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Photodynamic Diagnosis of Non–muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data

European Urology, 5, 64, pages 846 - 854

Abstract

Background

Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence.

Objective

To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence.

Design, setting, and participants

This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non–muscle-invasive bladder cancer (NMIBC).

Intervention

A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy.

Outcome measurements and statistical analysis

We studied the detection of NMIBC (intention to treat [ITT]: n = 831; six studies) and recurrence (per protocol: n = 634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection.

Results and limitations

BL cystoscopy detected significantly more Ta tumours (14.7%; p < 0.001; odds ratio [OR]: 4.898; 95% CI, 1.937–12.390) and CIS lesions (40.8%; p < 0.001; OR: 12.372; 95% CI, 6.343–24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p < 0.001), significant also in patients with primary (20.7%; p < 0.001) and recurrent cancer (27.7%; p < 0.001), and in patients at high risk (27.0%; p < 0.001) and intermediate risk (35.7%; p = 0.004). In 26.7% of patients, CIS was detected only by BL (p < 0.001) and was also significant in patients with primary (28.0%; p < 0.001) and recurrent cancer (25.0%; p < 0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p = 0.006; RR: 0.761 [0.627–0.924]), and lower in patients with T1 or CIS (p = 0.052; RR: 0.696 [0.482–1.003]), Ta (p = 0.040; RR: 0.804 [0.653–0.991]), and in high-risk (p = 0.050) and low-risk (p = 0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used.

Conclusions

This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9–12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

Take Home Message

A meta-analysis of the efficacy of blue light cystoscopy with hexaminolevulinate in the detection of bladder cancer confirmed that this approach significantly improves detection of bladder tumours and leads to improved clinical outcomes through reduction of recurrence at 1 yr.

Keywords: Bladder cancer, HAL blue light cystoscopy, Hexaminolevulinate.

1. Introduction

Non–muscle-invasive bladder cancer (NMIBC) has a highly variable recurrence rate related to various tumour- and host-related factors [1], [2], and [3]. There is increasing consensus that so-called early recurrence may in fact arise from residual tumour left behind at resection or from the growth of previously undetected microscopic lesions [4], [5], [6], [7], [8], [9], [10], and [11].Visual inspection of the bladder with white light (WL) is relatively reliable for the detection of papillary tumours, but flat carcinomas (particularly CIS), dysplasia, multifocal growth, and microscopic lesions can be overlooked or inadequately resected.

Photodynamic diagnosis (PDD) exploits the photoactive properties of compounds such as hexaminolevulinate (HAL) (Hexvix™, Cysview™). HAL is the lipophilic hexyl ester of 5-aminolevulinic acid (5-ALA). Following instillation, protoporphyrin IX accumulates preferentially in neoplastic tissue [12] . Illumination with blue-violet light (380–440 nm) produces a clearly demarcated red fluorescence from malignant tissue.

Previous meta-analyses on the role of PDD in the detection of bladder tumours used published data and combined studies on 5-ALA and HAL [13] and [14]. Because HAL is the only photoactive agent approved by European and US regulatory authorities for the detection of bladder cancer, it is reasonable to conduct a separate meta-analysis of the effects of HAL-assisted blue light (BL) cystoscopy.

The objective of this meta-analysis, carried out on raw data from original studies, was to evaluate the effect of HAL cystoscopy on the detection of papillary (Ta/T1) and flat (CIS) tumours, and the impact it may have on tumour recurrence.

2. Methods

A study was considered eligible if it (1) was prospective, enrolling consecutive patients, meeting predefined inclusion criteria; (2) recruited patients with known or suspected NMIBC (Ta, T1, or CIS) diagnosed by cystoscopy or positive urine cytology, or indicated by medical history; (3) compared a single application of HAL with BL and WL cystoscopy either in randomised controlled groups (recurrence up to 1 yr) or within-patient comparison (detection); (4) reported detection by lesion type and for WL and BL separately; (5) carried out HAL cystoscopy according to the recommended instructions; or (6) used histology to confirm the nature of lesions (true or false).

2.1. Data sources and searches

PubMed and the Cochrane Library were searched in July 2011 for controlled trials of PDD with HAL. Keywords used were Hexvix OR hexylaminolevulinate OR hexylaminolaevulinate OR “hexyl aminolevulinate” OR “hexyl aminolaevulinate” OR “hexaminolevulinate.” Completed but unpublished trials were sought through www.clinicaltrials.gov , www.clinicaltrialsregister.eu , and www.icmje.org/faq_clinical.html . No language or date restrictions were placed on results, which were then checked to remove duplicates and to ensure studies matched the eligibility criteria. Authors of all eligible trials were contacted and asked to contribute anonymised raw data.

2.2. Data extraction

Patient data for six of the studies (including five regulatory registration studies) were in a database custom built by the sponsor (Photocure) for the purposes of regulatory approval in Europe and the United States. For the other studies, raw data were provided by the investigators and entered into the database. Outcomes and some baseline characteristics (age, sex, primary [initial]/recurrent bladder cancer, previous treatments, risk status) were collected but not safety data.

2.3. Defined end points

The end point of detection was used to assess whether the addition of HAL BL to WL improved detection of Ta/T1 and CIS, at a lesion and patient level. Recurrence was used to assess whether improved tumour detection reduced the recurrence rate up to 12 mo. Subanalyses were used to assess whether detection with HAL cystoscopy is more or less effective in certain subgroups with different risk profiles, specifically primary versus recurrent bladder cancer, Ta/T1 or CIS, or patients at low, intermediate, or high risk of recurrence.

Patients were classified into clinically relevant risk groups derived from International Bladder Cancer Group recommendations [15] as follows: high, any Ta G3, T1, or CIS; intermediate, multiple Ta G1 or Ta G2; and low, single Ta G1 or Ta G2.

2.4. Statistical analytical methods

SAS v.9 was used to calculate end points, and the results were analysed using Comprehensive Meta-Analysis software v.2.2. Meta-analyses were performed using the random-effects model of DerSimonian and Laird [16] to obtain pooled relative risks and associated 95% confidence intervals (CIs) for outcomes for detection. This model explicitly accounts for any heterogeneity of studies, and it coincides with the inverse variance fixed-effects method if there is no heterogeneity. The fixed-effects model was used for recurrence analysis.

Studies included in the meta-analyses were weighted relative to the number of subjects in the study. Time to first recurrence was calculated for patients who had a recurrence. A survival analysis was carried out, and Kaplan-Meier estimates were calculated.

3. Results

Database searches revealed 122 publications up to July 2011; 103 were immediately rejected on the basis of titles or abstracts ( Fig. 1 ). Ten were rejected because they did not conform to inclusion criteria, leaving 11 eligible for inclusion.

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Fig. 1 Summary of search and screening results. 1[32] and [33]; 2 [34] ; 3 [35] ; 4[26] and [36]; 5[29] and [37]; 6[38] and [39].

One group [17] was unable to provide raw data; therefore 9 studies (10 papers) were available that recruited a total of 2212 patients (1345 HAL patients) ( Table 1 ). One study was reported in two separate publications [18] and [19].

Table 1 Characteristics of studies included in the analyses

Study No. of patients recruited Design Study arms Tumour types Detection/Recurrence
Jichlinski et al. [22] 52 Within-patient comparison; WL then BL Ta, T1, CIS D
Schmidbauer et al. [12] 286 Within-patient comparison; WL then BL Ta, T1, CIS D
Grossman et al. [19] ; Fradet et al. [18] 298 Within-patient comparison; WL then BL Ta, T1, CIS D
Jocham et al. [8] 162 Within-patient comparison; WL then BL Ta, T1, CIS D
Stenzl et al. [21] 814 Detection: within-patient comparison; WL then BL

Comparison of randomised parallel groups

Recurrence: group 1 vs group 2
Group 1: WL plus TURB; Group 2: WL plus BL plus TURB Ta, T1, CIS D, R 9 mo
Hermann et al. [24] 233 Comparison of randomised parallel groups. Detection and recurrence: group 1 vs group 2 Group 1: WL plus TURB.

Group 2: WL plus TURB, then BL plus TURB
Ta, T1, CIS D, R
Burgués et al. [23] 305 Within-patient comparison; WL then BL Ta, T1, CIS D
Drăgoescu et al. [25] 44 Comparison of randomised parallel groups Group 1: WL plus TURB

Group 2: WL plus BL plus TURB
Not specified D, R
Ray et al. [26] 18 Within-patient comparison; WL then BL Ta, T1, CIS D
Total 2212

BL = blue light; CIS = carcinoma in situ; D = detection; R = recurrence; TURB = transurethral resection of the bladder; WL = white light.

A search on clinical trials databases revealed three further studies. Two were not completed; the extension study reported by Grossman et al. looked retrospectively at long-term recurrence data from an earlier study and therefore was excluded [20] .

All of the studies except one (Hermann et al. [24] ) compared WL cystoscopy alone with WL plus BL cystoscopy, using PDD equipment from KARL STORZ GmbH, Germany as within-patient comparison before carrying out transurethral resection of the bladder (TURB), enabling documentation of lesions that could be detected with both methods, with BL only or with WL only. All histologic analysis was carried out by pathologists blinded to the detection process. In five studies, pathology was carried out at a central laboratory [8], [12], [18], [19], [21], and [22].

Five studies excluded patients who had received chemotherapy or bacillus Calmette-Guérin (BCG) in the previous 3 mo [8], [12], [18], [19], [21], and [22]. Burgués et al. used 6 wk as a cut-off [23] ; the remaining three studies did not mention prior therapy in the exclusion criteria.

3.1. Detection analysis: patient data

One study was excluded because a different study design was used [24] . Intention-to-treat (ITT) populations were used because this is clinically the most relevant. Table 2 shows the numbers of patients available for analysis in each study. Numbers do not always match those reported in the publications. In some cases patients have been excluded since publication; in others, further follow-up has been possible and raw data from additional patients were included. Burgués et al. provided data for 3 additional patients; Drăgoescu et al. provided detection data for 42 patients, rather than 44; and Ray et al. provided data for an additional 7 patients. Drăgoescu et al. [25] did not report tumour types, and Ray et al. did not report tumour types fully [26] . “Training patients” used in some studies to ensure familiarity with the technique [12], [18], [19], and [21] were excluded.

Table 2 Patients available for analysis of detection

Study Patients analysed Ta T1 Ta or T1 CIS
Jichlinski et al. [22] 52 38 7 41 12
Schmidbauer et al. [12] 211 137 51 154 80
Grossman et al. [19] ; Fradet et al. [18] 196 108 22 121 53
Jocham et al. [8] 146 66 18 75 29
Stenzl et al. [21] 365 262 63 286 41
Burgués et al. [23] 308 86 77 154 53
Drăgoescu et al. [25] 42        
Ray et al. [26] 25 16   16 4
Total 1345 713 238 847 272

CIS = carcinoma in situ.

Patients may have more than one tumour type.

3.2. Detection analysis: lesion data

Table 3 shows the numbers of lesions available for analysis. In the parallel group studies, only HAL-treated patients were included in this analysis [18], [19], and [25].

Table 3 Lesions available for analysis

Study Total Ta T1 CIS
Jichlinski et al. [22] 169 92 11 17
Schmidbauer et al. [12] 873 376 82 176
Grossman et al. [19] ; Fradet et al. [18] 651 218 24 113
Jocham et al. [8] 536 144 28 62
Stenzl et al. [21] 1117 580 95 66
Burgués et al. [23] 1659 211 * 132 93
Totals 5005 1621 372 527

* Four lesions were excluded because the detection method was missing from the database.

Three lesions were excluded because the detection method was missing from the database.

Twenty-four lesions were excluded because the detection method was missing from the database.

CIS = carcinoma in situ.

3.3. Additional detection of tumours

Table 4 lists the overall reported tumour detection rates of the studies included in the detection analysis. Individual detection rates can be found in the original publications.

Table 4 Detection of tumours, combined studies

Tumour type Both methods, n (%) BL only, n (%) WL only, n (%) Total Odds ratio (CI) in favour of BL p value
Total Ta 1298 (80.1) 239 (14.7) 84 (5.2) 1621 4.898 (1.937–12.390) <0.001
 Ta primary 495 (86.7) 64 (11.2) 12 (2.1) 571 5.146 (2.109–12.554) <0.001
 Ta recurrent 803 (76.5) 175 (16.7) 72 (6.9) 1050 4.637 (1.739–12.364) 0.002
 High risk 460 (77.3) 94 (15.8) 41 (6.9) 595 3.635 (1.474–8.966) 0.005
 Intermediate risk 674 (79.9) 138 (16.4) 32 (3.8) 844 7.056 (2.376–20.990) 0.005
 Low risk 164 (90.1) 7 (3.8) 11 (6.0) 182 0.849 (0.279–2.583) 0.773
Total T1 313 (84.1) 40 (10.8) 19 (5.1) 372 2.253 (0.999–5.081) 0.050
 Primary 201 (84.5) 30 (12.6) 7 (2.9) 238 4.478 (1.868–10.737 0.001
 Recurrent 112 (83.6) 10 (7.5) 12 (9.0) 134 0.962 (0.315–2.941) 0.946
Total CIS 285 (54.1) 215 (40.8) 27 (5.1) 527 12.372 (6.343–24.133) <0.001
 Primary * 119 (54.6) 94 (43.1) 5 (2.3) 218 21.316 (8.163–55.661 <0.001
 Recurrent * 166 (53.7) 121 (39.2) 22 (7.1) 309 7.947 (4.629–13.644) <0.001

* Primary and recurrent refer to the diagnosis of the patient at study entry.

BL = blue light; CI = confidence interval; CIS = carcinoma in situ; WL = white light.

Six studies reported additional detection of Ta tumours with BL cystoscopy, ranging from 9.7% to 40.2% of the total Ta tumours detected [8], [12], [18], [19], [21], and [23]. A total of 239 of 1621 additional Ta tumours (14.7%) were detected with BL cystoscopy alone ( Table 4 ). In all studies except one [21] the additional detection rate of Ta tumours is highly statistically significant, and overall the odds ratio (OR) in favour of BL is 4.898 (95% CI, 1.937–12.390; p < 0.001). Subgroup analyses show that the OR is significantly in favour of BL in patients with primary or recurrent cancer, and in high- and intermediate-risk groups ( Table 4 ).

Six studies reported detection of additional T1 tumours, ranging from 3.6% to 54.5% of the total T1 tumours detected [8], [12], [18], [19], [21], and [23]. Overall, 40 of 372 additional T1 tumours (10.8%) were detected with BL cystoscopy (p = 0.050; OR: 2.253; 95% CI, 0.999–5.081; Table 4 ). HAL BL cystoscopy was also of significant benefit in the group of T1 patients with primary cancer ( Table 4 ).

In all six studies there was significantly greater detection of additional CIS lesions ranging from 31.9% to 70.6% of the total CIS lesions detected [8], [12], [18], [19], [21], and [23]. Overall, 215 of 527 additional CIS lesions (40.8%) were detected with BL cystoscopy alone ( Table 4 ; p < 0.001; OR: 12.372; 95% CI, 6.343–24.133). Additional detection of CIS was highly significant both in primary and in recurrent cancer subgroups ( Table 4 ).

3.4. Additional detection at the patient level

The population for this analysis is patients who have been identified as having at least one Ta or T1 tumour ( Table 5 ). There were 188 of 831 patients (22.6%) who had at least one additional Ta or T1 tumour that was only seen with BL cystoscopy. The weighted meta-analysis rate, which will be referred to in all further results at a patient level, was 24.9% (95% CI, 0.184–1.328; p < 0.001; Table 5 , Fig. 2 ). The benefit was seen in patients with primary and recurrent cancer and in all risk groups ( Table 5 ).

Table 5 Detection of additional tumours in patients with at least one Ta or T1 tumour and additional carcinoma in situ (CIS) lesions in patients with at least one CIS lesion

Tumour type Patients in whom at least one Ta or T1 tumour was detected only by BL, n (%) Meta-analysis event rate Patients in whom at least one CIS lesion was detected only by BL, n (%) Meta-analysis event rate
Total 188/831 (22.6) 24.9%; p < 0.001 (0.184–0.328) 68/268 (25.4) 26.7%; p < 0.001 (0.183–0.371)
 Primary cancer 66/360 (18.3) 20.7%; p < 0.001 (0.131–0.312) 31/111 (27.9) 28.0%; p < 0.001 (0.193–0.388)
 Recurrent cancer 122/471 (25.9) 27.7%; p < 0.001 (0.218–0.343) 37/157 (23.6) 25.0%; p < 0.001 (0.168–0.354)
 High risk 97/397 (24.4) 27.0%; p < 0.001 (0.168–0.402)
 Intermediate risk 84/250 (33.6) 35.7%; p = 0.004 (0.271–0.453)
 Low risk 7/183 (3.8) 5.4%; p < 0.001 (0.026–0.106)

BL = blue light.

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Fig. 2 Meta-analysis: patients with at least one Ta or T1 lesion seen only with blue light (BL). CI = confidence interval; WL = white light.

In the group of patients who had at least one CIS lesion that was seen only with BL cystoscopy and who had no CIS lesions seen with WL, the detection of patients with CIS lesions using HAL cystoscopy was highly significant: 26.7% (95% CI, 0.183–0.371; p < 0.001; Fig. 3 ). The benefit was also significant in patients with both primary and recurrent cancer ( Table 5 ).

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Fig. 3 Meta-analysis: patients with at least one carcinoma in situ (CIS) lesion seen only with blue light (BL) where no CIS lesions were seen with white light (WL). CI = confidence interval.

3.5. Effect of intravesical therapy

Previous intravesical therapy had no effect on tumour detection. There was still a significant benefit from BL cystoscopy in the detection of Ta tumours and CIS, whether or not patients had received prior BCG or chemotherapy. The detection of T1 tumours using the two techniques remained unaffected. At a patient level, prior intravesical therapy had no effect on the ability of BL cystoscopy to identify additional patients with Ta/T1 or CIS. Detailed information is provided in Supplementary Tables 1–3 .

3.6. Analysis of recurrence

Recurrence was analysed in three studies using parallel groups (634 patients; Table 6 ) [21], [24], and [25]. Per-protocol populations were used because they give a more accurate picture of recurrence; ITT populations include imputed data on recurrence when patients were lost to follow-up.

Table 6 Overall recurrence rates up to 12 months

Patients treated with BL, n (%) Patients treated with WL, n (%) Total Follow-up period
Hermann et al. [24] 27/68 (39.7) 38/77 (49.4) 145 12 mo
Stenzl et al. [21] 72/200 (36.0) 92/202 (45.5) 402 9 mo
Drăgoescu et al. [25] 8/42 (19.0) 17/45 (37.8) 87 12 mo
Total 107/310 (34.5) 147/324 (45.4) 634* p = 0.006; RR = 0.761 (0.627–0.924)
 At least one T1 or CIS 26/74 (35.1) 45/87 (51.7) 161* p = 0.052; RR = 0.696 (0.482–1.003)
 At least one Ta 92/256 (35.9) 119/268 (44.4) 524* p = 0.040; RR = 0.804 (0.653–0.991)
 High-risk subgroup 46/126 (36.5) 70/144 (48.6)   p = 0.05; RR = 0.752 (0.565–1.000)
 Intermediate-risk subgroup 43/95 (45.3) 40/74 (54.1)   p = 0.246; RR = 0.836 (0.617–1.132)
 Low-risk subgroup 14/78 (17.9) 34/98 (34.7)   p = 0.029; RR = 0.561 (0.334–0.944)

BL = blue light; CIS = carcinoma in situ; RR = risk ratio; WL = white light.

Some patients appear in both subgroups (at least one T1 or CIS and at least one Ta).

The database received from the study by Drăgoescu et al. included an additional 20 BL and 23 WL patients with at least 12 mo of follow-up that were not included in the original publication, giving a total of 87 patients instead of 44.

Recurrence rate is defined as the number of patients in each group who has a recurrence, divided by the total number of patients in that group. Overall recurrence rates up to 12 mo are shown in Table 6 and Figure 4 . In all three studies, HAL BL cystoscopy was associated with a lower recurrence rate. The difference in overall recurrence rates, 34.5% versus 45.4%, is statistically significant in favour of BL, with an overall RR of 0.761 (0.627–0.924), p = 0.006 ( Fig. 4 ).

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Fig. 4 Meta-analysis: recurrence rates up to 12 mo. BL = blue light; CI = confidence interval; M-H = Mantel-Haenszel (test); WL = white light.

Recurrence rates are lower with BL in the subgroups of patients with T1 or CIS (p = 0.05; RR: 0.696 [0.482–1.003]) and those with Ta (p = 0.04; RR: 0.804 [0.653–0.991]) ( Table 6 ). The risk ratios indicate a reduction in risk despite borderline statistical significance. Recurrence in the HAL group was significantly lower in the high-risk (p = 0.050) and low-risk (p = 0.029) subgroups, but the difference was less pronounced in the intermediate-risk group (p = 0.246) ( Table 6 ). Only one study was available for analysis of the subgroup of patients receiving prior BCG or intravesical therapy [21] . Recurrence was still lower in the BL group of patients receiving prior therapy, although the difference was not significant, but there was a significant difference (p = 0.027) in the group of patients not receiving prior therapy.

Two of the studies [21] and [24] indicate that time to recurrence was longer for HAL patients, but the third showed opposite results ( Table 7 ) [25] . Overall, the difference was not significant (p = 0.276).

Table 7 Time to first recurrence in months

  Patients treated with BL Patients treated with WL
mean (SE) mean (SE)
Hermann et al. [24] 9.77 (0.44) 9.20 (0.44)
Stenzl et al. [21] 7.55 (0.17) 7.11 (0.18)
Drăgoescu et al. [25] 13.71 (0.53) 16.13 (1.06)

BL = blue light; SE = standard error; WL = white light.

4. Discussion

This meta-analysis confirmed that a single application of BL cystoscopy with HAL detects a significant number of additional lesions in patients with suspected bladder cancer and reduces recurrence rates up to 1 yr. Although published detection rates for HAL and WL cystoscopy vary widely, all report detection of additional lesions using HAL. By pooling the raw data into one population, the benefit of using BL cystoscopy as a diagnostic intervention becomes clearer.

Analysis found that the benefit on detection extended to most subgroups including primary and recurrent Ta patients, high- and intermediate-risk Ta patients, primary T1 patients, and primary and recurrent CIS patients. The groups of T1 patients with recurrent cancer and low-risk Ta were too small to reach significance. Nevertheless, because BL cystoscopy is an adjunct to WL, the clinically relevant point is that additional tumours are detected in all groups. HAL cystoscopy identified CIS in patients who were thought to be CIS free after inspection with WL: The effect was seen in patients with primary and recurrent cancer.

The subgroup of patients receiving intravesical therapy following enrolment into the studies in this meta-analysis was too small to be of significance, but in their follow-up study, Grossman et al. report that intravesical therapy does not appear to decrease the beneficial effects of HAL cystoscopy [20] .

Some studies were conducted before the definition of European Organisation for Research and Treatment of Cancer risk groups, but patients were assigned to risk groups according to these more stringent criteria.

Although data at a patient level may be more relevant clinically, most data are available at the lesion level. Detection of additional lesions can reduce the overall risk of recurrence and significantly change patient management plans. Other studies have shown that a single application of HAL cystoscopy has beneficial effects on recurrence extending up to 5 yr [8] and [20].

We could not draw any conclusions about time to recurrence or disease progression. The three studies reporting recurrence present contradictory results about time to recurrence. The only paper reporting long-term follow-up is Grossman et al. [20] . Regarding disease progression, the period of follow-up in the studies included in this meta-analysis only extended to 12 mo, which is insufficient to detect changes to invasive cancer. One of the studies in this meta-analysis extended the follow-up period [21] , which was then published in 2012 by Grossman et al. [20] . The findings on tumour progression were reported in this publication and demonstrated a trend towards a lower rate of progression [20] .

New studies have been published since this meta-analysis was carried out. Lapini et al. reported improved detection of tumours and significantly better sensitivity of BL compared with WL cystoscopy [27] . Karaolides et al. reported recurrence-free survival (RFS) of 91% and 82.5% at 12 and 18 mo, respectively, in HAL patients compared with 56.3% and 50.6% (WL: 102 patients) [28] . These studies, plus the study by Geavlete et al. [17] , support our findings and would have added to the robustness of the results if included.

There is some heterogeneity between the studies reporting Ta. For example, the large study by Stenzl et al. [21] shows no difference in the detection of Ta, particularly at recurrence, whereas other studies report significant differences. Despite such differences, the best estimate of the overall findings is through a meta-analysis using the DerSimonian and Laird method, as here, which has been developed to combine heterogeneous results. Because the strength of the analysis depends on the quality of the original data, we only included well-controlled studies to reduce bias.

The first published review of PDD in NMIBC [13] found that PDD was beneficial in detection and recurrence, but data from two agents (HAL and 5-ALA) had been combined. There are significant differences between the agents that may have an impact on detection rates. A more recent meta-analysis by Shen et al. found no significant difference in detection rate or RFS between WL and PDD [14] . However, this meta-analysis had a number of flaws: It included studies comparing BL and WL, whereas HAL cystoscopy is indicated as adjunctive therapy not as a replacement. Some major studies had not been included [8], [12], [18], [19], and [23], and the analysis combined data for 5-ALA and HAL with the justification that one study had shown them to be equivalent. It is not clear how some data were selected. For example, the RFS analysis does not include data by Geavlete et al., although this has recurrence data at 12 and 24 mo [29] .

Another recent publication [30] analysed pooled data from three HAL phase 3 studies (551 patients) focusing on the detection of CIS [8], [12], [18], and [19]. The overall additional CIS detection rate with HAL was found to be highly significant: 0.87 versus 0.75 for WL (p = 0.006).

Our meta-analysis focused solely on HAL, used as an add-on to WL cystoscopy, and was based on raw as opposed to published data. This improves statistical accuracy and gives a more accurate picture of the additional benefit of using HAL cystoscopy as an adjunct diagnostic tool.

European Association of Urology guidelines (2011) acknowledge the improved detection rate of fluorescence-guided cystoscopy for malignant tumours, particularly CIS [31] . Despite this, they express concern at the reduction of 9% in recurrence rate at 9 mo using HAL-assisted cystoscopy, reported in a single study [21] . Our meta-analysis, involving three studies reporting recurrence, found a significant overall reduction at 12 mo of approximately 11% (RR: 0.769). In patients with CIS or T1, the decrease in recurrence rate was 16.6% (RR: 0.696). Further studies reporting recurrence rates will help establish the real value of HAL-assisted cystoscopy.

5. Conclusions

This meta-analysis, carried out on raw data, confirms previously published data that a single application of PDD with HAL (Hexvix, Cysview) added to WL cystoscopy detects significantly more Ta, T1, and CIS tumours than WL cystoscopy alone. Pooling of the data allowed analysis of patient subgroups, and it was found that the benefit of HAL cystoscopy is particularly high in CIS patients, independent of the level of risk, and evident in patients with primary and recurrent cancer. The benefit of improved detection is seen in 12-mo recurrence rates that are significantly reduced and might have an impact on the need for frequent TURBs.


Author contributions: Maximilian Burger 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: Burger.

Acquisition of data: Burger, Grossman, Droller, Schmidbauer, Hermann, Drăgoescu, Ray, Fradet, Karl, Burgués, Witjes, Stenzl, Jichlinski, Jocham.

Analysis and interpretation of data: Burger, Grossman, Droller, Schmidbauer, Hermann, Drăgoescu, Ray, Fradet, Karl, Burgués, Witjes, Stenzl, Jocham.

Drafting of the manuscript: Burger, Grossman, Droller, Witjes, Stenzl, Jichlinski, Jocham.

Critical revision of the manuscript for important intellectual content: Burger, Grossman, Droller, Schmidbauer, Hermann, Drăgoescu, Ray, Fradet, Karl, Burgués, Witjes, Stenzl, Jichlinski, Jocham.

Statistical analysis: Burger, Grossman, Droller, Witjes, Stenzl, Jocham.

Obtaining funding: Burger, Grossman, Droller, Schmidbauer, Hermann, Drăgoescu, Ray, Fradet, Karl, Burgués, Witjes, Stenzl, Jocham.

Administrative, technical, or material support: None.

Supervision: Burger, Grossman, Droller, Witjes, Stenzl, Jocham.

Other (specify): None.

Financial disclosures: Maximilian Burger 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: All authors except Eleanor Ray, Juan Pablo Burgués, and Octavian Drăgoescu have received research grants in the past from Photocure to participate in clinical studies and have received financial support to present data at scientific meetings. Gregers Hermann and H. Barton Grossman have acted in the past as consultants to Photocure in the design of clinical studies.

Funding/Support and role of the sponsor: Photocure ASA, Oslo, Norway, and Ipsen, Paris, France, helped design and conduct the study, collect, manage, and analyze the data, and approved the manuscript.

Acknowledgement statement: We acknowledge the assistance of Jude Douglass, Healthcom Partners Ltd, Oxford, UK, for writing and editorial assistance. PharmaNet/i3, Cary, NC, USA, provided the statistical analysis.

Appendix A. Supplementary data

References

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Footnotes

a Department of Urology and Paediatric Urology, Julius-Maximilians University Medical Centre, Würzburg, Germany

b Department of Urology, MD Anderson Cancer Centre, Houston, TX, USA

c Mount Sinai Medical Centre, New York, NY, USA

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

e Department of Urology, Frederiksberg Hospital, Copenhagen, Denmark

f Department of Urology, Emergency County Hospital of Craiova, Craiova, Romania

g Urology Centre, Guys Hospital, London, UK

h Department of Urology, CHUQ Hôtel-Dieu de Quebec, Quebec, Canada

i Department of Urology, Klinikum Grosshadern, Munich, Germany

j Department of Urology, Hospital Universitario Son Espases, Palma de Mallorca, Spain

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

l Department of Urology, University of Tübingen, Tübingen, Germany

m Department of Urology, University Hospital, Lausanne, Switzerland

n Department of Urology, University of Lübeck, Lübeck, Germany

lowast Corresponding author. Oberdürrbacher Strasse 6 D, 97080 Würzburg, Germany. Tel. +49 931 201 32012; Fax: +49 931 201 32013.

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