Prof Petrisor Geavlete, Department of Urology, Saint John Emergency Clinical Hospital, Vitan-Barzesti 13, Sector 4, 042122, Bucharest, Romania. e-mail: firstname.lastname@example.org.
Study Type – Therapy (individual cohort)
Level of Evidence 2b
What's known on the subject? and What does the study add?
HAL fluorescence cystoscopy is known to improve tumour detection in NMIBC cases and to have a potentially favourable impact concerning the recurrence rates.
The present trial assessed the advantages of HAL cystoscopy with regard to postoperative treatment changes and 2 years' recurrence rates, subjects that are poorly evaluated in the literature.
• To evaluate in a prospective, randomized study the impact of hexaminolevulinate blue-light cystoscopy (HAL-BLC) on the diagnostic accuracy and treatment changes in cases of non-muscle invasive bladder cancer (NMIBC) compared with standard white-light cystoscopy (WLC).
• To compare the long-term recurrence rates in the two study arms.
PATIENTS AND METHODS
• In all, 362 patients suspected of NMIBC were included in the trial based on positive urinary cytology and/or ultrasonographic suspicion of bladder tumours and underwent transurethral resection of bladder tumours.
• A single postoperative mytomicin-C instillation was performed in all cases, intravesical chemotherapy for intermediate-risk patients and BCG instillations for high-risk cases.
• The follow-up protocol consisted of urinary cytology and WLC every 3 months for 2 years.
• Only first-time recurrences after the initial diagnosis were considered.
• In the 142 patients with NMIBC in the HAL-BLC series, tumour detection rates significantly improved for carcinoma in situ, pTa andoverall cases.
• In 35.2% of the cases, additional malignant lesions were found by HAL-BLC and consequently, the recurrence- and progression-risk categories of patients and subsequent treatment improved in 19% of the cases due to fluorescence cystoscopy.
• In all, 125 patients in the HAL-BLC group and 114 of the WLC group completed the follow-up.
• The recurrence rate at 3 months was lower in the HAL-BLC series (7.2% vs 15.8%) due to fewer ‘other site’ recurrences when compared with the WLC series (0.8% vs 6.1%).
• The 1 and 2 years recurrence rates were significantly decreased in the HAL-BLC group compared with the WLC group (21.6% vs 32.5% and 31.2% vs 45.6%, respectively).
• HAL-BLC was better than WLC for detecting NMIBC cases and improved tumour detection rates.
• HAL-BLC significantly modified the postoperative treatment of cases.
• The 3 months, 1 and 2 years recurrence rates were significantly improved in the HAL-BLC arm.
the European Organisation for the Research and Treatment of Cancer.
Bladder cancer, the most common malignancy of the urinary tract, remains an important and difficult to treat pathology in modern urology with non-muscle invasive bladder cancer (NMIBC) accounting for 75–85% of bladder tumours .
The standard approach in NMIBC management, white-light cystoscopy (WLC) and transurethral resection of bladder tumours (TURBT) is marked by recurrence rates as high as 50–70% within the first 5 years after the initial diagnosis . A very important factor concerning short-term recurrences is related to the failure to detect non-visible lesions in WL as well as to the incomplete resection of the primary tumours .
Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) was shown to markedly improve the detection rate of bladder tumours in general and flat lesions in particular . In the more recent years, the method has substantially improved due to the increased selectivity, brighter fluorescence and shorter instillation time provided by the introduction of hexaminolevulinate (HAL; Hexvix, GE Healthcare AS, Buckinghamshire, UK) cystoscopy .
Published trials have already established the favourable impact of HAL blue-light cystoscopy (HAL-BLC)on improving tumour detection as well as a more complete endoscopic resection, two of the main goals in NMIBC management .
As PDD has proved both applicable and profitable, especially in the detection of high-risk lesions, it has been stated that a decrease in recurrence rates may be expected, depending on data provided by prospective, randomized trials .
While 5-ALA fluorescence cystoscopy benefited from extensive long-term studies that proved a reduced recurrence risk in patients in which it was applied , evidence supporting the long-term advantages of HAL PDD is rather sparseat present.
Therefore, in the present study we attempted to determine the impact of HAL-BLC ondiagnosis of bladder cancer and changes in the postoperative treatment as well as recurrence rates during a follow-up period of 2 years in a prospective, randomized analysis.
PATIENTS AND METHODS
A single-centre, prospective, randomized, long-term trial was performed to evaluate the impact of HAL-BLC on the diagnostic accuracy, treatment changes and recurrence rates in patients with NMIBC compared with standard WLC.
The study was approved by the Local Ethics and Research Committee. In all, 362 patients (267 men and 95 women) with a mean (range) age of 66.8 (31–85) years suspected of bladder cancer were enrolled in the trial (under approved written informed consent properly explaining the aims, methods, anticipated benefits, potential hazards and any other aspect of the study relevant to the patient's decision to participate) and randomized by means of sealed envelopes, thus ensuring allocation concealment by the ‘sequentially-numbered, opaque, sealed envelopes’ method.
All patients underwent a standard investigation protocol that included general clinical examination, blood tests, urine analysis, urinary cytology, abdominal ultrasonography (US) and IVU or CT. The inclusion criteria were represented by positive urinary cytology and/or US suspicion of bladder tumours. The exclusion criteria consisted of: massive haematuria, moderate-to-severe leukocyturia, prior intravesical instillations earlier than ≤3 months and imaging aspects suggestive of upper urinary tract malignancy. Patients with cystoscopically detected bladder tumoursbefore inclusion were not enrolled in the trial.
In one arm, all 181 patients underwent standard (WLC) and fluorescence cystoscopy (HAL-BLC), conventional TURBT for all lesions visible in WL, BL resection for tumours only visible in BL and fluorescence control assessing the margins of the resection areas and eventual residual lesions. Separate bladder maps of all diagnosed lesions were described for the two types of cystoscopy. As part of the study protocol, during standard TURBT, the surgeon thoroughly followed the bladder map resulting from the WLC, thus avoiding resection of lesions only detected due to PDD. In each case, the urologist performing the procedure was informed on whether HAL-BLC would be available only after finishing the WLC to ensure maximum attention to the standard investigation. The 181 patients in the second arm benefited from standard WLC and TURBT alone.
A single postoperative mytomycin-C instillation was given during the first 6 h after surgery in all cases undergoing TURBT. All resected specimens were subjected to central pathology review. The overall, carcinoma in situ (CIS), pTa and pT1 cases and tumour detection rates were determined for both types of cystoscopy. According to the pathological results, all patients with no detected tumour as well as those with muscle-invasive bladder cancer were excluded from the trial.
The recurrence- and progression-risk category of every patient was established based on the European Organisation for the Research and Treatment of Cancer (EORTC) electronic calculators, as indicated by the European Association of Urology Guidelines 2010. Also in respect of the Guidelines, during follow-up, no additional instillations were applied in low-risk patients, while adjuvant mytomycin-C chemotherapy was used in intermediate-risk cases and intravesical immunotherapy with BCG for high-risk patients . The postoperative treatment changes related to the additional lesions found by either type of cystoscopy were also evaluated.
The follow-up protocol consisted of urinary cytology and WLC performed every 3 months for 2 years. Only first-time recurrences after the initial diagnosis were considered. Progression rates were also assessed.
To ensure the complete objectivity of the evaluation, the urologists performing the follow-up WLCs were unaware of the diagnostic and treatment method initially applied in each case. The recurrence rates were determined every 3 months for overall recurrences as well as to the initial tumour multiplicity and patients' history of bladder cancer.
The chi-square test and the binomial test were used to determine the statistical significance of differences between various variables in the study arms, with P < 0.05 considered to indicate statistical significance and a confidence level of at least 95%. With a sample size of 181 patients per arm at this confidence level, the trial was determined to have a power of 82.6% to detect a significant difference between the analysed characteristics of the study groups.
The proportion of patients diagnosed with NMIBC was significantly higher in the HAL-BLC series (78.5% vs 70.2%; P= 0.046), which also had significantly fewer tumour-free cases (7.2% vs 14.4%; P= 0.020) as well as a similar proportion of patients with muscle invasive bladder cancer (14.4% vs 15.5%; P= 0.441) compared with the WLC series (chi-square test).
For the 142 patients with NMIBC in the HAL-BLC group, there were significantly improved overall case and tumour detection rates compared with the standard WLC (85.9% vs 95.8% and 80.3% vs 92.2%, respectively). There were also significant differences in favour of HAL-BLC for CIS (Fig. 1) and pTa (Fig. 2) categories of patients and tumours, with a remarkable advantage provided by PDD for CIS lesions (detection rates per patients of 95.2% vs 71.4% and per lesions of 94.3% vs 62.9%). In pT1 tumours, better tumour detection was determined for HAL-BLC (Fig. 3) but this was not statistically significant. The diagnostic accuracy of HAL-BLC was significantly improved when compared with WLC regardless of tumour multiplicity and patients' history of bladder cancer (Table 1).
Additional tumours were found by HAL-BLC in a significantly higher proportion of NMIBC cases (Fig. 4) compared with the standard WLC (35.2% vs 14.1%). Thus, the superiority of HAL-BLC remained significant in all tumour stages and particularly in patients with CIS (47.6% vs 14.3%; Table 2).
Pathologically confirmed fluorescent-positive margins of WL diagnosed and resected tumours were found at the BL control in 8.5% of the cases (Fig. 5). The rate of false-positive results was slightly higher but not in a significant proportion for HAL-BLC (14.7% vs 11.6%; P= 0.052, binominal test).
There were no complications related to the HAL instillation.
Subsequent to the additionally found lesions, HAL-BLC significantly modified the recurrence- and progression-risk categories of patients as well as the related postoperative treatment compared with WLC (19% vs 6.3%). These treatment changes due to HAL-BLC were particularly important concerning the categories of patients that benefited from BCG immunotherapy and mytomicin-C chemotherapy instead of being declared tumour free (7.7% vs 1.4% and 4.2% vs 0.7%, respectively; Table 3).
Table 3. Risk category and postoperative treatment changes
Binomial test. LRR, low risk of recurrence; LRP, low risk of progression; IRR, intermediate risk of recurrence; IRP, intermediate risk of progression; HRR, high risk of recurrence; HRP, high risk of progression; I.I., immediate instillation.
No tumour → LRR, LRP
No treatment → 1 I.I.
No tumour → IRR, L/IRP
No treatment → Chemotherapy
No tumour → I/HRR, HRP
No treatment → BCG
LRR, LRP → IRR, IRP
1 I.I. → Chemotherapy
IRR, IRP → I/HRR, HRP
Chemotherapy → BCG
Overall risk category changes
Overall treatment changes
In the WLC group, 127 patients with NMIBC were diagnosed using only standard WLC and TURBT.
During the follow-up period, 17 patients in the HAL-BLC arm and 13 in the WLC arm did not complete the 2 years protocol and were consequently excluded from the trial.
There were no statistically significant differences in the NMIBC cases distribution related to tumour stage, grade, multiplicity and history of bladder cancer between the study groups that completed the 2-year follow-up.
At the 3-month WLC there was a significantly reduced recurrence rate in the HAL-BLC arm compared with the WLC arm (7.2% vs 15.8%), mostly due to less frequent ‘other site’ residual tumours (0.8% vs 6.1%). Throughout the entire 2 years follow-up, the recurrence rates remained significantly lower in the HAL-BLC arm. At 1 and 2 years, there were fewer recurrences after the initial HAL-BLC diagnosis (21.6% vs 32.5% and 31.2% vs 45.6%, respectively; Table 4).
Table 4. Recurrence rates during the 2-year follow-up period
The overall 2 years recurrence rates showed the significant advantages provided by HAL-BLC compared with the standard WLC in cases of initial multiple tumours (35.4% vs 54%) as well as regardless of the patients' history of bladder cancer (24.3% vs 37.1% in primary and 41.2% vs 59.1% in recurrent NMIBC cases; Table 4).
The progression rates were statistically similar (binominal test) in the HAL-BLC and WLC arms of the trial at 2.4% vs 4.4% (P= 0.195) at 1 year and 4% vs 7% (P= 0.123) at 2 years, respectively.
Published trials have described the significant improvements in endoscopic diagnosis of bladder tumours provided by fluorescence cystoscopy when compared with the standard WLC. The enhanced detection of the sometimes difficult to visualize flat lesions was emphasized as one of the most remarkable benefits of the method .
So, for CIS, one of the main targets of fluorescence cystoscopy, existing studies have established the clear advantages of PDD, with detection rates of 92–97% for HAL-BLC vs 58–68% for WLC [11–13].The present study also confirmed the superiority of HAL-BLC over WLC for CIS lesion detection, with a rate of 94.3% vs 62.9%.
The increased diagnostic accuracy of HAL-BLC compared with WLC has also been shown for pTa tumours, with detection rates of 95–97% vs 83–88% [12–14]. Data gathered during the course of the present trial confirmed these findings and established detection rates of 91.5% vs 80.9% for HAL-BLC vs WLC.
Both published data (96–97% vs 77–78%) [12,13] as well as the data from the present study (92.2% vs 80.3%) confirm the advantages provided by HAL-BLC over WLC for overall tumour detection rates.
Concerning the detection of NMIBC in patients, there are few published results, but publications confirm the superiority of PDD for detection of tumour-positive patients, particularly remarkable in patients with CIS .For CIS cases, detection rates have been reported of 87–96% for fluorescence cystoscopy and 77–83% for WLC [11,12]. Also, in the present study, CIS detection rates were significantly improved when using PDD (95.2% vs 71.4%).
The published overall detection rates of patients with NMIBC confirm the increased accuracy of HAL-BLC (96% vs 73%) ,which was also supported by the present findings (95.8% vs 85.9%). These results show that more than one in seven patients with NMIBC and more than one in four patients with CIS would have been diagnosed as tumour-free by standard WLC. The present trial also showed the advantages of HAL-BC for the detection of pTa patients (95.3% vs 87.1%).
Considering that significantly more patients with NMIBC were diagnosed in the HAL-BL arm compared with the WLC arm of the present study (78.5% vs 70.2%), it would appear that the HAL-BLC improved detection rate actually reflected on the overall results of this analysis for bladder cancer diagnosis.
On the other hand, both the primary and recurrent tumour detection rates were better in the HAL-BLC arm than the WLC arm (96.3% vs 87.6% and 95.1% vs 83.6%, respectively) and also in patients with single as well as multiple tumours (90.6% vs 73.6% and 98.9% vs 93.3%).
Published rates of false-positive results vary widely; however, they commonly report a relatively higher rate for fluorescence cystoscopy compared with WLC (13–39% vs 10–31%) [10–12]. The present study determined a slightly but not significantly increased rate of false-positive results for HAL-BLC (14.7% vs 11.6%), closer to the one obtained by Schmidbauer et al.  (13% vs 10%).
The proportion of cases in which PDD identified additional lesions has been described as significant in the published trials for all categories of tumour stage when compared with WLC: 41.5% vs 15.1% for CIS , 29.9% vs 9% for pTa  and 15.5% vs 5% for pT1 patients .The findings in present study were consistent with these and confirmed the superiority of HAL-BLC over WLC: 47.6% vs 14.3% for CIS, 30.6% vs 14.1% for pTa and 38.9% vs 13.9% for pT1 cases. Overall, at least one additional tumour was found using HAL-BLC in 35.2% of the NMIBC cases. In other words, in the absence of HAL-BLC, more than one in three patients would have left the operating room with at least one bladder tumour left in place, thus creating the premises for the future ‘recurrences’.
The improved cystoscopic examination under BL resulting in more tumours found and more NMIBC cases diagnosed naturally led to recurrence and progression risk category changes and to subsequently improved postoperative treatment. In all, 19% of the patients benefited from better adjuvant intravesical therapy. Published studies have also reported similar results in this particular category of patients as well as the related treatment changes, describing proportions of 13–17% for such cases [11,13,17].
It has been stated that BL resection can be expected to improve the quality of the endoscopic treatment by providing a more complete resection due to greater certainty of removing malignant lesions with a clear margin, including the sometimes barely visible extensions of the main tumour . In the present study, we found this presumption to be accurate, as 8.5% of the patients had pathologically confirmed fluorescent margins of WL resected tumours.
That there were no complications caused by the HAL instillation in the present series agrees with the satisfactory safety profile of HAL described in the literature .
Considering the improved tumour detection and more complete resections accomplished using fluorescence, various authors have confirmed the positive effect of this technology for patient management and follow-up, as well as for tumour recurrence .
As far as the standard diagnosis and treatment approach is concerned, a combined analysis of seven EORTC trials involving a total of 2410 NMIBC cases determined a recurrence rate of 13.1% at the first follow-up cystoscopy performed after a median period of 3 months .In the present trial there was a similar 3-month recurrence rate in the WLC arm (15.8%) but a significant decrease of in the HAL-BLC arm (7.2%). The ‘other site’ recurrence rate was similar in the above mentioned analysis and in the present WLC series (6.9% and 6.1%) and significantly reduced in the HAL-BLC series (0.8%). However, published data has already described the reduced but rather variable residual tumour rate obtained after initial 5-ALA PDD when compared with standard WLC (4.5–16% vs 25.2–39%) [8,21].
At the 9-month follow-up, the multi-centre prospective randomized trial by Stenzl et al.  reported significantly decreased recurrences obtained after initial HAL-BLC compared with WLC (36% vs 46%). The present study also confirmed the advantages of HAL-BLC vs standard WLC (17.6% vs 27.2%).
Variability in bladder cancer recurrence is commonly encountered in the literature. However, published studies are almost unanimously inclined towards the long-term beneficial impact of initial PDD. At 1 year, a combined analysis of 2596 patients that only underwent the standard WLC examination found a probability of recurrence of 15–61% .In this regard, extensive trials were performed to investigate the importance of 5-ALA PDD from the tumour recurrence point of view. Subsequently, 5-ALA cystoscopy was determined to reduce the recurrence rate in stage Ta/T1 bladder cancer .
The randomized trial by Daniltchenko et al.  reported a significantly improved 1-year recurrence rate in their 5-ALA series compared with the WLC series (43% vs 61%). In the present study, there was also a substantially improved 12 months recurrence rate in cases that initially benefited from HAL-BLC compared with those who only had standard WLC (21.6% vs 32.5%).
The overall recurrence rate also depends on the type of follow-up protocol applied in each study. The trial by Filbeck et al. , which used re-TUR as part of the treatment in all NMIBC cases, reportedthat for the BL and respectively WL study groups a residual tumour rate of 4.5% vs 25.2% and an additional 21-month recurrence rate of 11.4% vs 28.2%. In the present trial, the 21-month recurrence rate, which did not use re-TUR in any of the patients, was also significantly improved in the BL arm compared with the WL arm (29.6% vs 43.9%).
The advantages of BLC in cases of initial multiple tumours and recurrent NMIBC cases have been reported [22,24] and confirmed by the results of the present study where there was a reduced 2-year recurrence rate in HAL-BLC compared with the WLC group in these particular categories of patients (35.4% vs 54% and 41.2% vs 59.1%, respectively). Also, there was a difference in cases of primary NMIBC, which in the present trial benefited from decreased recurrence rates due to HAL-BLC (24.3% vs 37.1%). This aspect did not come as a surprise, as the published as well as the present data show that, from the clinical perspective, PDD offers a clear detection advantage at the time of primary diagnosis .
It is well-recognised that 5-ALA-induced fluorescence of the bladder significantly enhances the detection of CIS lesions  and that both 5-ALA and HAL-BLC detect significantly more tumour-positive patients than WLC alone , thus the question of differences in recurrence rates between the two types of PDD naturally arises.
Burger et al.  retrospectively analysed 5-ALA-BLC, HAL-BLC and WLC results and found significantly improved re-TUR residual tumour rates as well as 2-year recurrence rates for both kinds of fluorescence cystoscopy compared with the standard WLC (16% and 9% vs 32% at re-TUR; and 12% and 11% vs 21% at 24 months). Regardless of an apparent tendency of HAL-BLC to be better for the re-TUR rates, there was no statistically significant difference between 5-ALA-BLC and HAL-BLC, either during the short- or long-term follow-up. In the present study, the overall 2-year recurrence rate, which did not include re-TUR, was significantly decreased in the HAL-BL arm (31.2% vs 45.6%).
The issue of potentially improved long-term recurrence rates obtained from initial BLC diagnosisis still controversial. In the prospective, randomized study by Schumacher et al.  there was no clinical advantage of 5-ALA-BLC compared with standard WLC despite there being more CIS cases and more lesions found when using fluorescence, as the recurrence free-survival rates at 12 months were statistically similar in the 5-ALA-BLCand WLC arms of the study (50.4% vs 53.1%). From this perspective, the significantly reduced 1- and 2-year recurrence rates in the HAL-BLC arm of the present trial (21.6% vs 32.5% and 31.2% vs 45.6%, respectively) may be considered as promising, especially as other long-term recurrence data in HAL-BLC diagnosed patients apart from the trail by Burger et al.  are not available at this time.
As far as progression is concerned, in both the present study as well as published data no statistically significant difference in favour of PDD of patients has been found. For example, published trials have determined a 91.1% and 89.1% progression-free survival rate for the 5-ALA-BLC and WLC groups at 12 months , as well as a progression rate of 6% for 5-ALA, 4% for HAL and 3% for standard WLC series at 24 months . In the present trial, the progression rate was 2.4% vs 4.4% at 1 year and 4% vs 7% at 2 years for the HAL-BLC and WLC arms, respectively.
While long-term extensive trials have clarified the beneficial impact of PDD in the detection of bladder tumours  and the rather insignificant changes related to fluorescence cystoscopy with regard to progression , the effect of BL detection upon recurrence remains a point of debate. Although the advantages of BLC concerning the long-term recurrence rates in NMIBC cases are mostly confirmed by the literature , further randomized data specifically focused on HAL-BLC series will be required to confirm the importance of this method for tumour recurrence.
In conclusion, HAL-BLC significantly improved CIS, pTa and overall NMIBC patients' and tumours' detection rates compared with standard WLC. The diagnostic accuracy of fluorescence cystoscopy remained superior regardless of tumour multiplicity and patients' history of bladder cancer, while the rate of false-positive results was statistically similar for both methods.
For all tumour stages, additional lesions were found by HAL-BLC in a higher proportion of NMIBC cases compared with WLC. Consequently, fluorescence cystoscopy significantly modified the recurrence- and progression-risk categories of patients and improved the related postoperative intravesical instillation treatment.
At the 3-month follow-up, WLC revealed a significantly reduced recurrence rate in the HAL-BLC arm compared with the WLC arm, mostly due to the less frequent ‘other site’ residual tumours.
Throughout the entire 2 years follow-up, the recurrence rates remained significantly lower in the HAL-BLC arm. After 24 months follow-up, there were more frequent recurrences in the WLC arm in cases of initial multiple tumours, primary as well as recurrent bladder cancer. No significant impact of the initial PDD was established for tumour progression rate.
Further randomized, long-term studies will be necessary to confirm the potentially decreased recurrence rates provided by HAL-BLC in patients with NMIBC.
CONFLICT OF INTEREST
Bogdan Geavlete received honoraria from GE Healthcare when he spoke at a company-sponsored symposia.