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• Authors' Response
  Jian Huang
  Published on: 6 February 2020
• How to improve diagnosis of non-muscle invasive bladder cancer?
  Per-Uno Malmström
  Published on: 29 January 2020

• Published on: 6 February 2020

  Authors' Response

  • Jian Huang, Urological Surgeon Sun Yat-sen Memorial Hospital

  Thank you for your comments on our manuscript.
  Firstly, we applied meta-analysis to pool diagnostic accuracy for NBI, HAL and 5-ALA techniques for patients with NMIBC in comparison with WLC as the reference standard, which demonstrated the superior diagnostic performance of new imaging techniques in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection.
  We described The SROC curves for NBI, HAL and 5-ALA in Figure 3A and the pooled DOR for NBI, HAL and 5-ALA were 40.09 (95% CI, 20.08-80.01, Figure 2A), 78.14 (95% CI, 31.42-194.28, Figure 2B) and 18.14 (95% CI, 4.28-76.87, Figure 2C), showing significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level. While SROC curves for NBI, HAL and 5-ALA were showed in Figure 3B, DOR for NBI and HAL were 358.71 (95% CI, 44.50-2891.71, Figure 2D) and 59.95 (95% CI, 24.30-147.92, Figure 2E), presenting better performance compared with WLC. Figure 3 showed HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcome...

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  Thank you for your comments on our manuscript.
  Firstly, we applied meta-analysis to pool diagnostic accuracy for NBI, HAL and 5-ALA techniques for patients with NMIBC in comparison with WLC as the reference standard, which demonstrated the superior diagnostic performance of new imaging techniques in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection.
  We described The SROC curves for NBI, HAL and 5-ALA in Figure 3A and the pooled DOR for NBI, HAL and 5-ALA were 40.09 (95% CI, 20.08-80.01, Figure 2A), 78.14 (95% CI, 31.42-194.28, Figure 2B) and 18.14 (95% CI, 4.28-76.87, Figure 2C), showing significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level. While SROC curves for NBI, HAL and 5-ALA were showed in Figure 3B, DOR for NBI and HAL were 358.71 (95% CI, 44.50-2891.71, Figure 2D) and 59.95 (95% CI, 24.30-147.92, Figure 2E), presenting better performance compared with WLC. Figure 3 showed HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcomes in subgroup analysis. These results indicated NBI may be potentially the most promising diagnostic intervention.
  Secondly, our study has applied stringent methodology and inclusion criteria to synthesize obtained evidence. The PRISMA flow chart in Figure 1 demonstrated 103 full-text articles were processed in eligibility process. In order to perform diagnostic meta-analysis, diagnostic outcomes of SSY, SPY, NPV, PPV, FPR and FNR for individual studies should be obtained in studies with intra-patient comparison. Therefore, while 77 studies were excluded in final inclusion process with 41 studies providing non intra-patient comparison outcome. Furthermore, diagnostic performance of new imaging techniques should be calculated with the reference standard of WLC following standardized definitions: SSY was defined as the proportion of positive patients or lesions with index test in all cases of WLC-positive findings. SPY was defined as the proportion of negative patients or lesions with index test in all cases of WLC-negative findings. NPV was defined as the proportion of true negatives findings (both negative in index test and WLC) in all index test-negative cases or lesions; PPV was defined as the proportion of true positives findings (both positive in index test and WLC) in all index test-positive cases or lesions. FNR was defined as the proportion of index test-negative findings in all cases of WLC-positive cases or lesions; FPR was defined as the proportion of index test-positive findings in all cases of WLC-negative cases or lesions.
  Thirdly, our systematic review indicated that the pooled diagnostic performance of NBI, HAL or 5-ALA showed excellent efficacy compared with WLC. While the description “NBI could potentially be the most promising diagnostic intervention for patients with NMIBC, with advantages in terms of simplicity, cost, and reliability” in Discussion Session was inferred by results and references.
  Our results suggested HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcomes in subgroup analysis. Based on the review describing consensus in clinical practice of PDD, HAL is provided in a kit as 100mg of powder needed to be diluted within 2h before instillation. Then bladder should be emptied via a catheter and HAL solution is instilled. Patient must retain HAL solution in the bladder of 1-3h to ensure optimum fluorescence and receive cystoscopy[1]. While NBI avoid the need for pre-operative preparation, intravesical contrast administration and may be widely applied to detect bladder cancer as clinical routine.
  Pharmacoeconomic analysis indicated that the use of HAL leads to overall cost savings with longer recurrence-free intervals than WLC. Kutwin et al [2] performed a review demonstrating new imaging techniques in the management of bladder cancer. It suggested PDD and NBI improve the detection of bladder cancer and decrease recurrence rates of bladder tumors, which are cost-effective method for bladder cancer. It was also inferred that PDD has a stronger evidence base, NBI is still perceived as a reasonable alternative to PDD because of its simplicity. Studies suggested NBI could reduce recurrence rate of bladder cancer significantly[3,4]. While Lee et al[5] performed a network meta-analysis of comparing therapeutic outcomes among NBI, PDD and WLC, which suggested PDD- and NBI-assisted TUR decreased recurrence rate compared with WLC and did not significantly differ in recurrence rate. Also, we are going to further explore comparative efficacy outcomes among NBI, PDD and WLC with updated Bayesian network meta-analysis, which are in the process of submission. We found NBI (OR: 0.56, 95% CrI: 0.31-0.91), HAL (OR: 0.60, 95% CrI: 0.41-0.87) and 5-ALA (OR: 0.64, 95% CrI: 0.38-0.99) demonstrated benefits in reducing recurrence rate compared with WLC, and the cumulative probabilities of rank best were 49%, 27% and 24% in 1-year recurrence rate; NBI (OR: 0.37, 95% CrI: 0.13-0.99), HAL (OR: 0.49, 95% CrI: 0.25-0.91), and 5-ALA (OR: 0.51, 95% CrI: 0.26-0.88) showed lower recurrence rate than WLC, and the cumulative probabilities of rank best were 60%, 22% and 18% in 2-year recurrence rate; moreover, NBI (OR: 0.40, 95% CrI: 0.17-0.99), 5-ALA (OR: 0.54, 95% CrI: 0.28-0.95) and HAL (OR: 0.64, 95% CrI: 0.44-0.91) also presented significant lower recurrence rate compared with WLC in 5-year recurrence rate, the cumulative probabilities of rank best were 70%, 24% and 6%, respectively. Though NBI has not been evaluated in cost effective analysis, the above results inferred NBI may be the most promising intervention for bladder cancer. Despite of the inference, further cost effective analysis among NBI, PDD and WLC should be explored in addition to these diagnostic and therapeutic pooled analysis.
  Our study has applied stringent methodology, rigorous screening and data extraction process, standardized definition and analysis to guarantee reliable results and conclusion. New imaging techniques showed superior diagnostic performance in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection. NBI may be NBI is potentially the most promising diagnostic intervention.
  We hope the comments could resolve your questions.

  Reference
  [1] Daneshmand S, Schuckman AK, Bochner BH, et al. Hexaminolevulinate blue-light cystoscopy in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on appropriate use in the USA. Nat Rev Urol 2014;11(10):589-96. doi: 10.1038/nrurol.2014.245 [published Online First: 2014/09/24]
  [2] Kutwin P, Konecki T, Cichocki M, et al. Photodynamic Diagnosis and Narrow-Band Imaging in the Management of Bladder Cancer: A Review. Photomed Laser Surg 2017;35(9):459-64. doi: 10.1089/pho.2016.4217 [published Online First: 2017/05/26]
  [3] Naselli A, Introini C, Timossi L, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence. Eur Urol 2012;61(5):908-13. doi: 10.1016/j.eururo.2012.01.018 [published Online First: 2012/01/28]
  [4] Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol 2016;70(3):506-15. doi: 10.1016/j.eururo.2016.03.053 [published Online First: 2016/04/28]
  [5] Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer 2015;15:566. doi: 10.1186/s12885-015-1571-8 [published Online First: 2015/08/02]

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  Conflict of Interest:
  None declared.

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• Published on: 29 January 2020

  How to improve diagnosis of non-muscle invasive bladder cancer?

  • Per-Uno Malmström, Professor emeritus Urology at Academic University Hospital Uppsala

  In their recent paper Chen et al. presented a meta-analysis on the diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: They claim in their conclusion that narrow band imaging (NBI) showed the best diagnostic performance outcomes in a comparison to blue light cystoscopy with hexaminolevulinate (HAL) and 5-aminolevulinic acid (5-ALA). We cannot find the evidence for this in the result they present which deserves commenting.
  In the abstract it is written that NBI showed significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level (Pooled sensitivity 0.94, 95% CI 0.82 to 0.98; Pooled specificity 0.79, 95% CI 0.73 to 0.85; Diagnostic odds ratio (DOR) 40.09, 95% CI 20.08 to 80.01; Area under the receiver operating characteristic curve 0.88, 95% CI 0.85 to 0.91). That HAL showed superior lesion level detection results in all measured parameters is not mentioned. It is further stated that NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. The subgroup analysis, evaluating diagnostic performance in studies with low to moderate risk of bias and in studies with more than 100 patients, is only presented in supplementary material and similarly show how HAL and 5-ALA achieve comparable or improved diagnostic performance compared to NBI. Despite these results, the authors emphasize and conclude on behalf of NBI throughout the paper.
  While the con...

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  In their recent paper Chen et al. presented a meta-analysis on the diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: They claim in their conclusion that narrow band imaging (NBI) showed the best diagnostic performance outcomes in a comparison to blue light cystoscopy with hexaminolevulinate (HAL) and 5-aminolevulinic acid (5-ALA). We cannot find the evidence for this in the result they present which deserves commenting.
  In the abstract it is written that NBI showed significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level (Pooled sensitivity 0.94, 95% CI 0.82 to 0.98; Pooled specificity 0.79, 95% CI 0.73 to 0.85; Diagnostic odds ratio (DOR) 40.09, 95% CI 20.08 to 80.01; Area under the receiver operating characteristic curve 0.88, 95% CI 0.85 to 0.91). That HAL showed superior lesion level detection results in all measured parameters is not mentioned. It is further stated that NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. The subgroup analysis, evaluating diagnostic performance in studies with low to moderate risk of bias and in studies with more than 100 patients, is only presented in supplementary material and similarly show how HAL and 5-ALA achieve comparable or improved diagnostic performance compared to NBI. Despite these results, the authors emphasize and conclude on behalf of NBI throughout the paper.
  While the conclusion is not supported by the results presented in the analysis, the major objection to the presented study is the limited number of studies that have been included in the analysis. Although recognized by the authors as being a limitation of the study, especially the patient-level analysis appears anecdotal and highlights how the selection of underlying studies is crucial for a reliable meta-analysis. Twenty-six studies were included in this diagnostic meta-analysis, some with less than 20 patients. Without detailing, we found 39 other studies that seemed to fulfil the search criteria stipulated. Among them, several large multicentre studies [1–7] that probably would have made it possible to calculate the patient level results that the authors now state “could not be calculated because few studies included these data”.
  Further strengthening of the results could also have been possible if independent patient data had been used by the authors as in the meta-analysis by Burger et al. [8]. In that report, there were 25% patients with at least one additional Ta/T1 tumour seen with HAL, and 27% of patients with CIS was detected only by HAL. The improved detection lead to a reduction of recurrence and the report showed how the benefit was independent of the level of risk and evident in patients with Ta, T1, CIS, primary, and recurrent cancer. A similar analysis including both NBI and 5-ALA could have made an important contribution to the field of diagnosis and management of non-muscle-invasive bladder cancer.
  Finally, the authors state that one of the advantages of NBI is that it is cheaper. Such a conclusion should preferably be based on a cost effective analysis, where the effect of the improved diagnosis on the rate of recurrence and progression has to be included. Several studies have consistently shown the reduced recurrence rate with HAL while the data of NBI in this regard are limited. That HAL-guided surgery is a cost-effective tool through an effect on both diagnosis and recurrence, thereby reducing the burden of disease for patients and the health care system have been shown in several reports [9,10]. Similar results for NBI has not been published.

  In summary several flaws in the analysis is evident.

  References
  1 Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients With Nonmuscle Invasive Bladder Cancer. J Urol 2010;184:1907–14. doi:10.1016/j.juro.2010.06.148
  2 Bach T, Bastian PJ, Blana A, et al. Optimised photodynamic diagnosis for transurethral resection of the bladder (TURB) in German clinical practice: results of the noninterventional study OPTIC III. World J Urol 2017;35:737–44. doi:10.1007/s00345-016-1925-0
  3 Grossman HB, Gomella L, Fradet Y, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007;178:62–7. doi:10.1016/j.juro.2007.03.034
  4 Stenzl A, Penkoff H, Dajc-Sommerer E, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy. Cancer 2011;117:938–47. doi:10.1002/cncr.25523
  5 Schumacher MC, Holmäng S, Davidsson T, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic acid under visible and fluorescent light: Results of a prospective, randomized, multicentre study. Eur Urol 2010;57:293–9.
  6 Drejer D, Béji S, Oezeke R, et al. Comparison of White Light, Photodynamic Diagnosis, and Narrow-band Imaging in Detection of Carcinoma In Situ or Flat Dysplasia at Transurethral Resection of the Bladder: the DaBlaCa-8 Study. Urology 2017;102:138–42. doi:10.1016/j.urology.2016.11.032
  7 Drejer D, Béji S, Munk Nielsen A, et al. Clinical relevance of narrow-band imaging in flexible cystoscopy: the DaBlaCa-7 study. Scand J Urol 2017;:1–4. doi:10.1080/21681805.2017.1295101
  8 Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 2013;64:846–54. doi:10.1016/j.eururo.2013.03.059
  9 Rose JB, Armstrong S, Hermann GG, et al. Budget impact of incorporating one instillation of hexaminolevulinate hydrochloride blue-light cytoscopy in transurethral bladder tumour resection for patients with non-muscle-invasive bladder cancer in Sweden. BJU Int 2016;117:E102-113. doi:10.1111/bju.13261
  10 Garfield SS, Gavaghan MB, Armstrong SO, et al. The cost-effectiveness of blue light cystoscopy in bladder cancer detection: United States projections based on clinical data showing 4.5 years of follow up after a single hexaminolevulinate hydrochloride instillation. Can J Urol 2013;20:6682–9.

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  Conflict of Interest:
  Scientific advisor to Photocure AS

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