and ). Improvements in residual tumour rates were present for both pTa , , and  and pT1 tumours , , and . Although the majority of studies performed re-resection using WLC, Riedl et al.  used PDD-guided re-resection and found results comparable to other reports. All meta-analyses have found significantly reduced residual tumour rates with PDD , , and . The odds ratio of residual tumour with PDD is 0.28 (95% CI, 0.15–0.52) compared to WLC , and the RR of residual tumour is 2.77-fold higher (95% CI, 1.47–5.02; p = 0.002) with WLC compared . 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 , , , , , , , , , and . Five studies reported long-term RFS rates >48 mo (range: 48–96) , , , , and . Eight studies found significantly fewer recurrences at any time point of analysis with PDD compared to WLC , , , , , , , and . 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 , , and . Patients with multifocal or recurrent tumours seem to benefit most from PDD-guided TURBT , , , and .
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
|Study||Year||Prodrug||Interval since resection||RFS, %||PFS*, %||Time to recurrence, mo|
|Grossman  (n = 516)||2012||HAL||Median follow-up:||38**||32**||–||–||16.4||9.4|
|PDD: 55 mo|
|WLC: 53 mo|
|Geavlete et al.  (n = 362)||2012||HAL||3 mo||92.8||84.2||–||–|
|Hermann et al.  (n = 145)||2011||HAL||4 mo||83.1||68.9||–||–||–||–|
|Stenzl et al.  (n = 359)||2011||5-ALA||12 mo||68.9**||74.4**||89.4**||89.9**||–||–|
|Stenzl et al.  (n = 551)||2010||HAL||9 mo||53||44||–||–||–||–|
|Schumacher et al.  (n = 300)||2010||5-ALA||12 mo||55.1**||55.9**||91.1**||89.1**||–||–|
|Burger et al.  (n = 419)||2009||5ALA||12 mo||94||78||–||–||–||–|
|Denzinger et al.  (n = 46)||2008||5-ALA||48 mo||91||69||–||–|
|Denzinger et al.  (n = 301)||2007||5-ALA||24 mo||88||73||–||–||–||–|
|Burger et al.  (n = 101)||2007||5-ALA||85 mo||71||45||98**||98**||–||–|
|Daniltchenko et al.  (n = 102)||2005||5-ALA||2 mo||84||59||Overall: 92||Overall: 82||12||5|
|Babjuk et al.  (n = 122)||2005||5-ALA||10–15 wk||92||68||–||–||17.05||8.05|
|Filbeck et al.  (n = 191)||2002||5-ALA||12 mo||90||74||–||–||–||–|
* 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 , , and . However, two studies reported only short-term outcomes (at 9–12 mo)  and , but in the third, the median follow-up was 55 mo (PDD) and 53 mo (WLC) . In one study, the recurrence rate with WLC was lower than for PDD (68.9% vs 74.4%), but this did not reach significance . The difference in these findings (compared with other reports) may be the result of patient heterogeneity (proportion of patients with recurrent tumours ), high rates of low-grade disease  and low rates of CIS , differences in adjuvant intravesical therapy use, a more meticulous WLC within a randomised controlled trial (RCT) , or the underpowering of studies . 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 .
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  and , whilst two other studies with short-term follow-up did not confirm these findings  and .
Only one meta-analysis analysed data for RFS at 3 mo (n = 291) and 12 mo (n = 1658) . 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 , , and .
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  and , 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 , , and  reported patients without administration of adjuvant intravesical therapy, and in only one of these was RFS included . 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 .
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 , , , and . 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) , , , , , and , 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) . Of note, other studies have defined progression as invasion of the detrusor muscle , , , and , progression to a higher T stage, and/or presence of CIS . 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 . 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  and . Ray et al. looked at BCG timing and false-positive rates and found that a 6-wk delay was sufficient . Of note, there is little information regarding the false-positive rates for WLC.
Overview of false-positive detection rates between photodynamic diagnostic and white-light cystoscopy in selected prospective studies from the past 10 yr
|Study||Year||Prodrug||False-positive rate, %|
|Jichlinski et al. ||2003||HAL||21||7|
|Grimbergen et al. ||2003||5-ALA||26||11|
|Schmidbauer et al. ||2004||HAL||13||10|
|Jocham et al. ||2005||HAL||37||26|
|Loidl et al. ||2005||HAL||Flexible: 13||9|
|Witjes et al. ||2005||HAL||Flexible: 15||15|
|Fradet et al. ||2007||HAL||39||31|
|Colombo et al. ||2007||HAL/5-ALA||33||7|
|Burger et al. ||2009||HAL||29||17|
|Ray et al. ||2009||HAL||60||50|
|Ray et al. ||2009||HAL||29||3|
|Stenzl et al. ||2010||HAL||12||11|
|Ray et al. ||2010||HAL||63||72|
|Hermann et al. ||2011||HAL||25||16|
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% , , , , , and . 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 . 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.
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 , , , , , , and . 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 , , and . 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 , , , and . 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.  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  and . Daniltchenko and colleagues estimated a 25% reduction in additional TURBTs in the PDD arm because of fewer recurrences . 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 .
As recent reports have challenged the reduction in recurrence rate with PDD  and , 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 , 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.
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 , , , , , , , and . Although recent studies have challenged these findings, these reports require longer follow-up to ensure their durability  and  compared with more established data  and . 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  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  and .
Three meta-analyses of prospective PDD studies analysed the data to provide the best LoE and reported partially contrasting findings , , and . 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 , , , and . 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 , , and , 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  and ). 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 .
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.
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/scenario||Use of PDD recommendation||Current available evidence/comment|
|1. In-hospital setting|
|a) Primary tumour|
|General use of PDD||Recommended||• 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 tumours||Recommended||• PDD-guided cystoscopy improves the detection of papillary NMIBC.|
|• This effect seems pronounced in patients with multifocal tumours.|
|Detection of CIS||Highly recommended||• Level 1 evidence exists that PDD-guided cystoscopy improves CIS detection.|
|Completeness of TURBT||Highly recommended||• Level 1 evidence exists that PDD-guided cystoscopy reduces residual tumour rates.|
|Positive cytology but negative WLC||PDD 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 recurrence||Recommended||• 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 progression||Not recommended||• PDD-guided cystoscopy does not seem to influence disease progression.|
|b) Recurrent tumour/repeat TURBT|
|General use of PDD||See 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 surveillance||Not recommended||• No data available to assess a firm recommendation for PDD in surveillance of NMIBC.|
|2. Outpatient setting|
|General use of PDD||Not recommended||• Insufficient data available.|
|• Cost–benefit calculations are missing.|
|Use of PDD during flexible cystoscopy||Not 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.
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
-  European Cancer Observatory. International Agency for Research on Cancer Web site. http://eu-cancer.iarc.fr.
-  M. Babjuk, W. Oosterlinck, R. Sylvester, et al. EAU guidelines on non–muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59:997-1008
-  A. Pawinski, R. Sylvester, K.H. Kurth, et al. A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer. J Urol. 1996;156:1934-1940 discussion 1940–1
-  F. Thomas, A.P. Noon, N. Rubin, J.R. Goepel, J.W. Catto. Comparative outcomes of primary, recurrent, and progressive high-risk non–muscle-invasive bladder cancer. Eur Urol. 2013;63:145-154
-  K.D. Sievert, B. Amend, U. Nagele, et al. Economic aspects of bladder cancer: what are the benefits and costs?. World J Urol. 2009;27:295-300
-  M. Rink, E.K. Cha, D. Green, et al. Biomolecular predictors of urothelial cancer behavior and treatment outcomes. Curr Urol Rep. 2012;13:122-135
-  I. Kausch, M. Sommerauer, F. Montorsi, et al. Photodynamic diagnosis in non–muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol. 2010;57:595-606
-  J.A. Witjes, J.P. Redorta, D. Jacqmin, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non–muscle-invasive bladder cancer: review of the evidence and recommendations. Eur Urol. 2010;57:607-614
-  P. Jichlinski, D. Jacqmin. Photodynamic diagnosis in non–muscle-invasive bladder cancer. Eur Urol Suppl. 2008;7:529-535
-  S. Collaud, A. Juzeniene, J. Moan, N. Lange. On the selectivity of 5-aminolevulinic acid–induced protoporphyrin IX formation. Curr Med Chem Anticancer Agents. 2004;4:301-316
-  D. Jocham, H. Stepp, R. Waidelich. Photodynamic diagnosis in urology: state-of-the-art. Eur Urol. 2008;53:1138-1150
-  D.I. Daniltchenko, C.R. Riedl, M.D. Sachs, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol. 2005;174:2129-2133 discussion 2133
-  M. Kriegmair, D. Zaak, H. Stepp, et al. Transurethral resection and surveillance of bladder cancer supported by 5-aminolevulinic acid-induced fluorescence endoscopy. Eur Urol. 1999;36:386-392
-  C.R. Riedl, D. Daniltchenko, F. Koenig, R. Simak, S.A. Loening, H. Pflueger. Fluorescence endoscopy with 5-aminolevulinic acid reduces early recurrence rate in superficial bladder cancer. J Urol. 2001;165:1121-1123
-  D. Zaak, M. Kriegmair, H. Stepp, et al. Endoscopic detection of transitional cell carcinoma with 5-aminolevulinic acid: results of 1012 fluorescence endoscopies. Urology. 2001;57:690-694
-  Y. Fradet, H.B. Grossman, L. Gomella, et al., PC B302/01 Study Group. 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. J Urol. 2007;178:68-73 discussion 73
-  M.C. Schumacher, S. Holmang, T. Davidsson, B. Friedrich, J. Pedersen, N.P. Wiklund. 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. Eur Urol. 2010;57:293-299
-  A. Stenzl, H. Penkoff, E. Dajc-Sommerer, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy: a multicenter randomized, double-blind, placebo-controlled trial. Cancer. 2011;117:938-947
-  D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336-341
-  D. Moher, K.F. Schulz, D.G. Altman. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357:1191-1194
-  P.M. Bossuyt, J.B. Reitsma, D.E. Bruns, et al., Standards for Reporting of Diagnostic Accuracy. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. BMJ. 2003;326:41-44
-  M. Babjuk, V. Soukup, R. Petrik, M. Jirsa, J. Dvoracek. 5-aminolaevulinic acid–induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer. BJU Int. 2005;96:798-802
-  M. Burger, C.G. Stief, D. Zaak, et al. Hexaminolevulinate is equal to 5-aminolevulinic acid concerning residual tumor and recurrence rate following photodynamic diagnostic assisted transurethral resection of bladder tumors. Urology. 2009;74:1282-1286
-  M. Burger, D. Zaak, C.G. Stief, et al. Photodynamic diagnostics and noninvasive bladder cancer: is it cost-effective in long-term application? A Germany-based cost analysis. Eur Urol. 2007;52:142-147
-  R. Colombo, R. Naspro, P. Bellinzoni, et al. Photodynamic diagnosis for follow-up of carcinoma in situ of the bladder. Ther Clin Risk Manag. 2007;3:1003-1007
-  M.A. D’Hallewin, H. Vanherzeele, L. Baert. Fluorescence detection of flat transitional cell carcinoma after intravesical instillation of aminolevulinic acid. Am J Clin Oncol. 1998;21:223-225
-  C. De Dominicis, M. Liberti, G. Perugia, et al. Role of 5-aminolevulinic acid in the diagnosis and treatment of superficial bladder cancer: improvement in diagnostic sensitivity. Urology. 2001;57:1059-1062
-  S. Denzinger, M. Burger, B. Walter, et al. Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid–induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology. 2007;69:675-679
-  S. Denzinger, W.F. Wieland, W. Otto, T. Filbeck, R. Knuechel, M. Burger. Does photodynamic transurethral resection of bladder tumour improve the outcome of initial T1 high-grade bladder cancer? A long-term follow-up of a randomized study. BJU Int. 2008;101:566-569
-  A. Ehsan, F. Sommer, G. Haupt, U. Engelmann. Significance of fluorescence cystoscopy for diagnosis of superficial bladder cancer after intravesical instillation of delta aminolevulinic acid. Urol Int. 2001;67:298-304
-  T. Filbeck, U. Pichlmeier, R. Knuechel, W.F. Wieland, W. Roessler. Do patients profit from 5-aminolevulinic acid–induced fluorescence diagnosis in transurethral resection of bladder carcinoma?. Urology. 2002;60:1025-1028
-  T. Filbeck, U. Pichlmeier, R. Knuechel, W.F. Wieland, W. Roessler. Clinically relevant improvement of recurrence-free survival with 5-aminolevulinic acid induced fluorescence diagnosis in patients with superficial bladder tumors. J Urol. 2002;168:67-71
-  T. Filbeck, W. Roessler, R. Knuechel, M. Straub, H.J. Kiel, W.F. Wieland. Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid. J Endourol. 1999;13:117-121
-  T. Filbeck, W. Roessler, R. Knuechel, M. Straub, H.J. Kiel, W.F. Wieland. 5-aminolevulinic acid–induced fluorescence endoscopy applied at secondary transurethral resection after conventional resection of primary superficial bladder tumors. Urology. 1999;53:77-81
-  B. Geavlete, M. Jecu, R. Multescu, D. Georgescu, P. Geavlete. HAL blue-light cystoscopy in high-risk nonmuscle-invasive bladder cancer—re-TURBT recurrence rates in a prospective, randomized study. Urology. 2010;76:664-669
-  B. Geavlete, R. Multescu, D. Georgescu, M. Jecu, F. Stanescu, P. Geavlete. Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non–muscle-invasive bladder cancer (NMIBC)?. BJU Int. 2012;109:549-556
-  M.C. Grimbergen, C.F. van Swol, T.G. Jonges, T.A. Boon, R.J. van Moorselaar. Reduced specificity of 5-ALA induced fluorescence in photodynamic diagnosis of transitional cell carcinoma after previous intravesical therapy. Eur Urol. 2003;44:51-56
-  H.B. Grossman, L. Gomella, Y. Fradet, et al., PC B302/01 Study Group. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol. 2007;178:62-67
-  H.B. Grossman, A. Stenzl, Y. Fradet, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol. 2012;188:58-62
-  G.G. Hermann, K. Mogensen, S. Carlsson, N. Marcussen, S. Duun. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in Ta/T1 patients: a randomized two-centre study. BJU Int. 2011;108:E297-E303
-  E. Hungerhuber, H. Stepp, M. Kriegmair, et al. Seven years’ experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology. 2007;69:260-264
-  S.S. Jeon, I. Kang, J.H. Hong, H.Y. Choi, S.E. Chai. Diagnostic efficacy of fluorescence cystoscopy for detection of urothelial neoplasms. J Endourol. 2001;15:753-759
-  P. Jichlinski, L. Guillou, S.J. Karlsen, et al. Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer—a multicenter study. J Urol. 2003;170:226-229
-  D. Jocham, F. Witjes, S. Wagner, et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005;174:862-866 discussion 866
-  A. Karl, S. Tritschler, P. Stanislaus, et al. Positive urine cytology but negative white-light cystoscopy: an indication for fluorescence cystoscopy?. BJU Int. 2009;103:484-487
-  F. Koenig, F.J. McGovern, R. Larne, H. Enquist, K.T. Schomacker, T.F. Deutsch. Diagnosis of bladder carcinoma using protoporphyrin IX fluorescence induced by 5-aminolaevulinic acid. BJU Int. 1999;83:129-135
-  M. Kriegmair, R. Baumgartner, R. Knuchel, H. Stepp, F. Hofstädter, A. Hofstetter. Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. J Urol. 1996;155:105-109 discussion 109–10
-  M. Kriegmair, R. Baumgartner, R. Knuechel, et al. Fluorescence photodetection of neoplastic urothelial lesions following intravesical instillation of 5-aminolevulinic acid. Urology. 1994;44:836-841
-  M. Kriegmair, D. Zaak, K.H. Rothenberger, et al. Transurethral resection for bladder cancer using 5-aminolevulinic acid induced fluorescence endoscopy versus white light endoscopy. J Urol. 2002;168:475-478
-  W. Loidl, J. Schmidbauer, M. Susani, M. Marberger. Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance?. Eur Urol. 2005;47:323-326
-  E.R. Ray, K. Chatterton, M.S. Khan, et al. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette-Guerin. BJU Int. 2010;105:789-794
-  E.R. Ray, K. Chatterton, M.S. Khan, K. Thomas, A. Chandra, T.S. O’Brien. Hexylaminolaevulinate ‘blue light’ fluorescence cystoscopy in the investigation of clinically unconfirmed positive urine cytology. BJU Int. 2009;103:1363-1367
-  E.R. Ray, K. Chatterton, K. Thomas, M.S. Khan, A. Chandra, T.S. O’Brien. Hexylaminolevulinate photodynamic diagnosis for multifocal recurrent nonmuscle invasive bladder cancer. J Endourol. 2009;23:983-988
-  C.R. Riedl, E. Plas, H. Pfluger. Fluorescence detection of bladder tumors with 5-amino-levulinic acid. J Endourol. 1999;13:755-759
-  J. Schmidbauer, F. Witjes, N. Schmeller, R. Donat, M. Susani, M. Marberger, Hexvix PCB301/01 Study Group. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004;171:135-138
-  A. Stenzl, M. Burger, Y. Fradet, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010;184:1907-1913
-  J.A. Witjes, P.M. Moonen, A.G. van der Heijden. Comparison of hexaminolevulinate based flexible and rigid fluorescence cystoscopy with rigid white light cystoscopy in bladder cancer: results of a prospective phase II study. Eur Urol. 2005;47:319-322
-  D. Zaak, E. Hungerhuber, P. Schneede, et al. Role of 5-aminolevulinic acid in the detection of urothelial premalignant lesions. Cancer. 2002;95:1234-1238
-  G. Mowatt, J. N’Dow, L. Vale, et al., Aberdeen Technology Assessment Review (TAR) Grou. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. Int J Technol Assess Health Care. 2011;27:3-10
-  P. Shen, J. Yang, W. Wei, et al. Effects of fluorescent light-guided transurethral resection on non–muscle-invasive bladder cancer: a systematic review and meta-analysis. BJU Int. 2012;110:E209-E215
-  P. Jichlinski, M. Forrer, J. Mizeret, et al. Clinical evaluation of a method for detecting superficial surgical transitional cell carcinoma of the bladder by light-induced fluorescence of protoporphyrin IX following the topical application of 5-aminolevulinic acid: preliminary results. Lasers Surg Med. 1997;20:402-408
-  A. Marti, P. Jichlinski, N. Lange, et al. Comparison of aminolevulinic acid and hexylester aminolevulinate induced protoporphyrin IX distribution in human bladder cancer. J Urol. 2003;170:428-432
-  G.G. Hermann, K. Mogensen, B.G. Toft, A. Glenthoj, H.M. Pedersen. Outpatient diagnostic of bladder tumours in flexible cystoscopes: evaluation of fluorescence-guided flexible cystoscopy and bladder biopsies. Scand J Urol Nephrol. 2012;46:31-36
-  M.D. Shelley, T.J. Wilt, J. Court, B. Coles, H. Kynaston, M.D. Mason. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 2004;93:485-490
-  R.O. Draga, M.C. Grimbergen, E.T. Kok, T.N. Jonges, C.F. van Swol, J.L. Bosch. Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guérin immunotherapy and mitomycin C intravesical therapy. Eur Urol. 2010;57:655-660
-  M. Rink, F.K. Chun, T.F. Chromecki, et al. Advanced bladder cancer in elderly patients. Prognostic outcomes and therapeutic strategies [in German]. Urologe A. 2012;51:820-828
-  D. Zaak, W.F. Wieland, C.G. Stief, M. Burger. Routine use of photodynamic diagnosis of bladder cancer: practical and economic issues. Eur Urol Suppl. 2008;7:536-541
-  A. Stenzl, L. Höltl, G. Bartsch. Fluorescence assisted transurethral resection of bladder tumours: is it cost effective?. Eur Urol. 2001;39:31
-  A. Naselli, C. Introini, L. Timossi, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non–muscle-invasive bladder cancer recurrence. Eur Urol. 2012;61:908-913
-  C. Zheng, Y. Lv, Q. Zhong, R. Wang, Q. Jiang. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU Int. 2012;110:E680-E687
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.
© 2013 European Association of Urology, Published by Elsevier B.V.