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Keywords:

  • Ta/T1 bladder cancer;
  • recurrence-free interval;
  • fluorescence cystoscopy;
  • 5-aminolaevulinic acid;
  • transurethral resection

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVE

To assess the influence of 5-aminolaevulinic acid-induced fluorescence cystoscopy (FC) during transurethral resection (TUR) on the recurrence rate and the length of tumour-free interval in stage Ta/T1 transitional cell carcinoma (TCC) of the urinary bladder.

PATIENTS AND METHODS

In all, 122 patients with primary or recurrent stage Ta/T1 bladder TCC treated with TUR were enrolled in a prospective randomized study. In group A the TUR was performed with standard white-light endoscopy, and in group B with FC. The patients were followed using standard cystoscopy and urinary cytology. The recurrence-free interval was evaluated in whole groups, for single and multiple, and for primary and recurrent tumours separately.

RESULTS

At the time of the first cystoscopy (10–15 weeks after TUR) tumour recurrence was detected in 23 of 62 patients (37%) in group A, but only in five of 60 patients (8%) in group B. The recurrence-free survival rates in group A were 39% and 28% after 12 and 24 months, compared to 66% and 40% respectively in group B (P = 0.008, log-rank test). In separate analyses, the recurrence-free survival rates were significantly higher using FC in multiple (P = 0.001) and in recurrent (P = 0.02) tumours. In solitary and primary tumours the median time to recurrence was also longer in group B, but the difference was not statistically significant.

CONCLUSION

5-aminolaevulinic acid-induced FC during TUR reduces the recurrence rate in stage Ta/T1 bladder TCC. The most significant benefit is in patients with multiple and recurrent tumours.


Abbreviations
5-ALA

5-aminolaevulinic acid

FC

fluorescence cystoscopy

TUR

transurethral resection

CIS

carcinoma in situ.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Depending on the duration of follow-up, up to 80% of stage Ta/T1 bladder tumours will recur after transurethral resection (TUR) [1]. A substantial number of recurrences are reported as early as the first follow-up cystoscopy 3 months after the initial TUR. Many of these so-called ‘early recurrences’ are persistent tumours that were not noticed during resection [2]. Any method that improves endoscopic tumour detection would be beneficial, by enabling more effective tumour resection, especially in multifocal disease, and could decrease early recurrence rates.

Fluorescence cystoscopy (FC) using 5-aminolaevulinic acid (5-ALA) applied intravesically was first described in 1994 [3]. Subsequent research showed that significantly more tumour lesions could be detected with FC than with conventional cystoscopy [4–6]. The aim of the present prospective randomized study was to assess the influence of FC during TUR on the recurrence rate and length of tumour-free intervals in stage Ta/T1 bladder tumours.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Patients with suspected primary or recurrent superficial urinary bladder tumours planned for TUR who had been given a consent form were enrolled in the study from September 2001 to December 2003. Patients with a history of surgical or instillation intravesical therapy within the previous 3 months were excluded. The patients were randomly assigned to two groups: for group A, conventional cystoscopy with noncoherent white light was used; for group B, both conventional and 5-ALA-induced FC were used. The results were recorded by one person (V.S.). Patients with muscle-invasive tumours were excluded after histological examination. The study was approved by the ethical committee of our institution.

In group A, patients underwent a standard TUR of bladder tumours using white light. Except for small papillary tumours, a biopsy was taken from the tumour base. Suspicious flat lesions were resected or biopsied and coagulated. After TUR, endoscopy using a 70° telescope was always used to exclude the possibility of residual tumour.

In group B, 5-ALA was applied intravesically through a thin catheter 1.5–3 h before surgery. The solution was always prepared just before instillation by dissolving 1 g of 5-aminolaevulinic hydrochloric acid (Science for Life, Czech Republic) in 20 mL of sodium hydrogen carbonate to a final pH of 5.5–6.0. During the inspection and TUR a system for FC (Olympus Winter & Ibe GMBH, Germany) was used consisting of a source of light that enables alternation of white and blue excitatory light, and optics with a corresponding absorption filter. The strategy of resection was the same in group B as in group A. For inspection before, during and after resection both white and blue light was used.

Of the 128 patients entered into the study, six (two in group A and four in group B) were excluded after histological examination, as in two there was no histological evidence of TCC, in three there was muscle invasion, and in one there was a multiple T1G3 tumour with concomitant carcinoma in situ (CIS) treated with immediate cystectomy. The remaining 122 patients (62 in group A and 60 in group B) were appropriate candidates for the study. Table 1 gives a detailed description of both groups.

Table 1.  The baseline characteristics of patients
VariableGroup A (white light)Group B (FC)P
Total patients, n6260 
Mean age, years69.867.90.36
Female/male, n23/3917/430.3
Grade, n
G1/G2/G333/22/730/24/60.87
Ta/T137/2538/220.68
Primary/recurrent, n28/3420/400.18
Mean previous recurrences
in recurrent tumours, n 2.8 2.70.68
Mean previous disease-free
interval in recurrent tumours, months15.622.10.69
Single/multiple tumours, n24/3815/450.1
Tumour size (cm), n
<1/1–3/>316/34/1215/33/120.99
Mean (sd) follow-up, months20.7 (10.0)22.4 (9.6)0.62

The patients were followed using standard cystoscopy and urinary cytology after TUR. The first control was carried out 10–15 weeks after TUR and at 3-month intervals thereafter during the first year. In patients with low-risk tumours the interval was extended to 6 months in the second year. If there were suspicious endoscopic findings or positive cytology, resection or biopsy was performed after conventional endoscopy. Tumour recurrence and progression in invasive disease were always confirmed histologically.

None of the randomized patients with grade 1 or grade 2 tumours received adjuvant intravesical therapy during the study. All patients with grade 3 tumours (seven in group A and six in group B) had intravesical BCG (Connaught strain) immunotherapy, based on a standard 6-week course followed by three, weekly instillations (3-week course) at 3, 6 and 12 months. The first endoscopic control in these patients was performed under anaesthesia with white-light cystoscopy and with biopsies taken from suspect areas.

For comparing the means of two independent random samples, the anova test or Wilcoxon unpaired test (if there was a non-Gaussian distribution of measured variables) were used. The relation between nominal variables was analysed by a chi-square test or Fisher's exact test. The principal endpoint to assess the advantage of FC during TUR was the recurrence-free interval, defined as the time from TUR to the time of initial recurrence. Recurrence-free curves for both groups were also calculated according to the Kaplan-Meier method and compared by the log-rank test. Separate analyses were performed for solitary and multifocal tumours and for primary and recurrent tumours. The level of significance was selected as P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

There were no significant differences in tumour and demographic characteristics between the groups (Table 1). At the time of the first cystoscopy (10–15 weeks after TUR) tumour recurrence was detected in 23 of the 62 patients (37%) in group A (standard cystoscopy), but only in five of the 60 patients (8%) in group B (FC guided TUR). When the rate of tumour recurrence was considered separately according to the primary tumour characteristics it was also lower in patients in group B (Table 2).

Table 2.  The recurrence rate at first cystoscopy in relation to the primary tumour characteristics
Tumour characteristic at entry into the study% recurrence at first cystoscopy (n/N)
Group A (white light)Group B (FC)
All tumours37 (23/62) 8 (5/60)
G130 (10/33) 3 (1/30)
G246 (10/22)13 (3/24)
G3 3/7 1/6
Ta27 (10/37) 5 (2/38)
T152 (13/25)14 (3/22)
Primary29 (8/28) 5 (1/20)
Recurrent44 (15/34)10 (4/40)
Solitary17 (4/24) 2/15
Multiple50 (19/38) 7 (3/45)
Tumour size, cm
< 1  6/16 1/15
1–3 29 (10/34) 6 (2/33)
> 3  7/12 2/12

The recurrence-free curves for groups A and B are shown in Fig. 1. The recurrence-free survival rates in group A were 39% and 28% after 12 and 24 months compared to 66% and 40% respectively in group B (Table 3). The median time to recurrence was 8.05 months in group A and 17.05 months in group B (log-rank test, P = 0.008).

image

Figure 1. Kaplan-Meier curves of the percentage of patients remaining free of recurrence. Green, TUR with white light (group A, 62 patients); red, TUR with both FC and conventional cystoscopy (group B, 60 patients). Patients at risk at 0, 6, 12, 18, 24, 30 and 36 months: Group A, 62, 35, 23, 12, eight, six and three; Group B, 60, 52, 39, 20, 12, eight and two.

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Table 3.  Kaplan-Meier estimates of 12 and 24-month recurrence-free rates
 Group A (white light)Group B (FC)P (log-rank test)
Overall  0.008
Number of patients6260 
12 months, %3966 
24 months, %2840 
Multiple  0.001
Number of patients3845 
12 months, %3262 
24 months, %1339 
Solitary  0.47
Number of patients2415 
12 months, %5280 
24 months, %4846 
Primary  0.13
Number of patients2820 
12 months, %4685 
24 months, %3439 
Recurrent  0.02
Number of patients3440 
12 months, %3357 
24 months, %2340 

Recurrence-free curves were also calculated separately for single (not shown) and multiple tumours (Fig. 2). Of patients with multiple tumours, 32% and 13% of patients in group A were recurrence-free at 12 and 24 months respectively, compared to 62% and 39% of patients in group B (Table 3). The median time to recurrence in patients with multiple tumours was significantly shorter in group A than in group B (4.45 months vs 13.54 months; P = 0.0012). The difference in solitary tumour recurrence between the groups was not statistically significant. In separate analyses of primary (not shown) and recurrent tumours (Fig. 3) there was a significant difference only in recurrent tumours (P = 0.019).

image

Figure 2. Kaplan-Meier curves of the percentage of patients remaining free of recurrence of those with multiple tumours at entry into the study. Green, TUR with white light (group A, 38 patients); red, TUR with both FC and conventional cystoscopy (group B, 45 patients). Patients at risk at each time: Group B, 38, 17, 11, four, two, two and one; Group B, 45, 39, 27, 13, seven, four and one.

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image

Figure 3. Kaplan-Meier curves of the percentage of patients remaining free of recurrence, for patients with recurrent tumours at entry into the study. Green, TUR with white light (group A, 34 patients); red, TUR with both FC and conventional cystoscopy (group B, 40 patients). Patients at risk at each time: Group A, 34, 16, 11, seven, five, four and three; Group B, 40, 33, 22, 14, eight, five and one.

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When only patients with grade 3 tumours were evaluated, recurrence was detected in group A in three after 3 months, in one after 6 months and in one after 9 months. In group B recurrence was detected in one patient after 3 months and in one after 12 months. Progression in invasive disease appeared in five patients 6–15 months after initial TUR in group A and in five at 9–15 months after entry into the study in group B.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

There are four basic mechanisms explaining early recurrences of Ta/T1 urinary bladder tumours after TUR: a new occurrence of the tumour; implantation of cancer cells from the primary tumour at the areas of the epithelium that were damaged during resection; incomplete resection of the tumour; and growth of coexisting microscopic lesions not visible endoscopically during surgery [7]. The last two possibilities are based on an imperfect TUR, reflected by a reported rate of malignant tissue of 32–36% in a second resection 1–7 weeks after the initial TUR [8–10]. This risk is higher in T1G3 and in multiple tumours, where it increases with the number of tumour lesions [2,11]. The rate of tumour recurrence can thus be reduced when TUR is as complete as possible. It can be anticipated that the improved detection of tumour by FC during TUR can make eradication easier and more effective.

The residual tumour decrease when using FC during TUR has been shown by several studies. Riedl et al.[12] found, in a second TUR at 6 weeks after the initial TUR, that malignant tissue was present in 39% of patients in the white-light endoscopy group compared to only 16% in the FC group. Kriegmair et al.[13] compared the rate of residual tumours 10–14 days after initial resection. In an intent-to-treat analysis, they showed that 41% of tumours were resected tumour-free at primary TUR with white-light endoscopy, compared to 62% with FC-guided resection (on protocol analysis, 47% and 67%, respectively). Filbeck et al.[14], in a prospective randomized study with 191 patients, reported a residual tumour rate 5–6 weeks after TUR of 25% in the white-light group vs 5% in the FC group. The mean follow-up of > 20 months in that study allowed an assessment the influence of FC-guided TUR on the time to the first evidence of recurrence; recurrence-free survival was significantly higher in the FC group (89.6% after 12 and 24 months) than in the white-light group (73.8% and 65.9%).

The aim of the present study was to assess the influence of FC on the recurrence rate and length of the tumour-free interval. Unlike the study of Filbeck et al.[14], no second resection was performed and intravesical prophylaxis was limited to patients with grade 3 tumours. The present results show a lower recurrence rate in patients where FC-guided resection was used. The positive effect of FC on the recurrence rate was apparent even 24 months after TUR. This finding corresponds with the results of Filbeck et al.[14]; however, in the present study, the influence of the type of endoscopy on recurrence rate was more evident at 12 than at 24 months.

Separate analyses for solitary and multifocal tumours, and for primary and recurrent tumours, were performed to assess exact indications for FC. The reason for analysing these subgroups was that tumour multiplicity is considered the most important predictive factor for tumour recurrence. In separate analyses, the median time to recurrence was significantly longer using FC in multiple and in recurrent tumours. In solitary and primary tumours the median time to recurrence was also longer in the FC group, but the difference was not statistically significant. This can be explained by the advantage of the excellent visibility during FC-guided TUR that can be exploited better in multifocal tumours. Better results in patients with recurrent tumours in the FC group can be explained similarly. These tumours are more often multiple than are primary ones. In the present study, 54% of primary tumours in group A and 40% in group B were solitary, compared to only 27% of recurrent tumours in group A and 18% in group B. It is also possible that the differences were not statistically significant in solitary and primary tumours because there were too few patients and recurrences in these subgroups, with the associated low statistical power.

Most studies emphasize the value of FC in high-grade tumours, based particularly on the superiority of FC over standard cystoscopy for detecting CIS lesions [4–6,15]. The early detection and the estimate of adverse biological tumour potential can improve the patients’ therapy and outcome. Only 14 patients with grade 3 tumours were enrolled in the present study, which makes separate analysis of this subgroup impossible. Although there were few patients, there was a higher rate of concomitant CIS detected with FC (three of seven patients in group B but only in one in group A). In patients with grade 3 tumours, there were fewer recurrences when FC-guided TUR was performed (group B). The present results thus seem consistent with the conclusions of other authors who have studied the benefits of FC on recurrence rate in high-risk tumours [14]. Nevertheless, other studies are needed to confirm that FC use decreases the risk of progression and tumour-related death in high-risk superficial tumours.

We are aware of weaknesses in the present study, including the relatively few patients in some subgroups, and that this was not a multicentre study. Nevertheless, the findings are important for evaluating FC for stage Ta/T1 bladder tumours. The present results justify the use of FC during TUR in patients with multiple and recurrent tumours. However, in our department FC is used also for single and primary tumours, and we think that the decrease in the recurrence rate found in these subgroups will be statistically confirmed in a larger series of patients in the future.

From a practical perspective many other questions need to be answered. The low risk of residual tumour after FC-guided TUR raises the question about which patients with Ta/T1 bladder TCC should have a second TUR. It was confirmed that FC can effectively prevent tumour persistence in areas outside the first resection [12,14]. A second resection after FC-guided TUR should thus be limited to patients with a high risk of residual tumour at the base of the original resection area. This particularly includes patients where no muscle is present in the specimen, and patients with large T1G3 tumours. However, the individual strategy for different tumour groups must be clearly defined by a prospective study.

Similarly, the indication for adjuvant intravesical chemotherapy after FC-guided TUR needs to be considered carefully. The present results and those of other studies suggest that FC is unable to solve the whole problem of early recurrences in stage Ta/T1 bladder TCC [12–14]. The explanation can be found in tumours cells implantation, and is a strong argument for immediate postoperative chemotherapy instillation, the efficacy of which was recently confirmed by a large meta-analysis [16].

In conclusion, 5-ALA-induced FC used during TUR reduces the recurrence rate in stage Ta/T1 bladder TCC; a statistically significant benefit was confirmed for patients with multiple and recurrent tumours. The median time to recurrence in single and primary tumours was also shorter in the FC group (group B) but the difference was not statistically significant.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

We are grateful to our nurses, Eva Slavkovská and Jaroslava Cejnarová, for their assistance. The study was supported by the projects IGA MZ ND 6854–3 and ND 8095–3.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

None declared. Source of funding: Grant of Czech Health Ministry.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES
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