Why is advanced tumour visualisation useful? A constructive review of imaging (PDD, NBI, IMAGE1 S)
alone without SIIC was associated with a lower probability of a 12-months recurrence rate and the addition of SIIC further lowered recurrence rates. Results for NBI were comparable to those of PDD according to the surface under the cumulative ranking (SUCRA) curve. There were only a small number of randomised controlled clinical trials with NBI, which the authors noted as a limitation [2]. In another recent systematic review and meta- analysis of 12 randomised controlled trials (RCT) with 2,288 patients, authors compared TURBT using WLC to PDD. The primary outcomes were recurrence rates at 12 and 24 months. The secondary outcome was to evaluate reported adverse effects. Authors focused on the medium- and long-term effects of PDD and studies reporting results from shorter periods were excluded. Use of PDD led to a reduction of recurrence rates at both 12 months and 24 months. Use of WLC only was clearly associated with increased risk of recurrence after 12 and 24 months, respectively. According to GRADE analysis, the certainty of evidence was considered moderate for recurrence rate outcomes. Two included studies reported lower recurrence rates even after 60 months of follow up. Only two out of twelve studies reported all encountered adverse events, including haematuria and bladder irritation symptomatology (spasms, frequency and urgency). In one case, the frequency of adverse events was similar between PDD and WLC, while the other reported higher rates of symptoms in the PDD group (28% vs 17.5%) [3]. Partially opposed to these encouraging results, isa recent Cochrane systematic review that encompassed 16 randomised controlled trials up until March 2021. Although authors suggested that PDD may reduce the risk of tumour recurrence depending on the risk group, the certainty of evidence was low [4]. Some level of scepticism is supported by recently published results of the prospective randomised multicentre “PHOTO” trial. This research not only contradicted benefit in terms of mid-term recurrence rates but failed to find any cost-effectiveness of PDD compared to standard visualisation. Authors analysed results of 426 patients that underwent TURBT for primary NMIBC (209 with PDD and 217 with WLC). Median follow-up was 44 months. Baseline structure of tumour risk groups was comparable, as were the rates of postoperative single instillations and adjuvant intravesical treatments between the two arms. Three-year recurrence-free survival rates were also comparable at 57.8% and 61.6% for PDD and WLC, respectively. However, the number of recurrences in the WLC control group was higher during the first 12 months. The difference was the most pronounced in the course of the first 6 months (23 WLC group vs 12 PDD group). Proportion of recurrences reversed after one year of follow-up [5]. In real life we need to remember some practical limitations of PDD. This method expects special equipment (light source, telescope, camera) which must be mutually compatible. Together with the instilled substance, it significantly increases the cost of the procedure. Additionally, PDD is dependent on exogenous administration of the precursor that must be metabolised to photoactive form. This process requires a certain time. Usual recommendations for HAL are 1-2 hours before the procedure. Moreover, the photodynamic effect can be observed for a limited time only (photo- bleaching). Narrow-band imaging (NBI) Principle of the method In NBI technology white light is filtered into 2
Prof. Marko Babjuk Dept. of Urology, Hospital Motol and 2nd Faculty of Medicine, Charles University, Praha (CZ)
marek.babjuk@ fnmotol.cz
The success of treatment in Non-muscle-invasive bladder cancer (NMIBC) is dependent upon the biological characteristics of the tumour and on correctly selected and performed treatments. The strategy is based on transurethral resection, followed by individually tailored adjuvant treatment according to individual risk of tumour recurrence and progression. Transurethral resection of bladder cancer (TURBT) is the initial and critical step in the management of NMIBC. This procedure has a diagnostic and therapeutic role and its quality can be measured according to the early recurrence rate after completed procedures. In some studies, the 3-months recurrence rate varies between 0-61.3%, showing a huge heterogeneity in the quality of transurethral resection. It is well known, that up to 50% of patients develop a tumour recurrence within 12 months from primary treatment, most likely the result of missed lesions. There are more options for improving the outcomes of TURBT, one of them is getting a higher quality of tumour visualisation. When using the modern equipment (cameras and light source), white light cystoscopy (WLC) remains the gold standard in the diagnosis of bladder cancer. It may be today supplemented with enhanced optical technologies, which improve tumour detection, particularly of small papillary and flat lesions such as carcinoma in situ (CIS) and reduce the risk of undetected tumours.
Figure 2: Residual high-grade lesion after resection with PDD and WLC
Figure 3: TaLG papillary tumour with NBI and WLC
bandwidths of 415nm (blue) and 540nm (green). These wavelengths are strongly absorbed by haemoglobin, thus enhancing surface capillary visualisation and contrast between normal urothelium and hypervascular tumour areas. The utilisation of NBI is simple and devoid of a learning curve, with no need for patient preparation, no contraindications and no adverse effects. The surgeon is able to toggle between WL and NBI mode, taking on average an additional 3 minutes to complete the procedure. It can be used an endless number of times and the cost is likened to WLC TURBT. Clinical efficacy and available evidence The use of NBI in urology was first described in a study by Bryan et al in 2008 using a flexible cystoscope in a group of patients with recurrent NMIBC [6]. This was the first report of an increased tumour detection rate versus WLC. The improved detection rate of NBI comparing to WLC was demonstrated by more authors [7]. A prospective comparative study between WLC, NBI and PDD included 175 high-risk patients demonstrated that both NBI and PDD had a higher diagnostic sensitivity for CIS and flat dysplasia (95,7% vs WL 65,2%) with similar specificities (NBI 52%, PDD 48%, WL 56,8%) [8]. The research concluded that for this purpose, NBI is a reliable alternative to PDD. Similarly, a recently published retrospective single centre evaluation suggested non-inferiority of NBI compared to PDD in the detection of CIS [9]. The role of NBI-assisted resection on recurrence rates has been studied in a large randomised multicentre trial by the Clinical Research Office of the Endourological Society (CROES). This study included only primary tumours and revealed no differences in the tumour recurrence rate at 12 months, with the exception of the low-risk patient group [10]. However, the value was burdened with some methodological limitations. In 2022, the Cochrane group published results of their comprehensive literature search, which evaluated the potential benefit of NBI guided TURBT compared to WLC guided TURBT. Based on limited confidence in the time-to-event data, authors found that participants who underwent NBI + WLC TURBT had a lower risk of disease recurrence over time compared to participants who underwent WLC TURBT (6 studies, 1244 participants; low certainty of evidence). No studies examined disease progression as a time-to-event outcome or a dichotomous outcome. There was no effect on the risks of major or minor adverse events. [11].
The concept is based on several image enhancement modalities containing a white light, spectra A, spectra B, chroma and clara mode. Spectra A and B increases image contrasts by colour tone shift algorithms, chroma enhances the sharpness of the displayed image, and clara uses a local brightness adaptation in the image to achieve greater visibility of darker regions within the image. Additionally, the system is able to provide a standard WLC with the IMAGE1 S image simultaneously. Clinical efficacy and available evidence IMAGE1 S was recently investigated in a large prospective international trial organised by CROES. The results showed no difference in the overall recurrence rates between IMAGE1S and WL assistance 18-mo after TURBT in patients with NMIBC. However, IMAGE1S-assisted TURBT considerably reduced the likelihood of disease recurrence in primary, low/intermediate risk patients [12]. There is no doubt that the data needs further validation. Summary and conclusion Tumour visualisation using modern equipment and advanced imaging is essential for high quality TURBT. During procedures, it improves the visibility and detection of CIS and small papillary lesions (Figure 1) and improves the evaluation of tumour areas before, during and after resection (Figure 2,3). Most of the research data supports the opinion that these benefits are translated into a reduced number of recurrences in patients’ after TURBT. For this reason, the EAU guidelines recommend the application of advanced imaging during TURBT if these methods are available. The optimal method of advanced visualisation however remains to be specified. References 1. Mowatt, G. Int J Technol Assess Health Care 2011; 27: 3-10. 2. Sari Motlagh, R. BJU Int 2021; 128: 280-9. 3. Veeratterapillay, R. Eur Urol Open Sci 2021; 31: 17-27. 4. Maisch, P. Cochrane Database Syst Rev. 2021. 5. Heer, R. NEJM Evidence 2022. 6. Bryan, RT. BJU Int 2008; 101: 702-6. 7. Kim, SB. Investig Clin Urol 2018; 59: 98-105. 8. Drejer, D. Urology 2017; 102: 138-42. 9. Kumarasegaram, V, Urology, 2022; 61: 83−6. 10. Naito, S. Eur Urol 2016; 70: 506-15.
Fluorescence diagnosis (PDD) Principle of the method
Fluorescence-guided photodynamic diagnosis (PDD) is a technique of tumour visualisation based on the intravesical instillation of 5-aminolevulinic acid (5-ALA) or its hexyl ester (HAL). These prodrugs are metabolised into protoporphyrin IX, whereby, accumulation in cancer cells produces an intensive red fluorescence when excited by blue light. Clinical efficacy and available evidence It has been confirmed that fluorescence-guided biopsy is more sensitive than WLC for the detection of malignant lesions. This benefit was particularly evident in patients with CIS. In a systematic review and meta-analysis, PDD had higher sensitivity than WLC in the pooled estimates for analyses. It improved sensitivity at the patient-level from 71% to 92% and the biopsy-level from 65% to 93%. On the other hand, the specificity of PDD was 63%, which was lower than 81% of WLC [1]. Most often PDD-guided TURBT is connected with reduced recurrence rates compared to standard white-light TURB. In a recent systematic review and network meta-analysis that included 22 studies with 4519 patients, they compared the recurrence rates of NMIBC depending on the type of tumour visualiation during TURBT (WLC vs PDD vs NBI) combined with single immediate intravesical chemotherapy (SIIC) administration. In total, 6 subgroups were established, including a control group ‘WLC without SIIC’. In these settings, PDD
11. Lai, LY, Cohrane Database Syst Rev 2022. 12. De la Rosette, J. WJU 2022; 40: 727-38.
Saturday, 11 March 15:18 - 15:37 Thematic Session: Rapid-fire debates: Common problems and controversies in bladder cancer Yellow Area, eURO Auditorium 2
Professional Image Enhancement System (IMAGE1 S) Principle of the method
Figure 1: TaLG bladder cancer with PDD and WLC
European Urology Today
6
February/March 2023
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