Photodynamic diagnosis of non-muscle invasive bladder cancer using hexaminolevulinic acid.
ABSTRACT Bladder cancer (BC) is the most common tumor of the urinary tract. White light cystoscopy (WLC) is currently considered the standard investigation for diagnosis of bladder tumors. Recent studies suggest that using exogenous fluorescence (photodynamic diagnosis, PDD) can improve its diagnostic sensitivity and specificity.
Our study aims to analyze the value of using fluorescent cystoscopy (PDD) in the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC).
The study designed as a prospective randomized clinical trial was conducted over a 12 months period and included 44 patients with primitive NMIBC diagnosed and treated in our department in 2009. Twenty-two patients were included in the study group (PDD), while 22 patients were diagnosed and treated by conventional methods (WLC).
There were no statistically significant differences between the two groups regarding age, sex, place of origin, smoking history, clinical symptoms or presence of urological history as well as tumor size, location or number. Fluorescence cystoscopy examination identified 25.8% more tumors than the conventional examination (p=0.004). We demonstrated a significant reduction of tumor recurrence rates at 3, 6, 9 and 12 months by using PDD (HR=0.3271, 95% CI 0.1091-0.9809; p=0.0461).
The use of PDD in patients with NMIBC results in significant improvement of the efficiency of their initial diagnosis cystoscopy (by over 25%). We demonstrated improved patient prognosis and quality of life following conservative TUR treatment of these tumors by significantly reducing the tumor recurrence rate (by 9-27%) in the first year of follow-up.
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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.European Urology 04/2013; · 10.48 Impact Factor
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ABSTRACT: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the therapeutic outcome of fluorescence cystoscopy (FC) guided transurethral resection (TUR) in non-muscle invasive bladder cancer (NMIBC). Relevant RCTs were identified from electronic database (MEDLINE, Embase and the Cochrane Library). The proceedings of relevant congress were also searched. The primary parameters were recurrence rate, the time to fist recurrence, recurrence free survival rate (RFS) and progression rate. 12 RCTs including 2258 patients, which were identified for analysis in our study. Our study showed that the FC group have lower recurrence rate than the white light cystoscopy (WLC) group with statistically significant difference (OR: 0.5; p<0.00001). The time of the FC group first recurrence delayed significantly 7.39 weeks than WLC group (MD: 7.39 weeks; p<0.0001). There was a statistically significant difference in favor of FC in RFS at 1 yr (HR: 0.69; p<0.00001) and 2 yrs (HR: 0.65; p=0.0004). However, the FC group cannot significantly reduce the rate of progression into muscle invasive bladder cancer compared with the WLC group (OR: 0.85; p=0.39). FC guided TUR was demonstrated to be an effective procedure for delaying recurrence of NMIBC. Unfortunately, FC guided TUR could not significantly decrease the rate of progression into muscle invasive bladder cancer.PLoS ONE 01/2013; 8(9):e74142. · 3.53 Impact Factor
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ABSTRACT: Hexaminolevulinate (HAL) is an ester derivative of 5-aminolevulinate, and is used in conjunction with blue light (fluorescence) cystoscopy (BLC) to detect bladder cancer. In various studies, HAL-BLC was generally a better detection method than the gold standard method of white light cystoscopy (WLC), as assessed by endpoints including additional lesions (at both the lesion and patient levels) not detected by WLC, higher detection rates, and more complete treatment decisions as a result of improved detection. HAL-BLC in addition to WLC was associated with reduced tumor recurrence rates compared with WLC alone in randomized trials with up to 2 years' follow-up. HAL-BLC was generally well tolerated, and the most common adverse events (i.e. hematuria, dysuria, and bladder spasm) were also the most common adverse events in the WLC alone group, and were expected as a result of the resection procedure. Although its impact on disease progression and survival rates is not yet known, HAL-BLC is a valuable addition to WLC for the diagnosis of bladder cancer in patients who are suitable candidates for its use.Molecular diagnosis & therapy. 11/2013;
Rom J Morphol Embryol 2011, 52(1):123–127
O OR RI IG GI IN NA AL L P PA AP PE ER R
Photodynamic diagnosis of non-muscle
invasive bladder cancer using
O. DRĂGOESCU1), P. TOMESCU1), A. PĂNUŞ1), M. ENACHE1),
C. MARIA1), L. STOICA1), I. E. PLEŞEA2)
1)Department of Urology
2)Department of Pathology
Emergency County Hospital, Craiova
University of Medicine and Pharmacy of Craiova
Bladder cancer (BC) is the most common tumor of the urinary tract. White light cystoscopy (WLC) is currently considered the standard
investigation for diagnosis of bladder tumors. Recent studies suggest that using exogenous fluorescence (photodynamic diagnosis, PDD)
can improve its diagnostic sensitivity and specificity. Objective: Our study aims to analyze the value of using fluorescent cystoscopy (PDD)
in the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC). Patients and Methods: The study designed as a
prospective randomized clinical trial was conducted over a 12 months period and included 44 patients with primitive NMIBC diagnosed and
treated in our department in 2009. Twenty-two patients were included in the study group (PDD), while 22 patients were diagnosed and
treated by conventional methods (WLC). Results: There were no statistically significant differences between the two groups regarding age,
sex, place of origin, smoking history, clinical symptoms or presence of urological history as well as tumor size, location or number.
Fluorescence cystoscopy examination identified 25.8% more tumors than the conventional examination (p=0.004). We demonstrated a
significant reduction of tumor recurrence rates at 3, 6, 9 and 12 months by using PDD (HR=0.3271, 95% CI 0.1091–0.9809; p=0.0461).
Conclusions: The use of PDD in patients with NMIBC results in significant improvement of the efficiency of their initial diagnosis cystoscopy
(by over 25%). We demonstrated improved patient prognosis and quality of life following conservative TUR treatment of these tumors by
significantly reducing the tumor recurrence rate (by 9–27%) in the first year of follow-up.
Keywords: bladder cancer, recurrence, photodynamic diagnosis.
Bladder cancer (BC) is the most common tumor of
the urinary tract. At diagnosis, 70% of patients with
bladder cancer have superficial, non-muscle invasive
bladder cancer (NMIBC) . The natural evolution of
bladder cancer is marked by two distinct factors:
recurrence (up to 80%) that primarily affects quality of
life of patients and progression to infiltration and/or
metastasis (up to 15%) that affects the prognosis of
these patients leading to a 10-year disease specific
mortality of 4–36% [2, 3].
Pathological criteria (T-element), divide bladder
tumors into non-invasive BC (Tis, Ta) and invasive BC
(T1–T4). A series of clinical and prognosis criteria led
to their breakup into two therapeutic groups currently
widely accepted: superficial BC (Tis, Ta, T1 – non-
muscle invasive bladder cancer – NMIBC) and
infiltrative BC (T2–T4 muscle invasive and metastatic
bladder cancer) .
Cystoscopy and urine cytology are the standard
diagnosis methods for bladder cancer, but their
sensitivity is still unsatisfactory (65%). The standard
treatment for all NMIBC is the complete eradication by
transurethral electroresection (TUR), a relatively simple
procedure, but often incomplete, where BC recurrence
or presence of residual tumor are quite common (>35%)
. Thus, it became obvious the need to develop
diagnostic and therapeutic strategies designed to provide
early diagnosis and correct management of superficial
bladder tumors to reduce the recurrence rate and avoid
tumor progression. White light cystoscopy (WLC) is
currently considered the standard investigation for
diagnosis of bladder tumors. Recent studies suggest that
using exogenous fluorescence (Photodynamic diagnosis,
PDD) may improve diagnostic sensitivity and specificity
with an impact on the recurrence and progression rate of
Our study aims to analyze the significance of using
fluorescent cystoscopy (PDD) diagnosis and treatment
of non-muscle invasive bladder cancer (NMIBC). We
thus consider the possibility to improve the diagnostic
accuracy of cystoscopy examination using fluorescent
cystoscopy in patients with NMIBC and to increase
the radicality of the treatment of these tumors by
using photodynamic assisted TUR that may finally lead
to a reduction in the recurrence and tumor progression
R J M E
Romanian Journal of
Morphology & Embryology
O. Drăgoescu et al.
? Patients and Methods
The study designed as a prospective randomized
clinical trial was conducted over a 12 months period and
included 44 patients with primitive NMIBC diagnosed
and treated in our department in 2009. Of these, 22
patients were included in the study group (PDD group),
while 22 patients were diagnosed and treated by
conventional methods (WLC group). Distribution of
patients in both groups was conducted in a randomized
single blind manner.
Patients in the PDD group received 85 mg
Hexaminolevulinic Acid (HAL – Hexvix®) instillation
1–2 hours prior to cystoscopy. All patients initially
underwent a cystoscopy examination followed by the
resection of the tumors identified. Patients in the PDD
group underwent an additional PDD cystoscopy
examination with fluorescent D-Light® System
(STORZ) as well as photodynamic assisted tumor
resection (TUR – PDD).
Bladder biopsies were performed in selected cases
from bladder mucosa areas considered suspicious at
white light or PDD cystoscopy examination as well as
from normal bladder mucosa.
Given the high risk of relapse and/or progression
after TUR, modern treatment guidelines recommend the
use of intravesical chemotherapy (Mitomycin C or
Doxorubicin – Farmorubicin) within six hours after
TUR for all NMIBC. These tumors were divided based
on clinical and developmental study by the European
Organization for Research and Treatment of Cancer
(EORTC) in three risk categories that benefit from
different adjuvant treatment strategies as recommended
by the European Association of Urology (EAU) :
▪ low-risk NMIBC: pTaG1 – single <3 cm, non-
▪ intermediate risk NMIBC: pTaG3, pT1G1/G2
single pTaG1/G2 recurrent, multifocal;
▪ high-risk NMIBC: recurrent pT1, multifocal,
pT1G3, Ta/T1 >3 cm, CIS.
Depending on the risk group the recommendations
following TUR are: simple surveillance of the group
with low risk tumors, adjuvant intravesical chemo-
therapy for intermediate-risk group and adjuvant intra-
vesical immunotherapy with BCG vaccine for high-risk
group [7, 8].
Accordingly, all patients included in the study
underwent a postoperative chemotherapy instillation of
30–50 mg Farmorubicin within six hours after surgery
and then received additional treatment according to risk
group. Patients were followed by quarterly white light
cystoscopy examinations for 12 months as suggested by
recent studies .
Statistical data analysis was performed using the
MS Excel and MedCalc 10.2 software.
Mean patients age was 60.4 ± 9.4 years and most of
them were males (sex ratio = 7/2). Smoking has been
identified as a risk factor in 68.2% of patients. For 12
patients (27.2%) urological history was identified
(benign prostatic hyperplasia, urethral strictures, bladder
stones and chronic urinary tract infections). There were
no statistically significant differences between the two
study groups regarding age, sex, place of origin, smoking
history and presence of urological history (Table 1).
Table 1 – Characteristics of the two study groups
Age [years] 62.09±12.46 58.77±14.31 p=ns
Sex ratio (B/F) 2.66 4.5 –
Urban [%] 54.5 45.4 –
Smokers [%] 72.7 63.6 –
Urological history [%] 22.7 31.8 –
No. of tumors
Number of tumors PDD
group (*PDD vs. white
Location left / right (n=)
Location post. / bladder
1.48 ± 0.73 1.66±0.94 p=ns
8/5 6/6 –
4/4 5/4 –
2.02±0.84 1.95±0.58 p=ns
Ta/T1 (n=) 6/16 4/18 –
G1/G2/G3 (n=) 7/12/3 6/14/2 –
Clinically, most patients in both groups had gross
hematuria (34 cases – 77.2%; 18 in the WLC group –
81.8% and 16 in the PDD group – 72.7%) sometimes
associated with lower urinary tract symptoms (frequency
– 14 cases, 31.8%; dysuria – eight cases, 18.2%). In
eight patients, the diagnosis was established incidentally
during investigations for other pathological conditions.
There were no statistically significant differences
between the two groups in terms of clinical symptoms.
At the initial examination, cystoscopy identified
a total of 65 tumors in both groups while PDD
examination identified eight additional tumors (total
73). White light cystoscopy identified 34 tumors in the
WLC group and 31 in the PDD group (1.41 ± 0.59) as
well as seven cases of false positive bladder biopsies
(WLC sensitivity = 79.5%). Fluorescence cystoscopy
examination identified a significantly higher number of
tumors in the PDD group (39 tumors, average 1.77 ±
1.02), 25.8% more than conventional examination
(p=0.004). The PDD group included four cases of false
positive PDD results with negative bladder biopsies and
three patients with false negative PDD examination
(PDD sensitivity = 92.8%). We also performed eight
negative white light cystoscopy examinations and five
negative PDD examinations that were not included in
Average tumor size was 1.84 ± 0.57 cm (2.02 ± 0.84
cm for the WLC group and 1.95 ± 0.58 cm for the PDD
group). There were no statistically significant differences
between the two groups regarding tumor size, location,
or their number.
In terms of the depth of invasion (T), 77% of
tumors were T1 and 23% Ta. Also, regarding tumor
differentiation grade 36.3% of tumors were G1, 52.3%
G2 and 11.3% G3. By the EORTC risk classification,
intermediate risk was the predominant category (21
Photodynamic diagnosis of non-muscle invasive bladder cancer using hexaminolevulinic acid
patients – 47.7%) followed by the high-risk category
(15 patients – 34.1%).
WLC and PDD images of bladder cancers are
presented in Figures 1 and 2, showing characteristic red
fluorescence of bladder tumors and blue background
represented by the normal urothelial tissue under blue
light PDD cystoscopy examination using the D-Light
system at approximately 1–2 hours after Hexvix bladder
Figure 1 – Non-muscle invasive bladder tumor on
the left side wall (white light cystoscopy – left and
PDD – right) in a 60-year-old male patient (HP –
moderately differentiated urothelial carcinoma with
invasion of the sub-epithelial tissue – T1G2).
Figure 2 – Non-muscle invasive bladder tumor on
the posterior wall (white light cystoscopy – left and
PDD – right) in a 57-year-old male patient (HP –
poorly differentiated urothelial carcinoma with
invasion of sub-epithelial tissue – T1G3).
Figure 3 presents a 48-year-old female patient
diagnosed with T1G2 papillary tumor as well as un-
characteristic PDD positive multiple bladder nodules on
the posterior-lateral right bladder wall (right) that were
almost invisible under WLC examination (left). The
nodules were biopsied and pathological examination
showed high degree intraepithelial urothelial dysplasia
Figure 3 – Appearance of multiple bladder nodules
on the posterior-lateral right bladder wall (white light
cystoscopy – left and PDD – right) in a 48-year-old
female patient (HP – urothelial high degree intra-
This finding may be of crucial importance if PDD
proves to be able to early detect flat urothelial lesions
such as high degree premalignant dysplasia as well as
carcinoma in situ (CIS). Unfortunately, our study group
did not include any other similar lesions or CIS.
In terms of post-treatment recurrences, we identified
four cases (9.09%) of patients with tumor recurrences at
the first cystoscopy check performed at three months
(three in the WLC group – 13.64% and one in the PDD
group – 4.55%), seven cases – 15.91% at six months
(five in group WLC – 22.73% and two PDD group –
9.1%), 11 patients with recurrence at nine months –
25% (eight in group WLC – 36.36% and three the PDD
group – 13.64%) and 14 to 12 months of surveillance –
31.82% (10 in the WLC group – 45.45% and four PDD
group – 18.18%). Noticeably the recurrence rate was
decreased by 9.1%, 13.6%, 22.7% and 27.3% at 3, 6, 9,
and 12 months for the PDD group (Figure 5).
Using Kaplan–Meier survival curves (Figure 6), we
analyzed the recurrence-free survival rates for the two
groups in a timely manner and obtained better results
for the PDD group (HR=0.3271, 95% CI 0.1091–
0.9809; p=0.0461), which confirmed the significant
reduction of recurrence rates by using the PDD system
(p=0.0408) that becomes an independent positive
We identified three cases (6.8%) of tumor
progression (one in the PDD group and two in the WLC
group). Data was insufficient for a thorough analysis of
the tumor progression rates.
Figure 4 – The same patient: bladder wall with uneven, atrophic urothelium (HE stain, 40× – left); urothelial high
degree intraepithelial dysplasia – detail (HE stain, 200× – right).
O. Drăgoescu et al.
Figure 5 – Tumor recurrence rates for patients in the
two groups at the cystoscopy controls performed in
the first year of follow up (3, 6, 9, and 12 months).
Figure 6 – Kaplan–Meier analysis of recurrence-free
survival for the two groups during 12 months follow-
up demonstrates the advantages of PDD use
Based on a random bladder biopsies correlation
model, Kriegmair M et al.  were the first who
reported a significant increase in sensitivity of diagnosis
of flat urothelial lesions and papillary tumors by
assessing them with porphyrin-induced fluorescence
using aminolevulinic acid (ALA). Specificity was up to
97% with a sensitivity of 65% comparable to white light
cystoscopy (WLC). In a larger study, a Münich Group
 reported similar values of specificity and sensitivity
of 96% and 65% on a group of over 1000 patients.
According to their data, 34% of tumors detected by
PDD with ALA were not observed during WLC and
38.7% of tumors were high-risk group. In a later study
they showed that PDD identified 30% more urothelial
dysplasia lesions and 53% more CIS than WLC
showing that PDD is clearly more effective than WLC
in detecting flat urothelial lesions . Using the new
WHO classification of urothelial tumors (2004), many
of the injuries previously considered moderate dysplasia
cancers are now considered high-risk intra-epithelial
carcinoma supporting the importance of increasing the
rate of detection of these tumors with PDD  as
suggested by our study as well.
At the same time, similar to our study, several
studies have compared the effectiveness of PDD using
HAL with the conventional white light cystoscopy
(WLC). Jichlinski P et al.  reported a sensitivity of
96% (similar to ALA) compared to 73% for WLC.
Another study including 211 patients with primary or
recurrent bladder cancer, who received an instillation of
HAL, shows that the diagnosis efficiency is increased
by up to 28% compared to the WLC method. Data is
similar to our findings – 25.8% increase of diagnosis
Resection or complete destruction of all bladder
tumors is considered as the main factor preventing the
recurrence of bladder tumors . In this context, the
clinical relevance of PDD was highlighted by many
authors. In prospective randomized trials, patients with
clinical suspicion of bladder tumor were divided into
risk groups and were treated by white light TUR or after
administration of ALA. At 2–6 weeks, they underwent
a new cystoscopy and TUR. Riedl CR et al. 
investigated 102 such patients showing a 59% reduction
in the tumor recurrence rate in patients with photo-
dynamic assisted tumor resection, which was confirmed
by other trials [16, 17].
To prove if the growth rate of detection of tumor
lesions as well as lower residual tumor rate affects the
rate of tumor recurrence, Filbeck T et al. [18, 19]
conducted a randomized trial to compare the white light
TUR and PDD assisted TUR (ALA). Patients were then
followed at three months with urinary cytology and
classic cystoscopy. Average follow up was 43 months
for 191 patients. Recurrence-free rates at 12, 24 and 48
months were 90.9%, 90.9% and 90.85% in the PDD
group and 78.6%, 69.9% and 60.7% respectively in the
white light TUR group (p<0.001). PDD obvious
superiority became an independent prognostic factor
with an adjusted hazard rate of 0.29 between the two
groups (95% CI 0.15–0.56) similar to our result
(HR=0.3271, 95% CI 0.1091–0.9809; p=0.0461).
Use of photodynamic diagnosis (PDD) in patients
with NMIBC results in significant improvement of
the sensitivity and efficiency of their initial diagnosis
cystoscopy (by 25%). We demonstrated improved
patient prognosis and quality of life following conser-
vative PDD assisted TUR treatment of these tumors by
significantly reducing the tumor recurrence rate (by 9–
27%) in the first year of follow-up. Our results also
suggest that PDD may be able to early detect flat
urothelial lesions such as high degree pre-malignant
dysplasia or CIS. More complete results will obviously
require including more patients in the study and having
longer follow-up periods.
BC – bladder cancer;
NMIBC – non-invasive bladder cancer;
WLC – white light cystoscopy;
TUR – transurethral resection;
Photodynamic diagnosis of non-muscle invasive bladder cancer using hexaminolevulinic acid
PDD – photodynamic diagnosis;
ALA – aminolevulinic acid;
HAL – hexaminolevulinic acid;
HR – hazard ratio;
CI – confidence interval.
This clinical study was conducted with financing
from the National Exploratory Research Project
Program (PCE–2), CNCSIS Contract No. 1287/2008.
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Accepted: February 18th, 2011