- Email: [email protected]
RETRACTED: Narrowing the Cystoscopy Gap
EUROPEAN UROLOGY 67 (2015) 609–611
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Author Referring to the article published on pp. 605–608 of this issue
Narrowing the Cystoscopy Gap [TD$FIRSNAME]Peter C.[TD$FIRSNAME.] [TD$SURNAME]Black * Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
In this month’s issue of European Urology, Herr reports on the largest prospective randomized trial to date investigating the clinical benefit of narrow-band imaging (NBI) in the management of non–muscle-invasive bladder cancer (NMIBC) [1]. Herr is to be congratulated for achieving this milestone and for doing so single-handedly in such precise fashion. Randomization was perfect, no patient required hospital admission, every patient completed induction bacillus Calmette-Gue´rin (BCG) therapy, and not a single patient was lost to follow-up. We know from prior reports that NBI enhances detection [2,3] and reduces recurrence rates of NMIBC [4] (this latter citation is noticeably absent from the current paper). Herr and Donat also previously demonstrated in a nonrandomized fashion that NBI reduces recurrence specifically of lowrisk NMIBC [5]. In the current study, Herr has therefore attempted to demonstrate the benefit of NBI in high-risk NMIBC [1]. While the rationale for this attempt is not explicitly outlined in the paper, the analysis is justified by the increased risk of recurrence and progression in high-risk disease, as well as the different therapeutic interventions administered in this patient cohort. The trial demonstrated a reduction in rate of recurrence at 2 yr from 33% to 22% ( p = 0.05) but was underpowered to reach the desired 20% risk reduction [1]. Since the trial was performed in the setting of a second transurethral resection of bladder tumor (TURBT), 38% of patients had no disease in the pathologic specimen, which may have negatively affected the value of NBI. The anticipated 20% effect size was optimistic and was equivalent to a best-case scenario when compared with prior similar studies with fluorescent cystoscopy [6,7]. While it is always challenging to define a clinically meaningful treatment benefit, the ease and low cost of NBI would suggest that this benefit is well
below 20%. This is especially true in high-risk patients, for whom any recurrence could lead to radical cystectomy. In hindsight, one can also suggest that a potential opportunity was missed with this trial. Given the high-risk nature of the patient cohort studied, a somewhat larger trial may have been powered to identify a difference in disease progression, which was found to be 6% in the NBI group and 13% in the white-light imaging (WLI) group ( p = 0.06). Three major issues with this trial [1] reduce its generalizability. First, the NBI cystoscopy in this study was done at the time of the second TURBT and not at the time of initial TURBT. This situation is understandable, given the nature of Herr’s practice. However, urologists with the ability to use NBI will presumably use it with every TURBT, so using NBI for the second TURBT after not using it for initial TURBT is an artifact of referral patterns and will be relevant only at tertiary centers. One would hypothesize that if NBI were used for the initial TURBT, it would be less valuable at the time of the second TURBT. Second, because of Herr’s well-established opposition to maintenance BCG [8], all patients received inadequate treatment according to usual guidelines [9]. More effective treatment with maintenance therapy could further blunt any benefit of NBI with respect to rates of recurrence and progression. The absence of a single postoperative dose of mitomycin C was likely not relevant, since this was a highrisk cohort. The third main limitation to generalizing the results is the single-surgeon nature of this trial [1]. However, if one assumes that Herr performs a more effective WLI TURBT than most, NBI could have a larger impact in the hands of the general urologist. There appear to be obstacles to wider adoption of NBI. Although it is commonly highlighted that this technique
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.06.049. * Vancouver Prostate Centre, University of British Columbia, Level 6, 2775 Laurel St., Vancouver, BC, V5Z 1M9, Canada. Tel. +1 604 875 4301; Fax: +1 604 875 5604. E-mail address: [email protected]. 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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EUROPEAN UROLOGY 67 (2015) 609–611
carries no additional cost, this is true only for urologists with Olympus cystoscopy systems that already contain the necessary filtering processes. Although specific training is not required, every new technology requires some degree of learning and adjustment, so urologists have to be willing to invest the time and effort to learn the nuances of NBI. More evidence supporting the clinical benefit of NBI is important, but the ease of use and low cost of NBI would dictate that the level of evidence required to adopt it should be relatively low compared with many of the other technologies we use. A common criticism of this type of trial design is the ‘‘second look effect.’’ It has been suggested that the benefit of NBI, which is performed after complete visualization of the bladder with WLI, may be related to the fact that the surgeon is inspecting the bladder more carefully a second time. Some studies have avoided this potential confounding [4], but this really does not appear to be an important point clinically. As Herr states, NBI is likely to be used after WLI, so the second look will be a routine part of clinical practice. The next, and perhaps definitive, chapter in the NBI story will come later this year or in 2015 with the publication of a nearly 1000-patient trial sponsored by Olympus and led by the Clinical Research Office of the Endourological Society, which includes Herr as a member of the study steering committee (NCT01180478) [10]. This global study is comparing NBI to WLI at the time of initial TURBT in patients with first-time tumors. Not to be outdone, Storz has developed similar technology, which it calls the Storz Professional Image Enhancement System. A trial is planned through the Clinical Research Office of the Endourological Society for this technology as well (pers. comm., J. de la Rosette).
References [1] Herr HW. Randomized trial of narrow-band versus white-light cystoscopy for restaging (second-look) transurethral resection of bladder tumors. Eur Urol 2015;67:605–8. [2] Herr HW, Donat SM. A comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences. BJU Int 2008;102:1111–4. [3] Bryan RT, Billingham LJ, Wallace DM. Narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder. BJU Int 2008;101:702–5, discussion 705–6. [4] 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;61:908–13. [5] Herr HW, Donat SM. Reduced bladder tumour recurrence rate associated with narrow-band imaging surveillance cystoscopy. BJU Int 2011;107:396–8. [6] Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010;184:1907–13. [7] Daniltchenko DI, Riedl CR, Sachs MD, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol 2005;174:2129–33, discussion 2133. [8] Ehdaie B, Sylvester R, Herr HW. Maintenance bacillus CalmetteGue´rin treatment of non-muscle-invasive bladder cancer: a critical evaluation of the evidence. Eur Urol 2013;64:579–85. [9] Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on nonmuscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639–53. [10] de la Rosette J, Gravas S. A multi-center, randomized international study to compare the impact of narrow band imaging versus white light cystoscopy in the recurrence of bladder cancer. J Endourol 2010;24:660–1.
http://dx.doi.org/10.1016/j.eururo.2014.07.025 Conflicts of interest: The author has nothing to disclose.
Platinum Priority Reply from Author re: Peter C. Black. Narrowing the Cystoscopy Gap. Eur Urol 2015;67:609–10 A Better Transurethral Resection—Proved or Not! [TD$FIRSNAME]Harry W.[TD$FIRSNAME.] [TD$SURNAME]Herr * Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
One cannot argue with Black’s astute discussion [1] of the weaknesses of our study [2] comparing re-resection of high-risk non–muscle-invasive bladder tumors using narrow-band imaging (NBI) versus white-light imaging
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2014.06.049, http://dx.doi.org/10.1016/j.eururo.2014.07.025. * MSKCC, 1275 York Avenue, New York, NY 10021, USA. Tel. +1 646 422 4411; Fax: +1 212 988 0768. E-mail address: [email protected].
(WLI) cystoscopy. The primary aim of the trial was to reduce the short-term (2-yr) tumor recurrence rate by 20% with NBI-assisted transurethral resection (TUR). This ambitious, and perhaps unrealistic, statistic was not achieved in this high-risk population, especially because, as expected, a significant minority had no residual tumor in re-resected tissue. We observed, however, an 11% risk reduction, which seems clinically significant for high-risk tumors and because NBI is associated with low cost and no added morbidity. If NBI detects more tumors and thereby facilitates better TURs when used in addition to standard WLI-assisted TUR, then any degree of benefit is likely worthwhile. The results of the trial [2], as Black sagely points out [1], cannot be generalized to the initial TUR or to other urologists or patient populations. Although ultimate outcomes depend on unique tumor characteristics in a unique host, what urologists can do is completely remove
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Author Referring to the article published on pp. 605–608 of this issue
Narrowing the Cystoscopy Gap [TD$FIRSNAME]Peter C.[TD$FIRSNAME.] [TD$SURNAME]Black * Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
In this month’s issue of European Urology, Herr reports on the largest prospective randomized trial to date investigating the clinical benefit of narrow-band imaging (NBI) in the management of non–muscle-invasive bladder cancer (NMIBC) [1]. Herr is to be congratulated for achieving this milestone and for doing so single-handedly in such precise fashion. Randomization was perfect, no patient required hospital admission, every patient completed induction bacillus Calmette-Gue´rin (BCG) therapy, and not a single patient was lost to follow-up. We know from prior reports that NBI enhances detection [2,3] and reduces recurrence rates of NMIBC [4] (this latter citation is noticeably absent from the current paper). Herr and Donat also previously demonstrated in a nonrandomized fashion that NBI reduces recurrence specifically of lowrisk NMIBC [5]. In the current study, Herr has therefore attempted to demonstrate the benefit of NBI in high-risk NMIBC [1]. While the rationale for this attempt is not explicitly outlined in the paper, the analysis is justified by the increased risk of recurrence and progression in high-risk disease, as well as the different therapeutic interventions administered in this patient cohort. The trial demonstrated a reduction in rate of recurrence at 2 yr from 33% to 22% ( p = 0.05) but was underpowered to reach the desired 20% risk reduction [1]. Since the trial was performed in the setting of a second transurethral resection of bladder tumor (TURBT), 38% of patients had no disease in the pathologic specimen, which may have negatively affected the value of NBI. The anticipated 20% effect size was optimistic and was equivalent to a best-case scenario when compared with prior similar studies with fluorescent cystoscopy [6,7]. While it is always challenging to define a clinically meaningful treatment benefit, the ease and low cost of NBI would suggest that this benefit is well
below 20%. This is especially true in high-risk patients, for whom any recurrence could lead to radical cystectomy. In hindsight, one can also suggest that a potential opportunity was missed with this trial. Given the high-risk nature of the patient cohort studied, a somewhat larger trial may have been powered to identify a difference in disease progression, which was found to be 6% in the NBI group and 13% in the white-light imaging (WLI) group ( p = 0.06). Three major issues with this trial [1] reduce its generalizability. First, the NBI cystoscopy in this study was done at the time of the second TURBT and not at the time of initial TURBT. This situation is understandable, given the nature of Herr’s practice. However, urologists with the ability to use NBI will presumably use it with every TURBT, so using NBI for the second TURBT after not using it for initial TURBT is an artifact of referral patterns and will be relevant only at tertiary centers. One would hypothesize that if NBI were used for the initial TURBT, it would be less valuable at the time of the second TURBT. Second, because of Herr’s well-established opposition to maintenance BCG [8], all patients received inadequate treatment according to usual guidelines [9]. More effective treatment with maintenance therapy could further blunt any benefit of NBI with respect to rates of recurrence and progression. The absence of a single postoperative dose of mitomycin C was likely not relevant, since this was a highrisk cohort. The third main limitation to generalizing the results is the single-surgeon nature of this trial [1]. However, if one assumes that Herr performs a more effective WLI TURBT than most, NBI could have a larger impact in the hands of the general urologist. There appear to be obstacles to wider adoption of NBI. Although it is commonly highlighted that this technique
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.06.049. * Vancouver Prostate Centre, University of British Columbia, Level 6, 2775 Laurel St., Vancouver, BC, V5Z 1M9, Canada. Tel. +1 604 875 4301; Fax: +1 604 875 5604. E-mail address: [email protected]. 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
610
EUROPEAN UROLOGY 67 (2015) 609–611
carries no additional cost, this is true only for urologists with Olympus cystoscopy systems that already contain the necessary filtering processes. Although specific training is not required, every new technology requires some degree of learning and adjustment, so urologists have to be willing to invest the time and effort to learn the nuances of NBI. More evidence supporting the clinical benefit of NBI is important, but the ease of use and low cost of NBI would dictate that the level of evidence required to adopt it should be relatively low compared with many of the other technologies we use. A common criticism of this type of trial design is the ‘‘second look effect.’’ It has been suggested that the benefit of NBI, which is performed after complete visualization of the bladder with WLI, may be related to the fact that the surgeon is inspecting the bladder more carefully a second time. Some studies have avoided this potential confounding [4], but this really does not appear to be an important point clinically. As Herr states, NBI is likely to be used after WLI, so the second look will be a routine part of clinical practice. The next, and perhaps definitive, chapter in the NBI story will come later this year or in 2015 with the publication of a nearly 1000-patient trial sponsored by Olympus and led by the Clinical Research Office of the Endourological Society, which includes Herr as a member of the study steering committee (NCT01180478) [10]. This global study is comparing NBI to WLI at the time of initial TURBT in patients with first-time tumors. Not to be outdone, Storz has developed similar technology, which it calls the Storz Professional Image Enhancement System. A trial is planned through the Clinical Research Office of the Endourological Society for this technology as well (pers. comm., J. de la Rosette).
References [1] Herr HW. Randomized trial of narrow-band versus white-light cystoscopy for restaging (second-look) transurethral resection of bladder tumors. Eur Urol 2015;67:605–8. [2] Herr HW, Donat SM. A comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences. BJU Int 2008;102:1111–4. [3] Bryan RT, Billingham LJ, Wallace DM. Narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder. BJU Int 2008;101:702–5, discussion 705–6. [4] 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;61:908–13. [5] Herr HW, Donat SM. Reduced bladder tumour recurrence rate associated with narrow-band imaging surveillance cystoscopy. BJU Int 2011;107:396–8. [6] Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010;184:1907–13. [7] Daniltchenko DI, Riedl CR, Sachs MD, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol 2005;174:2129–33, discussion 2133. [8] Ehdaie B, Sylvester R, Herr HW. Maintenance bacillus CalmetteGue´rin treatment of non-muscle-invasive bladder cancer: a critical evaluation of the evidence. Eur Urol 2013;64:579–85. [9] Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on nonmuscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639–53. [10] de la Rosette J, Gravas S. A multi-center, randomized international study to compare the impact of narrow band imaging versus white light cystoscopy in the recurrence of bladder cancer. J Endourol 2010;24:660–1.
http://dx.doi.org/10.1016/j.eururo.2014.07.025 Conflicts of interest: The author has nothing to disclose.
Platinum Priority Reply from Author re: Peter C. Black. Narrowing the Cystoscopy Gap. Eur Urol 2015;67:609–10 A Better Transurethral Resection—Proved or Not! [TD$FIRSNAME]Harry W.[TD$FIRSNAME.] [TD$SURNAME]Herr * Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
One cannot argue with Black’s astute discussion [1] of the weaknesses of our study [2] comparing re-resection of high-risk non–muscle-invasive bladder tumors using narrow-band imaging (NBI) versus white-light imaging
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2014.06.049, http://dx.doi.org/10.1016/j.eururo.2014.07.025. * MSKCC, 1275 York Avenue, New York, NY 10021, USA. Tel. +1 646 422 4411; Fax: +1 212 988 0768. E-mail address: [email protected].
(WLI) cystoscopy. The primary aim of the trial was to reduce the short-term (2-yr) tumor recurrence rate by 20% with NBI-assisted transurethral resection (TUR). This ambitious, and perhaps unrealistic, statistic was not achieved in this high-risk population, especially because, as expected, a significant minority had no residual tumor in re-resected tissue. We observed, however, an 11% risk reduction, which seems clinically significant for high-risk tumors and because NBI is associated with low cost and no added morbidity. If NBI detects more tumors and thereby facilitates better TURs when used in addition to standard WLI-assisted TUR, then any degree of benefit is likely worthwhile. The results of the trial [2], as Black sagely points out [1], cannot be generalized to the initial TUR or to other urologists or patient populations. Although ultimate outcomes depend on unique tumor characteristics in a unique host, what urologists can do is completely remove