(Second-look) Transurethral Resection of

EUROPEAN UROLOGY 67 (2015) 605–608
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Priority – Brief Correspondence
Editorial by Peter C. Black on pp. 609–610 of this issue
Randomized Trial of Narrow-band Versus White-light Cystoscopy
for Restaging (Second-look) Transurethral Resection of Bladder
Tumors
Harry W. Herr *
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Article info
Abstract
Article history:
Accepted June 28, 2014
Narrow-band imaging (NBI) cystoscopy detects more bladder tumors than standard
white-light imaging (WLI) cystoscopy, but it is unclear whether NBI improves transurethral resection (TUR) of bladder tumors. This study compares 2-yr recurrence-free
survival (RFS) of patients with non–muscle-invasive bladder tumors following restaging
TUR using NBI or WLI cystoscopy. Patients were randomized 1:1 to undergo NBI-assisted
TUR (NBI-TUR) or WLI-assisted TUR (WLI-TUR). The main outcome was number of
patients free of tumor recurrence after 2-yr follow-up and 2-yr RFS times. Of 254
patients, 127 underwent NBI-TUR and 127 had WLI-TUR. Within 2 yr, 22% of the patients
in the NBI-TUR group recurred compared with 33% after WLI-TUR ( p = 0.05). The mean
RFS time was 22 mo (95% confidence interval [CI], 20–23) for the NBI-TUR group versus
19 mo (95% CI, 18–21) for the WLI-TUR group ( p = 0.02). Limitations are that this was a
single-surgeon study and that a 20% difference in the number of patients free of
recurrence was not achieved, suggesting the study was underpowered. In addition,
observer bias may have contributed to results because NBI-TUR was performed after
both WLI and NBI cystoscopy was used to inspect the bladder. Although the results
suggest reduced recurrence rates and improved RFS times after restaging NBI-TUR
compared with WLI-TUR, a larger study is needed.
Patient summary: Narrow-band imaging enhances visibility of bladder tumors over
conventional white-light cystoscopy. This report compares transurethral resection of
bladder tumors using narrow-band cystoscopy with white-light cystoscopy. The results
show that narrow-band cystoscopy improves surgical removal of bladder tumors, which
reduces the frequency of early and later tumor recurrences.
# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords:
Narrow-band cystoscopy
Transurethral resection
Bladder tumors
* MSKCC, 1275 York Avenue, New York, NY 10021, USA. Tel. +1 646 422 4411; Fax: +1 212 988 0768.
E-mail address: [email protected].
We [1] and others [2–4] have shown that narrow-band
imaging (NBI) cystoscopy detects more bladder tumors than
conventional white-light imaging (WLI) cystoscopy. We
also showed that NBI surveillance cystoscopy and fulguration of low-risk papillary tumors is associated with fewer
patients having tumor recurrences, with fewer numbers of
recurrent tumors, and with longer recurrence-free survival
(RFS) times than WLI cystoscopy [5]. The therapeutic
impact of NBI-assisted transurethral resection (NBI-TUR) of
high-risk non–muscle-invasive tumors has not been defined. One study found that a second transurethral resection
(TUR) using NBI detected more tumors that were missed
during a second TUR using WLI, suggesting that NBI
facilitates more complete tumor resections [6]. The same
http://dx.doi.org/10.1016/j.eururo.2014.06.049
0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
606
EUROPEAN UROLOGY 67 (2015) 605–608
authors also showed it was feasible to perform TUR using
only NBI cystoscopy [7]. Reliable identification of all
neoplastic lesions and feasibility of TURs assisted by NBI
might logically reduce the frequency of early tumor
recurrences owing to incomplete resections. This paper
presents results of a prospective randomized trial comparing restaging WLI-assisted TUR (WLI-TUR) versus NBI-TUR
of high-risk non–muscle-invasive bladder cancer (NMIBC).
Patients with high-risk (high-grade pTa, pT1, carcinoma
in situ [CIS]) bladder neoplasms were evaluated. They were
diagnosed by prior biopsy by outside urologists, and non–
muscle-invasive tumor was confirmed by review of
submitted histology. Per institutional policy, all patients
underwent second-look (restaging) TUR 2–4 wk after the
first WLI-TUR. Before surgery, patients were randomized
1:1 by random permuted blocks to undergo either WLIassisted or NBI-assisted second TUR. The study was
approved by the institutional review board, and patients
provided informed consent.
Patients assigned to have WLI-TUR had initial WLI
cystoscopy and then WLI-TUR. NBI cystoscopy was not used
at all during the procedure. Patients assigned to NBI-TUR
had WLI cystoscopy first, followed by NBI cystoscopy to
map bladder lesions. The TUR was performed using NBI
cystoscopy. Both WLI and NBI cystoscopies were used to
inspect the bladder to verify complete resection.
The TURs were performed under general anesthesia and
lasted from 15 min to 30 min. Visible papillary, solid, and
flat tumors were resected using either WLI or NBI
cystoscopy. Margins and depth of predominant tumors
were resected and submitted separately. The goal of each
TUR was to remove all visible tumors and to verify that
remaining bladder mucosa appeared to be normal. Patients
upstaged to muscle invasion on restaging TUR were
excluded from analysis.
Starting 2 wk after TUR, a 6-wk induction course of
intravesical bacillus Calmette-Guérin (BCG) therapy was
given. Patients underwent a biopsy after 3 mo from start
of BCG to determine response and were followed every
3–6 mo by outpatient WLI and NBI flexible digital
cystoscopy. Maintenance BCG and perioperative chemotherapy was not used.
End points were early response to BCG at 3 mo (absence
of tumor), number of patients who remain tumor free
(regardless of BCG response), and RFS times at 2 yr. Tumor
recurrence was defined as disease on follow-up cystoscopy
and biopsy. Tumor progression was evaluated; however, the
study was not powered to show a difference in progressionfree rates or survival times. Tumor progression was defined
as T1 cancer recurrence after BCG therapy (prompting early
cystectomy) and muscle-invasive tumor.
A sample size of 250 patients was planned to provide 90%
power (with two-sided type I error of 5%) to detect a
clinically meaningful difference of 20% in tumor-free
recurrence rates between the two groups, assuming equal
distribution of patients and allowing 5% loss to follow-up.
Variables between patient groups were correlated by
x2 test. Kaplan-Meier curves were constructed for survival
times and compared using the log-rank test. All tests
were two-sided, and p values <0.05 were considered
significant.
From May 2009 to May 2012, 254 patients underwent a
second resection (127 by WLI-TUR and 127 by NBI-TUR) and
were confirmed to have high-grade NMIBC. Patients were
discharged on the same day as the TUR. One patient was
returned to the operating room for bleeding after NBI-TUR
and was discharged a few hours later. No one was
readmitted for complications.
Table 1 shows that patient groups were balanced for
high-risk tumor burden. Patients undergoing NBI-TUR were
found to have more CIS, suggesting increased detection by
NBI cystoscopy over WLI cystoscopy. All patients received
six full-dose BCG intravesical instillations over 6–8 wk.
At first follow-up cystoscopy at 3 mo after the start of BCG
therapy, 14 patients (11%) in the NBI group and 30 (24%) in
the WLI group had residual tumor ( p = 0.01).
All patients were followed for a minimum of 2 yr, and
none were lost to follow-up. Twenty-eight patients (22%)
recurred after NBI-TUR compared with 42 (33%) who
underwent WLI-TUR ( p = 0.05), for an 11% reduction in
recurrence rate using NBI-TUR. Figure 1 shows that RFS time
favored the NBI-TUR group over the WLI-TUR group. The
mean survival time for the NBI group was 22 mo (95%
confidence interval [CI], 20–23) versus 19 mo (95% CI,
18–21) for the WBI group ( p = 0.02). Figure 2 shows 2-yr
progression-free survival was 94% and 87% in the NBI-TUR
and WLI-TUR groups, respectively ( p = 0.06).
Re-resection of NMIBC detects residual cancer in a
substantial number of cases, reduces the frequency of early
tumor recurrences, and improves response to BCG therapy
[8]. Results from this randomized study suggest that
Table 1 – Patient characteristics
Variable
No. of cases
Age, yr, median (range)
Sex, n
Male
Female
Tumor type, n
TaHG
T1HG
Carcinoma in situ, n
Yes
No
No. of tumors, n
Single
Multiple
Tumor size*, n
Small, <1–2 cm
Medium, 2–5 cm
Large, >5 cm
Re-TUR pathology, n
pT0
pTis
pTa
pT1
*
WLI-TUR
NBI-TUR
127
68 (42–99)
127
67 (36–93)
95
32
88
39
81
46
80
47
84
43
97
30
15
112
19
108
9
97
21
10
97
20
46
39
22
20
49
32
25
21
p
0.92
0.33
0.89
0.06
0.31
0.25
0.55
Largest size of papillary or solid tumor or cluster of tumors, excluding
carcinoma in situ.
HG = high grade; NBI = narrow-band imaging; TUR = transurethral resection;
WLI = white-light imaging.
EUROPEAN UROLOGY 67 (2015) 605–608
[(Fig._1)TD$IG]
Fig. 1 – Two-year tumor recurrence-free survival after restaging
transurethral resection by narrow-band imaging (NBI) or white-light
imaging (WLI) cystoscopy.
restaging TUR using NBI cystoscopy improves outcomes
over standard WLI-TUR. Fewer patients failed to respond
initially to BCG or had tumors recur within 2 yr after
restaging NBI-TUR than patients undergoing second-look
WLI-TUR. Recurrences occurred earlier after WLI-TUR, often
within the first year, supporting evidence of more thorough
re-resections using NBI cystoscopy. Fewer patients in the
NBI-TUR group progressed, but the difference was not
significant and included early cystectomy for recurrent T1
cancers.
This study has several weaknesses. First, although NBITUR prolonged the RFS time over WLI-TUR, the primary aim
of number of patients who remained free of disease at 2 yr
did not achieve the ambitious 20% difference, suggesting the
study was underpowered. Second, it is a single-surgeon
study. Although this means that the results may not be
generalizable, it maintains consistency in the quality of the
TURs—an important and unquantifiable factor inherent in
multicenter trials. Third, NBI was used as an add-on
[(Fig._2)TD$IG]
607
procedure to WLI cystoscopy to inspect and then resect
visible or suspected tumors. This suggests observer bias
favoring NBI used as a second look after the WLI ‘‘first-look’’
inspection; however, in practice, it is likely that NBI will be
used most often as a supplement to conventional WLI, and it
is also possible that both WLI and NBI may prove to be
better than either modality used alone. Finally, cost–benefit
analysis for NBI in the management of bladder tumors was
not done. The cost of the surgical procedure (WLI-TUR or
NBI-TUR) itself was the same; however, operating room
costs may have been higher owing to longer NBI procedures
in some patients. Another variable confounding interpretation of new optical methods is surgeon diligence. In patients
scheduled to undergo NBI-TUR, perhaps I looked a little
closer, tried a little harder, resected wider, and took more
time to do the procedure than conventional WLI-TUR. The
sequence of WLI cystoscopy, NBI cystoscopy, NBI-TUR, and
post-TUR WLI and NBI cystoscopy took longer than WLI
cystoscopy and WLI-TUR alone and may have contributed to
better resections and resulting in fewer tumor recurrences.
For example, competence measurements during colonoscopy, such as withdrawal times, correlate directly with
polyp detection and removal [9]. Similar validated surgeonperformance measures are needed for TUR of bladder
tumors using both WLI and NBI cystoscopy.
Although the study is borderline significant, it justifies
further study of NBI-TUR by others to confirm or refute the
results. A multicenter, randomized, large, international
study is ongoing to compare the impact of NBI-TUR with
WLI-TUR on the early and subsequent tumor recurrence risk
[10]. This and other studies will help better define the role of
NBI in management of NMIBC.
Author contributions: Harry W. Herr had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Herr.
Acquisition of data: Herr.
Analysis and interpretation of data: Herr.
Drafting of the manuscript: Herr.
Critical revision of the manuscript for important intellectual content: Herr.
Statistical analysis: Herr.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: None.
Other (specify): None.
Financial disclosures: Harry W. Herr certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript (eg,
employment/affiliation, grants or funding, consultancies, honoraria, stock
ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
References
[1] Herr HW, Donat SM. A comparison of white-light cystoscopy and
Fig. 2 – Two-year progression-free survival after transurethral resection
by narrow-band imaging (NBI) or white-light imaging (WLI) cystoscopy.
narrow-band imaging cystoscopy to detect bladder tumor recurrences. BJU Int 2008;102:1111–4.
608
EUROPEAN UROLOGY 67 (2015) 605–608
[2] Bryan RT, Billingham LI, Wallace DMA. Narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the
bladder. BJU Int 2007;101:702–6.
[3] Cauberg EC, Kloen S, Visser M, et al. Narrow band imaging cystoscopy improves detection of non-muscle-invasive bladder cancer.
Urology 2010;76:658–63.
transurethral resection of newly diagnosed non-muscle-invasive
high-grade bladder cancer. BJU Int 2009;105:208–11.
[7] Naselli A, Introini C, Bertolotto F, et al. Feasibility of transurethral
resection of bladder lesion performed entirely by means of narrowband imaging. J Endourol 2010;24:1131–4.
[8] Herr HW. Restaging TUR of high risk superficial bladder cancer im-
[4] Tatsugami K, Kuroiwa K, Kamoto T, et al. Evaluation of narrow-band
proves the initial response to BCG therapy. J Urol 2005;174:2134–7.
imaging as a complimentary method for the detection of bladder
[9] Lim G, Viney SK, Chapman BA, et al. A prospective study of endos-
cancer. J Endourol 2010;24:1807–11.
[5] Herr HW, Donat SM. Reduced bladder tumor recurrence rate associated with narrow-band imaging surveillance cystoscopy. BJU Int
2011;107:396–8.
[6] Naselli A, Introini C, Bertolotto F, et al. Narrow band imaging
for detecting residual/recurrent cancerous tissue during second
copist-blinded colonoscopy withdrawal times and polyp detection
rates. NZ Med J 2012;125:52–9.
[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.