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Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: A systematic review and meta-analysis
Journal Pre-proof Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: a systematic review and meta-analysis Shicong Lai, Runqi Guo, Samuel Seery, Pengjie Wu, Jianyong Liu, Yaoguang Zhang, Shengcai Zhu, Xiaoguang Li, Ming Liu, Jianye Wang PII:
S1743-9191(20)30026-1
DOI:
https://doi.org/10.1016/j.ijsu.2020.01.016
Reference:
IJSU 5223
To appear in:
International Journal of Surgery
Received Date: 5 September 2019 Revised Date:
15 January 2020
Accepted Date: 16 January 2020
Please cite this article as: Lai S, Guo R, Seery S, Wu P, Liu J, Zhang Y, Zhu S, Li X, Liu M, Wang J, Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: a systematic review and meta-analysis, International Journal of Surgery, https://doi.org/10.1016/ j.ijsu.2020.01.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.
Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: a systematic review and meta-analysis Running title: Distal ureter management techniques for UTUC patients Authors and Affiliations: Shicong Lai1,2,3#; Runqi Guo2,4#; Samuel Seery5; Pengjie Wu1,2; Jianyong Liu1,2,3, Yaoguang Zhang1,2,3; Shengcai Zhu1,2; Xiaoguang Li2,4; Ming Liu1,2,3*; Jianye Wang1,2,3* 1 Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing 100730, China 2 Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China 3 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China 4 Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Beijing 100730, China 5 School of Humanities and Social Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China # Shicong Lai and Runqi Guo contributed as the co-first author * Correspondence author: Ming Liu and Jianye Wang Address for correspondence: Ming Liu, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; Tel: +86 13911036970
Email: [email protected]
Fax: +86-010-85136272
Jian-Ye Wang, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; Tel: +86 13901058760
Email: [email protected]
Fax: +86-010-85136272
1
Assessing the impact of different distal ureter management techniques during
2
radical nephroureterectomy for primary upper urinary tract urothelial
3
carcinoma on oncological outcomes: a systematic review and meta-analysis
4
Key words: Distal ureter management; Prognosis; Radical nephroureterectomy (RNU);
5
Systematic review and meta-analysis; Upper urinary tract urothelial carcinoma (UTUC)
6 7
Abbreviations: CI=confidence interval; CSS=cancer-specific survival ； EVBC=extravesical
8
incision of the bladder cuff; HR=hazard ratio; IVBC=intrasvesical incision of the bladder cuff；
9
IRFS = intravesical recurrence-free survival；NIVBC=non-intrasvesical incision of the bladder
10
cuff; OS=overall survival; PRISMA=Preferred Reporting Items for Systematic Reviews and
11
Meta-analysis;
12
TUBC=transurethral incision of the bladder cuff; UTUC=upper urinary tract urothelial carcinoma
RFS=recurrence-free
survival
13 14 15
1 / 16
；
RNU=radical
nephroureterectomy;
Abstract
16 17 18
Objectives： ：
19
To assess the oncological outcomes of several distal ureter management techniques in patients
20
administered with radical nephroureterectomy (RNU) for primary upper urinary tract urothelial
21
carcinoma (UTUC).
22 23
Methods:
24
A systematic search of PubMed, EMBASE, and the Cochrane Library was conducted to identify
25
studies comparing outcomes following RNU under various surgical methods for bladder cuff
26
management. Standard cumulative analyses of hazard ratios (HRs) with 95% confidence intervals
27
(CIs) were performed using Review Manager (5.3).
28 29
Results:
30
Nine studies involving 4,683 patients were selected based upon eligibility criteria. Meta-analysis
31
of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences
32
among intravesical incision of the bladder cuff (IVBC), extravesical incision of the bladder cuff
33
(EVBC) and transurethral incision of the bladder cuff (TUBC) techniques. However, the IVBC
34
technique appeared to have better recurrence-free survival (RFS) (HR= 1.37, p<0.01) and
35
intravesical recurrence-free survival (IRFS) (HR=1.45, p<0.01) compared with non-IVBC
36
methods, including both TUBC and EVBC. When studies involving patients with bladder tumour
37
history were excluded, the pooled statistic appeared to confirm that IVBC was associated with
38
improved IRFS (HR=1.25, p=0.03) compared with EVBC and TUBC. No significant difference
39
was found between the EVBC and TUBC groups (HR=1.81, p=0.32).
40 41
Conclusions:
42
The findings suggest that IVBC is associated with improved oncologic outcomes and that it may
43
be recommended for distal ureter management. However, caution must be taken because this
44
recommendation is based upon a very limited number of clinical studies. Further research with
45
enhanced outcome data collection and improved reporting is required to confirm these findings.
46
2 / 16
47 48
Introduction
49
Upper urinary tract urothelial carcinomas (UTUCs) manifest through the urothelial lining of the
50
urinary tract from renal calyces to the ureteral orifice. While relatively rare, this cluster of
51
neoplasms still accounts for 5-10% of all urothelial malignancies
52
nephroureterectomy (RNU) with en bloc resection of the ipsilateral bladder cuff is the standard
53
procedure for patients with non-metastatic UTUC and normal contralateral kidney functions. RNU
54
has remained the standard procedure because several studies have observed lower rates of
55
recurrent malignancies and improved survival
56
since Clayman and colleagues performed the first laparoscopic nephroureterectomy in 1991
57
However, the optimal technique for excising the distal ureter and bladder cuff has yet to be
58
determined.
59
Typically, these techniques are classified as either open, laparoscopic, or endoscopic management
60
methods. The most common approach appears to be intravesical incision of the bladder cuff
61
(IVBC) which involves a cystotomy procedure with intravesical excision of the intravesical ureter,
62
ureteric orifice and surrounding bladder cuff. The second most commonly administered
63
intervention is extravesical incision of the bladder cuff (EVBC) which involves dissecting the
64
distal ureter and bladder cuff extravesically. The third technique is transurethral incision of the
65
bladder cuff (TUBC). For this method, ureteral endoscopic approaches, such as transurethrally
66
occluding the free orifice and incising around the ureteric orifice, which were originally proposed
67
as complementary first steps of nephroureterectomy, are carried out, and then the ureteric orifice
68
and perimeatal bladder are completely removed extravesically [11].
69
While each technique described continues to be widely used, many controversies exist. It is not
70
yet known which surgical intervention provides superior oncologic outcomes [12-14]. Therefore, the
71
aim of this study is to provide evidence for guiding decision making and improving management
72
strategies for UTUC patients. As such, we performed a systematic review and meta-analysis to
73
assess the efficacy of these three different distal ureter management techniques in patients
74
undergoing RNU for primary UTUC.
. At present, radical
[1, 5, 6]
75 76 77
[1-4]
Methods
3 / 16
. Several techniques have been developed [7-10]
.
78 79
Search and Selection
80
Two authors (SC-L and RQ-G) performed a systematic computerized search of PubMed,
81
EMBASE, and the Cochrane Library up until April 20, 2019, to identify clinical studies
82
comparing oncologic outcomes following RNU under surgical procedures described for bladder
83
cuff management in the UTUC population.
84
The search terms included; upper urinary tract urothelial carcinoma OR upper tract urothelial
85
neoplasms OR upper tract urothelial cancer OR transitional cell carcinoma of the upper urinary
86
tract AND distal ureter OR lower ureter AND bladder cuff AND nephroureterectomy. In addition,
87
manual searching was performed for associated studies and citations. The search strategy was
88
designed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis
89
(PRISMA) statement and AMSTAR (Assessing the methodological quality of systematic reviews)
90
Guidelines.
91 92 93 94 95 96 97
Inclusion criteria Studies were included, if they met all of the following criteria: (1) Randomized controlled trials (RCTs) or retrospective studies analysing the relationship between distal ureter management methods and UTUC prognoses;
98
(2) Patients with primary UTUC without previous or concomitant muscle-invasive bladder
99
cancer, lymph node or distant metastases, and bilateral synchronous upper urinary tract
100 101 102 103
tumours at the time of diagnosis; (3) Outcomes included cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) or intravesical recurrence-free survival (IRFS); (4) Survival data included hazard ratios (HRs) and corresponding 95%
104
confidence intervals (CIs), or Kaplan–Meier curves comparing survival between IVBC
105
and non-IVBC (NIVBC, including both TUBC and EVBC) methods.
106 107
When multiple studies reported findings based upon an identical study population, only the most
108
recent study was included in the analysis.
109 110
Systematic review process 4 / 16
111 112
After duplicates were removed, two authors (SC-L and RQ-G) performed independent reviews of
113
617 reports, ultimately selecting nine studies for data extraction and quality assessment.
114
Discrepancies were resolved by consensus. The PRISMA flowchart depicting the review process
115
is presented in Fig. 1.
116 117
Data extraction
118 119
Data were extracted from full length articles by two reviewers (SC-L and RQ-G) independently
120
using a standardized-items form. The extracted information, included; author/s, year of publication,
121
country/region, type of study, sample size, number of participants in each group, mean/median age,
122
gender, tumour location and grade, pathological stage, previous bladder tumour history,
123
perioperative chemotherapy, median follow-up, and outcomes, including; CSS, OS, RFS, or
124
IVRFS.
125 126
Quality of data assessment
127 128
The quality of the studies was assessed independently by two reviewers (SC-L and RQ-G) using
129
the Newcastle–Ottawa scale, which is recommended for the assessment of non-randomised studies
130
[15]
131
and outcomes). To compare cohorts, we concentrated on variables that had been identified as
132
independent predictors in previous multivariate studies (i.e., age, tumour location, histological
133
grade and pathological stage). Any divergences of opinion were settled by discussion or through
134
arbitration with a third reviewer (SS), if no agreement could be reached.
135 136
Statistical analyses
. This scale assesses risk across three domains (i.e., patient selection, comparability of groups
137 138
Log HR and variance were extracted from all studies and meta-analyzed. For each trial, the HR
139
with the corresponding 95% CI related to the survival rate was assessed for the impact on distal
140
ureter management during RNU in patients with UTUC. If meta-analysis revealed moderate to
141
low heterogeneity among studies (I2 <50% and p<0.1), the fixed-effects model (Mantel–Haenszel
142
method) was implemented to pool the results 5 / 16
[16]
. Otherwise, the random-effects model
[17]
.
143
(DerSimonian and Laird method) was applied, which provides more conservative estimates
144
When comparing IVBC and NIVBC, pertinent studies with appropriate data allowed us to perform
145
subgroup analyses accordingly.
146
Differences in clinicopathological parameters, such as; location, tumour multifocality, stage, grade
147
and history of previous non–muscle-invasive bladder cancer were analysed to explore the potential
148
causes of heterogeneity. Differences between groups using continuous variables were then
149
analysed using the standard Chi-square test and Fisher’s exact test for categorical variables.
150
Further, publication bias was assessed using funnel plots and Egger’s regression analysis
151
Review manager version 5.3 (Cochrane Collaboration, Oxford, UK) and STATA version 14.0
152
(State Corporation, College Station, TX, USA) were used for data analysis. A p value of less than
153
0.05 was considered statistically significant.
[18]
.
154
Results
155 156
[11, 12, 19-25]
157
Nine studies consisting of 4,683 participants were included in the final meta-analysis
158
1,482 patients underwent EVBC, 2,503 participants underwent IVBC and the remaining 616
159
people underwent TUBC. The studies were conducted in different countries/regions with a >12
160
month duration, after RNU. Of the nine eligible studies, six studies
161
3,419 patients were designed to investigate the impact of distal ureter management on CSS
162
following RNU. Three studies [19, 22, 23] involving 2,789 patients investigated OS and a further four
163
studies
164
consisting of 3,984 patients investigated IRFS. The detailed demographic characteristics of the
165
participants within the studies are summarized in Table 1 and Table 2.
166
Some significant differences regarding pathological features, including tumour stage and tumour
167
grade were found among these groups. Overall, the median follow-up of this worldwide cohort
168
included patients from Asia, Europe and North America and ranged from 19 to 57.5 months
169
without any significant differences within the sample. All studies were retrospective and evidence
170
was determined to be level III, obtaining scores of ≥6, which was considered adequate for the
171
following meta-analysis.
172 173
Cancer specific survival
[11, 19, 20, 22]
[12, 19-21, 23, 24]
involving 3,687 patients investigated RFS. Five of the studies
6 / 16
.
consisting of
[11, 12, 19, 21, 23]
174 175
Six studies involving 3,419 patients compared NIVBC against IVBC, and reported CSS.
176
Substantial heterogeneity was observed across these trials (I2 = 77%, p<0.01); hence, the
177
random-effects model was applied for statistical analysis. Pooled analysis suggested that there was
178
no significant difference in CSS between IVBC and NIVBC (HR=0.77, 95% CI: 0.48–1.23,
179
p=0.27).
180
Further subgroup analysis was also unable to identify significant differences among IVBC, EVBC
181
and TUBC which suggested that these three methods had similar CSS outcomes (Fig. 2A). When
182
comparing EVBC with TUBC, the combined HRs revealed that there was no significant difference
183
in CSS between the two methods (HR=0.92, 95% CI: 0.61–1.37, p=0.67, Fig. 2B).
184 185 186
Overall Survival
187
Available OS data were reported in only three studies, and there was no apparent heterogeneity (I2
188
= 0%, p=0.80). Therefore, the fixed-effects model was utilized, although pooled analysis revealed
189
no substantial difference in OS between IVBC and NIVBC (HR=0.98, 95% CI 0.88–1.09, p=0.71,
190
Fig. 2C).
191 192 193
Recurrence-free survival
194
No significant heterogeneity was detected across the five studies that compared NIVBC with
195
IVBC. The fixed-effects model was applied and the pooled HR was 1.37 (95% CI 1.23–1.52, p＜
196
0.01), suggesting that IVBC may be associated with better RFS than NIVBC (Fig. 2D). Likewise,
197
no significant heterogeneity was identified between TUBC and EVBC (I2 = 0%, p = 0.79). Again,
198
the fixed-effects model was applied; however, no significant difference was found (HR=1.15, 95%
199
CI: 0.89–1.48, p=0.28, Fig. 2E).
200 201 202
Intravesical recurrence-free survival
203
Five of the nine studies involving 3984 patients reported IRFS and compared NIVBC against
204
IVBC were included in the meta-analysis. No significant heterogeneity was identified across these
205
trials (I2 = 41%, p=0.1); hence, the fixed-effects model was applied. The pooled HR for IVRFS
206
was 1.45 (95% CI: 1.29–1.63, p＜0.01), suggesting that IVBC is associated with better IVRFS 7 / 16
207
than NIVBC in patients with UTUC (Fig. 3A). When excluding patients with bladder tumour
208
history, the pooled statistic appeared to confirm the previous finding (see Fig. 3B).
209
To compare EVBC with TUBC, a total of four studies involving 1900 participants were included.
210
There was moderate heterogeneity, although this finding was not technically significant (I2 = 49%,
211
p=0.12); hence, the fixed-effects model was applied. The pooled statistic suggested that EVBC
212
compared with TUBC was associated with improved IRFS in patients with UTUC (HR=1.23, 95%
213
CI: 1.08–1.41, p＜0.01, Fig. 3C). In an attempt to identify the source of this moderate amount of
214
heterogeneity, we also excluded studies involving patients with bladder tumor history. Only two
215
studies involving 875 patients were included for further analysis, although no significant
216
difference was detected between the two groups (HR=1.81, 95% CI: 0.57–5.74, p=0.32; Fig. 3D).
217 218 219
Publication bias
220
The basic symmetry of the funnel plots suggests that there was no obvious publication bias across
221
these results (Fig. 4). Further, the PEgger values for CSS, OS, RFS, and IRFS were 0.282, 0.433,
222
0.433, and 0.893 respectively, which suggested that there was no evidence of publication bias.
223 224 225
Discussion
226
Complete resection of the ipsilateral distal ureter and bladder cuff plays an important role in
227
reducing intravesical recurrence rates. This is in part due to the fact that UTUC has a propensity
228
for multifocality and a high rate of ureteral stump recurrence
229
RNU for primary UTUC is therefore recommended according to the European Association of
230
Urology guidelines
231
TUBC are widely utilized even though evidence is still needed to identify the most appropriate
232
method for lower ureter management during RNU. This has necessitated the use of systematic
233
reviews of published studies and standardized meta-analyses to identify the optimal method and to
234
guide surgical practice.
235
Nine studies were deemed eligible according to our predetermined inclusion criteria. Pertinent
236
data were then extracted and cumulative survival rates were quantitatively summarized. The
237
pooled results derived from the meta-analysis found that the intravesical approach (TVBC) was
238
associated with improved IRFS compared to both extravesical (EVBC) and endoscopic (TUBC)
[1, 6]
[26-30]
. Bladder cuff excision during
. However, different management strategies including EVBC, IVBC and
8 / 16
239
approaches. However, no significant difference was found in this outcome when comparing EVBC
240
and TUBC, directly.
241
We postulate that the wide variability in these results may be related to the following mechanisms.
242
First and foremost, the traditional open technique guarantees that grossly visible tumour masses
243
can be completely removed. The intravesical procedure, on the other hand, may facilitate
244
enhanced control of the tumour by avoiding over-manipulation and a wider surgical safety margin
245
[12, 25]
246
clamping or stapling. Therefore, it may be easier to misperceive the ureter edge, which creates a
247
high risk within the surgical margin, particularly in patients where exposure is difficult, i.e., in
248
obese patients
249
The utilization of the bladder cuff resection technique is limited due to concerns in reference to
250
damaging the contralateral ureteric orifice. To the best of our knowledge, if the distal ureter is not
251
completely removed, recurrence rates can be as high as 75% in ureteric remnants, even in the
252
absence of positive surgical margins
253
outcomes observed in the TUBC group might have contributed to the inadequate ureteral
254
occlusion during the transurethral incision procedure or periureteric or perivesical seeding
255
secondary to extravasation.
256
Several pieces of clinical and experimental evidence support the notion that subsequent recurrence
257
within the bladder after RNU is due to seeding or intra-epithelial spreading of the original cancer
258
cells
259
implantation of cancer cells from UTUC occurs during surgery, rather than a priori
260
early complete coagulation of the ureteral orifice before bladder cuff excision and the early
261
ligation of the ureter below the distal border of the tumour prior to nephroureterectomy have been
262
recommended to minimize the possibility of tumour seeding. Additionally, intravesical
263
chemotherapy administered immediately after RNU may also significantly decrease recurrence
264
rates within the bladder and prevent the need for additional surgical interventions.
265
Notably, the occurrence of intravesical recurrence after RNU is subject to highly variable
266
inter-individual variations, including demographics, tumour characteristics, and treatment
267
specifics
268
meta-analysis should have adjusted for other important clinicopathological parameters, such as
. Conversely, EVBC is a method of managing the distal ureter through blind extravesical
[31, 32]
[11]
.
[11, 26-28]
. On the other hand, the inferior oncological
. For example, Ito et al. suggest that intravesical seeding and the inadvertent [32]
. Thus,
[2, 33, 34]
. These factors are likely to have influenced our findings, and in retrospect, this 9 / 16
269
tumour multiplicity, location, stage, grade and gender. These adjustments may have increased the
270
precision, although this was only an initial investigation involving a limited number of studies. For
271
example, only one study was identified in which multivariate analysis was conducted regarding
272
this outcome, and therefore, no available data could be used to perform an adjusted meta-analysis.
273
According to the largest multi-institutional study conducted by Xylinas and colleagues, TUBC and
274
EVBC both have a high risk of intravesical recurrence, although only the former is thought to be
275
significant [19]. Certainly, the superiority of IVBC over TUBC has yet to be determined [13, 35]. Ko
276
et al. once conducted a comparative study of the clinicopathologic outcomes between IVBC and
277
TUBC and only tentatively recommended TUBC as safe, providing UTUC is limited to the kidney
278
and proximal ureter. The advantage of this approach when combined with laparoscopic surgery is
279
that it preserves the tenets of minimally invasive surgery and has great appeal in that this
280
intervention decreases postoperative morbidity
281
By attempting to minimize the source of apparent heterogeneity and controlling for confounding
282
variables, we created a subgroup that included only studies of patients without previous or
283
concomitant bladder cancer. The analysis of the pooled results appears to corroborate the earlier
284
findings. Both TUBC and EVBC had significantly higher risks of overall tumour recurrence
285
compared with IVBC, whereas no significant difference was observed between TUBC and EVBC
286
outcomes. Interestingly, TUBC appeared to be associated with improved CSS compared with
287
IVBC. This study elaborates on this point by investigating different proportions of tumour grade
288
between the two groups. Table 2 presents evidence that the proportion of high-grade tumours in
289
the IVBC group was significantly higher than that in the TUBC group. This is consistent with
290
previous studies and therefore confirms the fact that CSS appears to be highly dependent upon
291
pathologic stage and grade [2, 21, 37, 38].
292
Overall survival in the IVBC and NIVBC groups were approximately the same, although a slight
293
improvement in oncologic outcomes was observed in the IVBC group. Unfortunately, there were
294
insufficient data to evaluate morbidities in any detail between these surgical procedures. It is
295
worth noting that an additional incision, more extensive dissection and a longer operative time are
296
required for the IVBC procedure. However, morbidities such as post-procedural complications,
297
life expectancy, and quality of life have not been formally investigated
298
researchers with a logical next step for developing this evidence base.
[36]
.
10 / 16
[6]
, which presents
299
To the best of our knowledge, we are the first to evaluate the relationship between different distal
300
ureter management techniques and survival in patients with UTUC using standard meta-analytical
301
techniques and following the PRISMA guidelines. However, limitations should be considered
302
when drawing conclusions. Firstly, because most of the included studies were retrospective, it is
303
likely that biases from the original reports, such as selection bias, information bias and other
304
confounding factors, have become embedded in this analysis. Although all nine eligible studies
305
involving 3,998 patients were of moderate quality (≥6 scores) according to the Newcastle–Ottawa
306
scale, intrinsic bias remained, which might have rendered these results less reliable. Secondly, in
307
addition to the distal ureteral approach, other important clinicopathological parameters, such as
308
tumour multiplicity, location, stage, grade and gender were independent predictors of intravesical
309
recurrence. The use of adjusted HRs in this meta-analysis would have resulted in a more
310
appropriate interpretation of our results. However, not all nine trials conducted or reported
311
multivariate analysis. Therefore, it was impossible for us to perform an adjusted meta-analysis so
312
additional confirmatory RCTs are required.
313
Thirdly, although previous research and EAU guidelines purport that laparoscopic RNU has
314
equivalent oncological efficacy to open RNU when adhering to strict oncological principles
315
conducting subgroup analysis to compare the efficacy of these two approaches may have made the
316
findings more generalizable. Unfortunately, we were unable to perform this analysis due to
317
insufficient data. Therefore, we hope that intercalating additional data will shed light on these
318
outcomes in the future.
319
Finally, despite the well-recognized advantages of meta-analysis, the results were predictably
320
affected by the quality of the included studies and reporting biases which may have manifested
321
through the lack of studies confirming the null or non-significant results. These studies were
322
historically more difficult to publish compared to studies reporting statistically significant findings.
323
One would hope that as the publication process matures, this evidence-base will become more
324
sophisticated, thereby limiting the impact of publication bias. Given these limitations, we hope
325
that future prospective trials are designed to verify the findings of this meta-analysis.
326 327 328
Conclusions
11 / 16
[1, 39]
,
329
Despite limitations, these findings suggest that compared to EVBC and TUBC, IVBC during RNU
330
for patients with UTUC is associated with a better overall outcome and IRFS. The findings also
331
suggest that IVBC is the superior approach; however, further larger, well-designed RCTs are
332
required to confirm this assertion. There is also a need for standardized reporting that would
333
include more detail surrounding the participant characteristics, as this would enable researchers to
334
identify and align specific interventions to sub-populations, thereby improving outcomes.
335
Ethical approval
336
Ethics committee approval was not necessary because all data were carefully extracted from
337
existing literature, and this article did not involve handling individual patient data. In addition,
338
neither patients nor the public were involved in the design or planning of this study.
339 340
Consent for publication
341
Not required
342 343
Sources of funding
344
This research did not receive any specific grant from funding agencies in the public, commercial,
345
or not-for-profit sectors.
346 347
Unique identifying number (UIN)
348
This study was registered with the Research Registry and the unique identifying number is: review
349
registry 741.
350 351
Conflict of interest
352
Authors declared that this study has received no financial support and that there were no
353
conflicting interests.
354 355
Availability of data and materials
356
Not applicable.
357 358
Acknowledgements
359
Not applicable.
360 12 / 16
361 362
Provenance and peer review Not commissioned, externally peer-reviewed
363
References
364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403
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[33] T.F. Chromecki, K. Bensalah, M. Remzi, G. Verhoest, E.K. Cha, D.S. Scherr, et al., Prognostic factors for upper urinary tract urothelial carcinoma, Nat Rev Urol 8(8) (2011) 440-447. [34] M. Remzi, A. Haitel, V. Margulis, P. Karakiewicz, F. Montorsi, E. Kikuchi, et al., Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients, BJU Int. 103(3) (2009) 307-311. [35] C.B. Allard, A. Alamri, S. Dason, F. Farrokhyar, E.D. Matsumoto, A. Kapoor, The method of bladder cuff excision during laparoscopic radical nephroureterectomy does not affect oncologic outcomes in upper tract urothelial carcinoma, World J Urol 31(1) (2013) 175-181. [36] R. Ko, B.H. Chew, D.R. Hickling, H. Razvi, P.P. Luke, J.L. Chin, et al., Transitional-cell carcinoma recurrence rate after nephroureterectomy in patients who undergo open excision of bladder cuff v transurethral incision of the ureteral orifice, J. Endourol. 21(7) (2007) 730-734. [37] C.C. Li, T.H. Chang, W.J. Wu, H.L. Ke, S.P. Huang, P.C. Tsai, et al., Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients, Eur. Urol. 54(5) (2008) 1127-1134. [38] G. Novara, V. De Marco, F. Gottardo, O. Dalpiaz, V. Bouygues, A. Galfano, et al., Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multi-institutional dataset from 3 European centers, Cancer 110(8) (2007) 1715-1722. [39] S. Ni, W. Tao, Q. Chen, L. Liu, H. Jiang, H. Hu, et al., Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies, Eur. Urol. 61 (2012) 1142-1153.
468 469
15 / 16
470 471 472 473
Figure legends
474
Figure 2. Forest plot comparing survival and subgroup analysis of different distal ureter
475
management techniques. (A) CSS in patients receiving NIVBC versus IVBC; (B) CSS in patients
476
receiving EVBC versus TUBC; (C) OS in patients receiving NIVBC versus IVBC; (D) RFS in
477
patients receiving NIVBC versus IVBC; (E) RFS in patients receiving EVBC versus
478
TUBC.(CSS=cancer-specific survival; EVBC=extravesical incision of the bladder cuff;
479
IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical recurrence-free survival；
480
NIVBC=non-intrasvesical incision of the bladder cuff; OS=overall survival; RFS=recurrence-free
481
survival；TUBC=transurethral incision of the bladder cuff)
Figure 1.
Flowchart of study selection.
482 483
Figure 3.
484
excluding prior bladder tumour history; Forest plot comparing IRFS between EVBC and TUBC:
485
(C) in all patients, (D) excluding prior bladder tumour history. (EVBC=extravesical incision of the
486
bladder cuff; IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical recurrence-free
487
survival；NIVBC=non-intrasvesical incision of the bladder cuff; TUBC=transurethral incision of
488
the bladder cuff)
Forest plot comparing IRFS between NIVBC and IVBC: (A) in all patients, (B)
489 490
Figure 4. Funnel plot for the evaluation of potential publication bias: (A) CSS between NIVBC
491
and IVBC; (B) CSS between TUBC and EVBC; (C) OS between NIVBC and IVBC; (D) RFS
492
between NIVBC and IVBC;(E) RFS between TUVBC and EVBC; (F) IRFS between NIVBC and
493
IVBC;(G) IRFS between TUVBC and EVBC. (CSS=cancer-specific survival; EVBC=extravesical
494
incision of the bladder cuff; IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical
495
recurrence-free survival； NIVBC=non-intrasvesical incision of the bladder cuff; OS=overall
496
survival; RFS=recurrence-free survival；TUBC=transurethral incision of the bladder cuff)
497
16 / 16
Table 1. Study characteristics Study
Study design
NOS
Region/
Number of patients (n)
Country
Total
IVBC
NIVBC EVBC
Mean/Median
Gender
age (year)
(F/M)
Tumor location
Tumor grade
Pathologic
History of
Perioperative
Open/
Follow-up
Low
tumor
bladder
chemotherapy
Laparoscopic
median
stage
cancer
(n, %)
High
TUBC
Outcome
(month)
(n, %) Carrion et
Retrospective,
al 2016
single center
7
Spain
117
49
68
(41.9%)
(58.1%)
70.26
32/85
Renal pelvis 74
23
94
≤pT1 47
Ureter 38
pT2 26
Both 5
pT3 33
37 (31.6)
0 (0%)
0/117
20
CSS
NA
91 (11.1%)
382/438
24.6
ORFS;
pT4 11 Kapoor et
Retrospective,
al 2014
multi center
8
Canada
820
406
316
98
(49.5%)
(38.5%)
(12%)
69.6
300/520
Renal pelvis 432
295
525
≤pT1 376
Ureter 198
pT2 126
Both 176
pT3 181
IRFS
pT4 40 Krabbe et
Retrospective,
al 2014
single center
8
USA
122
76(62%)
46(38%)
69
45/77
Renal pelvis 88
27
95
Ureter 34
≤pT1 81
41 (34%)
19 (19.6%)
26 /96
32
pT2 6
CSS; IRFS
pT3 31 pT4 4 Luo et al
Retrospective,
2013
single center
7
Taipei, China
396
240
156
(60.6%)
(39.4%)
66.41
206/190
Renal pelvis 263
39
357
Ureter 133
≤pT1 208
94 (23.7%)
NA
NA
40.65
CSS
770 (28.7%)
0 (0%)
2170 /511
57.5
OS;
pT2 81 pT3 107 pT4 0
Xylinas et
Retrospective,
al 2012
multi center
Li et al
Retrospective,
2010
single center
8
USA, Austria, Italy, Canada,
8
2681
Germany,
1811
785
85
(67.5%)
(29.3%)
(3.2%)
68.4
873/1808
Renal pelvis 1730
415
2242
pT2 519
RFS;
UK, France, Spain,
pT3 810
IRFS
Japan
pT4 131
Taipei, China
301
81
129
91
(27%)
(43%)
(30%)
Ureter 951
≤pT1 1221
65.4
170/131
Renal pelvis 105
130
171
≤pT1 122
Ureter 142
pT2 88
Multifocal 54
pT3 77
0 (0%)
0 (0%)
246 /55
33
CSS; IRFS
pT4 14 Walton et
Retrospective,
al 2009
multi center
8
UK
138
48
90
IVBC 66.5
(35%)
(65%)
TUBC 66.4
51/87
Renal pelvis 56
100
38
≤pT1 88
Ureter 57
pT2 21
Multifocal 25
pT3 29
29(21%)
NA
138 /0
43
CSS; RFS
pT4 0 Matin and
Retrospective,
Gill 2005
single center
6
USA
48
12
36
TUBC 68.8
(25%)
(75%)
EVBC 72.4
15/33
Renal pelvis 29
19
29
≤pT1 26
Ureter 14
pT2 3
Multifocal 4
pT3 13
21 (44%)
0 (0%)
0 /48
TUBC 22
OS;
EVBC 19
RFS
IVBC 42
CSS;
TUBC 32
IRFS
pT4 5 Saika et al
Prospective
2004
nonrandomized, single center
6
Japan
60
32
28
IVBC 69.8
(53%)
(47%)
TUBC 65.2
20/40
NA
45
15
≤pT1 32 pT2 3 pT3 22
0 (0%)
NA
60/0
pT4 6 CSS=cancer-specific survival； ；EVBC=extravesical incision of the bladder cuff; F= female; IVBC=intrasvesical incision of the bladder cuff； ；IRFS = intravesical recurrence-free survival； ；M=male; NIVBC=non-intrasvesical incision of the bladder cuff; NA =not available; NOS= Newcastle-Ottawa Scale; OS=overall survival; RFS=recurrence-free survival； ；TUBC=transurethral incision of the bladder cuff;
Table 2. Chi-squared test results Variable
TUBC (n, %)
EVBC (%)
p value
TUBC(%)
Renal pelvic
314（63.1）
863（55.8）
0.02
Ureteral
166（33.3）
Both
18 （3.6）
Yes
110（23.6）
373（25.2）
No
356（76.4）
1109（74.8）
Low grade or ≤G2
141（30.1）
497（33.5）
High grade or >G2
327（69.9）
985（66.5）
≤pT1
247（53.8）
621（43.2）
pT2
79（17.2）
pT3 pT4
IVBC (%)
EVBC (%)
IVBC (%)
211（64.3） 1391（60.1） 0.06
721（59.9）
1382（60.8） 0.05
615（39.7）
99 （30.2） 835 （36.1）
414（34.4）
804（35.3）
69 （4.5）
18 （5.5） 89 （3.8）
69 （5.7）
89 （3.9）
289（23.5）
546（32.7）
941（76.5）
1122（67.3）
276（22.4）
494（21.5）
189（48.2） 1831（77）
954（77.6）
1804（78.5）
215（55.9） 1125（48.3） 0.02
496（41.8）
1085（48.2） ＜0.01
314（21.8）
69 （17.9） 432（18.5）
255（21.5）
423（18.8）
120（26.1）
433（30.1）
91 （23.6） 662（28.4）
366（30.9）
636（28.2）
13 （2.9）
70 （4.9）
10 （2.6） 112（4.8）
69 （5.8）
107（4.8）
Yes
7
41
41 （3.4）
43 （2.6）
No
303（97.8）
p value
p value
Tumor location
Multifocal 0.50
77 （21.2） 554（32.3）
＜0.01
287（78.8） 1162（67.7）
＜0.01
Tumor grade 0.17
203（51.8） 547 （23）
＜0.01
0.52
Tumor stage
＜0.01
Perioperative chemotherapy （2.2）
（3.3）
1201（96.7）
0.34
7
（2.6） 43
（2.6）
267（97.4） 1625（97.4）
0.98
1181（96.6） 1625（97.4）
0.22
History of bladder cancer Yes
54 （16.3）
255（22.1）
no
278（83.7）
899（77.9）
0.02
41 （3.9） 565（42.1） 253（86.1） 777（57.1）
＜0.01
193（21.1）
555（44.0）
721（78.9）
707（56.0）
EVBC=extravesical incision of the bladder cuff; IVBC=intrasvesical incision of the bladder cuff；TUBC=transurethral incision of the bladder cuff.
＜0.01
Highlights Findings suggest intravesical incision of the bladder cuff (IVBC) during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial carcinoma (UTUC) is associated with a better overall outcome. IVBC also appears to be associated with better intravesical recurrence-free survival (IRFS) when directly compared to extravesical incision of the bladder cuff (EVBC) and transurethral incision of the bladder cuff (TUBC). IVBC is the superior approach, however, meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences among the three different surgical techniques.
Data statement All the data were presented in the manuscript. No additional data are available.
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This study was registered with the Research Registry and the unique identifying number is: reviewregistry741. https://www.researchregistry.com/register-now#registryofsystematicreviewsmetaanalyses/registryofsystematicreviewsmetaanalysesdetails/5d6f2c292339cc00117a5f97/
1
Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Contribution: Shicong Lai and Runqi Guo designed and conducted the systematic search to identify all relevant studies. Shicong Lai and Samuel Seery then assessed eligibility and the quality of each study, before extracting data and conducting statistical analysis. Pengjie Wu, Jianyong Liu and Yaoguang Zhang coordinated the study and performed data acquisition. Shengcai Zhu, Xiaoguang Li and Shicong Lai participated in data interpretation and drafting this article. Samuel Seery, Ming Liu and Jianye Wang reviewed and revised this report for critical content and scientific rigour. All authors read and approved the final manuscript.
Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. In this meta-analysis, the guarantors are Shicong Lai and Jianye Wang
2
S1743-9191(20)30026-1
DOI:
https://doi.org/10.1016/j.ijsu.2020.01.016
Reference:
IJSU 5223
To appear in:
International Journal of Surgery
Received Date: 5 September 2019 Revised Date:
15 January 2020
Accepted Date: 16 January 2020
Please cite this article as: Lai S, Guo R, Seery S, Wu P, Liu J, Zhang Y, Zhu S, Li X, Liu M, Wang J, Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: a systematic review and meta-analysis, International Journal of Surgery, https://doi.org/10.1016/ j.ijsu.2020.01.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.
Assessing the impact of different distal ureter management techniques during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma on oncological outcomes: a systematic review and meta-analysis Running title: Distal ureter management techniques for UTUC patients Authors and Affiliations: Shicong Lai1,2,3#; Runqi Guo2,4#; Samuel Seery5; Pengjie Wu1,2; Jianyong Liu1,2,3, Yaoguang Zhang1,2,3; Shengcai Zhu1,2; Xiaoguang Li2,4; Ming Liu1,2,3*; Jianye Wang1,2,3* 1 Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing 100730, China 2 Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China 3 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China 4 Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Beijing 100730, China 5 School of Humanities and Social Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China # Shicong Lai and Runqi Guo contributed as the co-first author * Correspondence author: Ming Liu and Jianye Wang Address for correspondence: Ming Liu, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; Tel: +86 13911036970
Email: [email protected]
Fax: +86-010-85136272
Jian-Ye Wang, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; Tel: +86 13901058760
Email: [email protected]
Fax: +86-010-85136272
1
Assessing the impact of different distal ureter management techniques during
2
radical nephroureterectomy for primary upper urinary tract urothelial
3
carcinoma on oncological outcomes: a systematic review and meta-analysis
4
Key words: Distal ureter management; Prognosis; Radical nephroureterectomy (RNU);
5
Systematic review and meta-analysis; Upper urinary tract urothelial carcinoma (UTUC)
6 7
Abbreviations: CI=confidence interval; CSS=cancer-specific survival ； EVBC=extravesical
8
incision of the bladder cuff; HR=hazard ratio; IVBC=intrasvesical incision of the bladder cuff；
9
IRFS = intravesical recurrence-free survival；NIVBC=non-intrasvesical incision of the bladder
10
cuff; OS=overall survival; PRISMA=Preferred Reporting Items for Systematic Reviews and
11
Meta-analysis;
12
TUBC=transurethral incision of the bladder cuff; UTUC=upper urinary tract urothelial carcinoma
RFS=recurrence-free
survival
13 14 15
1 / 16
；
RNU=radical
nephroureterectomy;
Abstract
16 17 18
Objectives： ：
19
To assess the oncological outcomes of several distal ureter management techniques in patients
20
administered with radical nephroureterectomy (RNU) for primary upper urinary tract urothelial
21
carcinoma (UTUC).
22 23
Methods:
24
A systematic search of PubMed, EMBASE, and the Cochrane Library was conducted to identify
25
studies comparing outcomes following RNU under various surgical methods for bladder cuff
26
management. Standard cumulative analyses of hazard ratios (HRs) with 95% confidence intervals
27
(CIs) were performed using Review Manager (5.3).
28 29
Results:
30
Nine studies involving 4,683 patients were selected based upon eligibility criteria. Meta-analysis
31
of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences
32
among intravesical incision of the bladder cuff (IVBC), extravesical incision of the bladder cuff
33
(EVBC) and transurethral incision of the bladder cuff (TUBC) techniques. However, the IVBC
34
technique appeared to have better recurrence-free survival (RFS) (HR= 1.37, p<0.01) and
35
intravesical recurrence-free survival (IRFS) (HR=1.45, p<0.01) compared with non-IVBC
36
methods, including both TUBC and EVBC. When studies involving patients with bladder tumour
37
history were excluded, the pooled statistic appeared to confirm that IVBC was associated with
38
improved IRFS (HR=1.25, p=0.03) compared with EVBC and TUBC. No significant difference
39
was found between the EVBC and TUBC groups (HR=1.81, p=0.32).
40 41
Conclusions:
42
The findings suggest that IVBC is associated with improved oncologic outcomes and that it may
43
be recommended for distal ureter management. However, caution must be taken because this
44
recommendation is based upon a very limited number of clinical studies. Further research with
45
enhanced outcome data collection and improved reporting is required to confirm these findings.
46
2 / 16
47 48
Introduction
49
Upper urinary tract urothelial carcinomas (UTUCs) manifest through the urothelial lining of the
50
urinary tract from renal calyces to the ureteral orifice. While relatively rare, this cluster of
51
neoplasms still accounts for 5-10% of all urothelial malignancies
52
nephroureterectomy (RNU) with en bloc resection of the ipsilateral bladder cuff is the standard
53
procedure for patients with non-metastatic UTUC and normal contralateral kidney functions. RNU
54
has remained the standard procedure because several studies have observed lower rates of
55
recurrent malignancies and improved survival
56
since Clayman and colleagues performed the first laparoscopic nephroureterectomy in 1991
57
However, the optimal technique for excising the distal ureter and bladder cuff has yet to be
58
determined.
59
Typically, these techniques are classified as either open, laparoscopic, or endoscopic management
60
methods. The most common approach appears to be intravesical incision of the bladder cuff
61
(IVBC) which involves a cystotomy procedure with intravesical excision of the intravesical ureter,
62
ureteric orifice and surrounding bladder cuff. The second most commonly administered
63
intervention is extravesical incision of the bladder cuff (EVBC) which involves dissecting the
64
distal ureter and bladder cuff extravesically. The third technique is transurethral incision of the
65
bladder cuff (TUBC). For this method, ureteral endoscopic approaches, such as transurethrally
66
occluding the free orifice and incising around the ureteric orifice, which were originally proposed
67
as complementary first steps of nephroureterectomy, are carried out, and then the ureteric orifice
68
and perimeatal bladder are completely removed extravesically [11].
69
While each technique described continues to be widely used, many controversies exist. It is not
70
yet known which surgical intervention provides superior oncologic outcomes [12-14]. Therefore, the
71
aim of this study is to provide evidence for guiding decision making and improving management
72
strategies for UTUC patients. As such, we performed a systematic review and meta-analysis to
73
assess the efficacy of these three different distal ureter management techniques in patients
74
undergoing RNU for primary UTUC.
. At present, radical
[1, 5, 6]
75 76 77
[1-4]
Methods
3 / 16
. Several techniques have been developed [7-10]
.
78 79
Search and Selection
80
Two authors (SC-L and RQ-G) performed a systematic computerized search of PubMed,
81
EMBASE, and the Cochrane Library up until April 20, 2019, to identify clinical studies
82
comparing oncologic outcomes following RNU under surgical procedures described for bladder
83
cuff management in the UTUC population.
84
The search terms included; upper urinary tract urothelial carcinoma OR upper tract urothelial
85
neoplasms OR upper tract urothelial cancer OR transitional cell carcinoma of the upper urinary
86
tract AND distal ureter OR lower ureter AND bladder cuff AND nephroureterectomy. In addition,
87
manual searching was performed for associated studies and citations. The search strategy was
88
designed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis
89
(PRISMA) statement and AMSTAR (Assessing the methodological quality of systematic reviews)
90
Guidelines.
91 92 93 94 95 96 97
Inclusion criteria Studies were included, if they met all of the following criteria: (1) Randomized controlled trials (RCTs) or retrospective studies analysing the relationship between distal ureter management methods and UTUC prognoses;
98
(2) Patients with primary UTUC without previous or concomitant muscle-invasive bladder
99
cancer, lymph node or distant metastases, and bilateral synchronous upper urinary tract
100 101 102 103
tumours at the time of diagnosis; (3) Outcomes included cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) or intravesical recurrence-free survival (IRFS); (4) Survival data included hazard ratios (HRs) and corresponding 95%
104
confidence intervals (CIs), or Kaplan–Meier curves comparing survival between IVBC
105
and non-IVBC (NIVBC, including both TUBC and EVBC) methods.
106 107
When multiple studies reported findings based upon an identical study population, only the most
108
recent study was included in the analysis.
109 110
Systematic review process 4 / 16
111 112
After duplicates were removed, two authors (SC-L and RQ-G) performed independent reviews of
113
617 reports, ultimately selecting nine studies for data extraction and quality assessment.
114
Discrepancies were resolved by consensus. The PRISMA flowchart depicting the review process
115
is presented in Fig. 1.
116 117
Data extraction
118 119
Data were extracted from full length articles by two reviewers (SC-L and RQ-G) independently
120
using a standardized-items form. The extracted information, included; author/s, year of publication,
121
country/region, type of study, sample size, number of participants in each group, mean/median age,
122
gender, tumour location and grade, pathological stage, previous bladder tumour history,
123
perioperative chemotherapy, median follow-up, and outcomes, including; CSS, OS, RFS, or
124
IVRFS.
125 126
Quality of data assessment
127 128
The quality of the studies was assessed independently by two reviewers (SC-L and RQ-G) using
129
the Newcastle–Ottawa scale, which is recommended for the assessment of non-randomised studies
130
[15]
131
and outcomes). To compare cohorts, we concentrated on variables that had been identified as
132
independent predictors in previous multivariate studies (i.e., age, tumour location, histological
133
grade and pathological stage). Any divergences of opinion were settled by discussion or through
134
arbitration with a third reviewer (SS), if no agreement could be reached.
135 136
Statistical analyses
. This scale assesses risk across three domains (i.e., patient selection, comparability of groups
137 138
Log HR and variance were extracted from all studies and meta-analyzed. For each trial, the HR
139
with the corresponding 95% CI related to the survival rate was assessed for the impact on distal
140
ureter management during RNU in patients with UTUC. If meta-analysis revealed moderate to
141
low heterogeneity among studies (I2 <50% and p<0.1), the fixed-effects model (Mantel–Haenszel
142
method) was implemented to pool the results 5 / 16
[16]
. Otherwise, the random-effects model
[17]
.
143
(DerSimonian and Laird method) was applied, which provides more conservative estimates
144
When comparing IVBC and NIVBC, pertinent studies with appropriate data allowed us to perform
145
subgroup analyses accordingly.
146
Differences in clinicopathological parameters, such as; location, tumour multifocality, stage, grade
147
and history of previous non–muscle-invasive bladder cancer were analysed to explore the potential
148
causes of heterogeneity. Differences between groups using continuous variables were then
149
analysed using the standard Chi-square test and Fisher’s exact test for categorical variables.
150
Further, publication bias was assessed using funnel plots and Egger’s regression analysis
151
Review manager version 5.3 (Cochrane Collaboration, Oxford, UK) and STATA version 14.0
152
(State Corporation, College Station, TX, USA) were used for data analysis. A p value of less than
153
0.05 was considered statistically significant.
[18]
.
154
Results
155 156
[11, 12, 19-25]
157
Nine studies consisting of 4,683 participants were included in the final meta-analysis
158
1,482 patients underwent EVBC, 2,503 participants underwent IVBC and the remaining 616
159
people underwent TUBC. The studies were conducted in different countries/regions with a >12
160
month duration, after RNU. Of the nine eligible studies, six studies
161
3,419 patients were designed to investigate the impact of distal ureter management on CSS
162
following RNU. Three studies [19, 22, 23] involving 2,789 patients investigated OS and a further four
163
studies
164
consisting of 3,984 patients investigated IRFS. The detailed demographic characteristics of the
165
participants within the studies are summarized in Table 1 and Table 2.
166
Some significant differences regarding pathological features, including tumour stage and tumour
167
grade were found among these groups. Overall, the median follow-up of this worldwide cohort
168
included patients from Asia, Europe and North America and ranged from 19 to 57.5 months
169
without any significant differences within the sample. All studies were retrospective and evidence
170
was determined to be level III, obtaining scores of ≥6, which was considered adequate for the
171
following meta-analysis.
172 173
Cancer specific survival
[11, 19, 20, 22]
[12, 19-21, 23, 24]
involving 3,687 patients investigated RFS. Five of the studies
6 / 16
.
consisting of
[11, 12, 19, 21, 23]
174 175
Six studies involving 3,419 patients compared NIVBC against IVBC, and reported CSS.
176
Substantial heterogeneity was observed across these trials (I2 = 77%, p<0.01); hence, the
177
random-effects model was applied for statistical analysis. Pooled analysis suggested that there was
178
no significant difference in CSS between IVBC and NIVBC (HR=0.77, 95% CI: 0.48–1.23,
179
p=0.27).
180
Further subgroup analysis was also unable to identify significant differences among IVBC, EVBC
181
and TUBC which suggested that these three methods had similar CSS outcomes (Fig. 2A). When
182
comparing EVBC with TUBC, the combined HRs revealed that there was no significant difference
183
in CSS between the two methods (HR=0.92, 95% CI: 0.61–1.37, p=0.67, Fig. 2B).
184 185 186
Overall Survival
187
Available OS data were reported in only three studies, and there was no apparent heterogeneity (I2
188
= 0%, p=0.80). Therefore, the fixed-effects model was utilized, although pooled analysis revealed
189
no substantial difference in OS between IVBC and NIVBC (HR=0.98, 95% CI 0.88–1.09, p=0.71,
190
Fig. 2C).
191 192 193
Recurrence-free survival
194
No significant heterogeneity was detected across the five studies that compared NIVBC with
195
IVBC. The fixed-effects model was applied and the pooled HR was 1.37 (95% CI 1.23–1.52, p＜
196
0.01), suggesting that IVBC may be associated with better RFS than NIVBC (Fig. 2D). Likewise,
197
no significant heterogeneity was identified between TUBC and EVBC (I2 = 0%, p = 0.79). Again,
198
the fixed-effects model was applied; however, no significant difference was found (HR=1.15, 95%
199
CI: 0.89–1.48, p=0.28, Fig. 2E).
200 201 202
Intravesical recurrence-free survival
203
Five of the nine studies involving 3984 patients reported IRFS and compared NIVBC against
204
IVBC were included in the meta-analysis. No significant heterogeneity was identified across these
205
trials (I2 = 41%, p=0.1); hence, the fixed-effects model was applied. The pooled HR for IVRFS
206
was 1.45 (95% CI: 1.29–1.63, p＜0.01), suggesting that IVBC is associated with better IVRFS 7 / 16
207
than NIVBC in patients with UTUC (Fig. 3A). When excluding patients with bladder tumour
208
history, the pooled statistic appeared to confirm the previous finding (see Fig. 3B).
209
To compare EVBC with TUBC, a total of four studies involving 1900 participants were included.
210
There was moderate heterogeneity, although this finding was not technically significant (I2 = 49%,
211
p=0.12); hence, the fixed-effects model was applied. The pooled statistic suggested that EVBC
212
compared with TUBC was associated with improved IRFS in patients with UTUC (HR=1.23, 95%
213
CI: 1.08–1.41, p＜0.01, Fig. 3C). In an attempt to identify the source of this moderate amount of
214
heterogeneity, we also excluded studies involving patients with bladder tumor history. Only two
215
studies involving 875 patients were included for further analysis, although no significant
216
difference was detected between the two groups (HR=1.81, 95% CI: 0.57–5.74, p=0.32; Fig. 3D).
217 218 219
Publication bias
220
The basic symmetry of the funnel plots suggests that there was no obvious publication bias across
221
these results (Fig. 4). Further, the PEgger values for CSS, OS, RFS, and IRFS were 0.282, 0.433,
222
0.433, and 0.893 respectively, which suggested that there was no evidence of publication bias.
223 224 225
Discussion
226
Complete resection of the ipsilateral distal ureter and bladder cuff plays an important role in
227
reducing intravesical recurrence rates. This is in part due to the fact that UTUC has a propensity
228
for multifocality and a high rate of ureteral stump recurrence
229
RNU for primary UTUC is therefore recommended according to the European Association of
230
Urology guidelines
231
TUBC are widely utilized even though evidence is still needed to identify the most appropriate
232
method for lower ureter management during RNU. This has necessitated the use of systematic
233
reviews of published studies and standardized meta-analyses to identify the optimal method and to
234
guide surgical practice.
235
Nine studies were deemed eligible according to our predetermined inclusion criteria. Pertinent
236
data were then extracted and cumulative survival rates were quantitatively summarized. The
237
pooled results derived from the meta-analysis found that the intravesical approach (TVBC) was
238
associated with improved IRFS compared to both extravesical (EVBC) and endoscopic (TUBC)
[1, 6]
[26-30]
. Bladder cuff excision during
. However, different management strategies including EVBC, IVBC and
8 / 16
239
approaches. However, no significant difference was found in this outcome when comparing EVBC
240
and TUBC, directly.
241
We postulate that the wide variability in these results may be related to the following mechanisms.
242
First and foremost, the traditional open technique guarantees that grossly visible tumour masses
243
can be completely removed. The intravesical procedure, on the other hand, may facilitate
244
enhanced control of the tumour by avoiding over-manipulation and a wider surgical safety margin
245
[12, 25]
246
clamping or stapling. Therefore, it may be easier to misperceive the ureter edge, which creates a
247
high risk within the surgical margin, particularly in patients where exposure is difficult, i.e., in
248
obese patients
249
The utilization of the bladder cuff resection technique is limited due to concerns in reference to
250
damaging the contralateral ureteric orifice. To the best of our knowledge, if the distal ureter is not
251
completely removed, recurrence rates can be as high as 75% in ureteric remnants, even in the
252
absence of positive surgical margins
253
outcomes observed in the TUBC group might have contributed to the inadequate ureteral
254
occlusion during the transurethral incision procedure or periureteric or perivesical seeding
255
secondary to extravasation.
256
Several pieces of clinical and experimental evidence support the notion that subsequent recurrence
257
within the bladder after RNU is due to seeding or intra-epithelial spreading of the original cancer
258
cells
259
implantation of cancer cells from UTUC occurs during surgery, rather than a priori
260
early complete coagulation of the ureteral orifice before bladder cuff excision and the early
261
ligation of the ureter below the distal border of the tumour prior to nephroureterectomy have been
262
recommended to minimize the possibility of tumour seeding. Additionally, intravesical
263
chemotherapy administered immediately after RNU may also significantly decrease recurrence
264
rates within the bladder and prevent the need for additional surgical interventions.
265
Notably, the occurrence of intravesical recurrence after RNU is subject to highly variable
266
inter-individual variations, including demographics, tumour characteristics, and treatment
267
specifics
268
meta-analysis should have adjusted for other important clinicopathological parameters, such as
. Conversely, EVBC is a method of managing the distal ureter through blind extravesical
[31, 32]
[11]
.
[11, 26-28]
. On the other hand, the inferior oncological
. For example, Ito et al. suggest that intravesical seeding and the inadvertent [32]
. Thus,
[2, 33, 34]
. These factors are likely to have influenced our findings, and in retrospect, this 9 / 16
269
tumour multiplicity, location, stage, grade and gender. These adjustments may have increased the
270
precision, although this was only an initial investigation involving a limited number of studies. For
271
example, only one study was identified in which multivariate analysis was conducted regarding
272
this outcome, and therefore, no available data could be used to perform an adjusted meta-analysis.
273
According to the largest multi-institutional study conducted by Xylinas and colleagues, TUBC and
274
EVBC both have a high risk of intravesical recurrence, although only the former is thought to be
275
significant [19]. Certainly, the superiority of IVBC over TUBC has yet to be determined [13, 35]. Ko
276
et al. once conducted a comparative study of the clinicopathologic outcomes between IVBC and
277
TUBC and only tentatively recommended TUBC as safe, providing UTUC is limited to the kidney
278
and proximal ureter. The advantage of this approach when combined with laparoscopic surgery is
279
that it preserves the tenets of minimally invasive surgery and has great appeal in that this
280
intervention decreases postoperative morbidity
281
By attempting to minimize the source of apparent heterogeneity and controlling for confounding
282
variables, we created a subgroup that included only studies of patients without previous or
283
concomitant bladder cancer. The analysis of the pooled results appears to corroborate the earlier
284
findings. Both TUBC and EVBC had significantly higher risks of overall tumour recurrence
285
compared with IVBC, whereas no significant difference was observed between TUBC and EVBC
286
outcomes. Interestingly, TUBC appeared to be associated with improved CSS compared with
287
IVBC. This study elaborates on this point by investigating different proportions of tumour grade
288
between the two groups. Table 2 presents evidence that the proportion of high-grade tumours in
289
the IVBC group was significantly higher than that in the TUBC group. This is consistent with
290
previous studies and therefore confirms the fact that CSS appears to be highly dependent upon
291
pathologic stage and grade [2, 21, 37, 38].
292
Overall survival in the IVBC and NIVBC groups were approximately the same, although a slight
293
improvement in oncologic outcomes was observed in the IVBC group. Unfortunately, there were
294
insufficient data to evaluate morbidities in any detail between these surgical procedures. It is
295
worth noting that an additional incision, more extensive dissection and a longer operative time are
296
required for the IVBC procedure. However, morbidities such as post-procedural complications,
297
life expectancy, and quality of life have not been formally investigated
298
researchers with a logical next step for developing this evidence base.
[36]
.
10 / 16
[6]
, which presents
299
To the best of our knowledge, we are the first to evaluate the relationship between different distal
300
ureter management techniques and survival in patients with UTUC using standard meta-analytical
301
techniques and following the PRISMA guidelines. However, limitations should be considered
302
when drawing conclusions. Firstly, because most of the included studies were retrospective, it is
303
likely that biases from the original reports, such as selection bias, information bias and other
304
confounding factors, have become embedded in this analysis. Although all nine eligible studies
305
involving 3,998 patients were of moderate quality (≥6 scores) according to the Newcastle–Ottawa
306
scale, intrinsic bias remained, which might have rendered these results less reliable. Secondly, in
307
addition to the distal ureteral approach, other important clinicopathological parameters, such as
308
tumour multiplicity, location, stage, grade and gender were independent predictors of intravesical
309
recurrence. The use of adjusted HRs in this meta-analysis would have resulted in a more
310
appropriate interpretation of our results. However, not all nine trials conducted or reported
311
multivariate analysis. Therefore, it was impossible for us to perform an adjusted meta-analysis so
312
additional confirmatory RCTs are required.
313
Thirdly, although previous research and EAU guidelines purport that laparoscopic RNU has
314
equivalent oncological efficacy to open RNU when adhering to strict oncological principles
315
conducting subgroup analysis to compare the efficacy of these two approaches may have made the
316
findings more generalizable. Unfortunately, we were unable to perform this analysis due to
317
insufficient data. Therefore, we hope that intercalating additional data will shed light on these
318
outcomes in the future.
319
Finally, despite the well-recognized advantages of meta-analysis, the results were predictably
320
affected by the quality of the included studies and reporting biases which may have manifested
321
through the lack of studies confirming the null or non-significant results. These studies were
322
historically more difficult to publish compared to studies reporting statistically significant findings.
323
One would hope that as the publication process matures, this evidence-base will become more
324
sophisticated, thereby limiting the impact of publication bias. Given these limitations, we hope
325
that future prospective trials are designed to verify the findings of this meta-analysis.
326 327 328
Conclusions
11 / 16
[1, 39]
,
329
Despite limitations, these findings suggest that compared to EVBC and TUBC, IVBC during RNU
330
for patients with UTUC is associated with a better overall outcome and IRFS. The findings also
331
suggest that IVBC is the superior approach; however, further larger, well-designed RCTs are
332
required to confirm this assertion. There is also a need for standardized reporting that would
333
include more detail surrounding the participant characteristics, as this would enable researchers to
334
identify and align specific interventions to sub-populations, thereby improving outcomes.
335
Ethical approval
336
Ethics committee approval was not necessary because all data were carefully extracted from
337
existing literature, and this article did not involve handling individual patient data. In addition,
338
neither patients nor the public were involved in the design or planning of this study.
339 340
Consent for publication
341
Not required
342 343
Sources of funding
344
This research did not receive any specific grant from funding agencies in the public, commercial,
345
or not-for-profit sectors.
346 347
Unique identifying number (UIN)
348
This study was registered with the Research Registry and the unique identifying number is: review
349
registry 741.
350 351
Conflict of interest
352
Authors declared that this study has received no financial support and that there were no
353
conflicting interests.
354 355
Availability of data and materials
356
Not applicable.
357 358
Acknowledgements
359
Not applicable.
360 12 / 16
361 362
Provenance and peer review Not commissioned, externally peer-reviewed
363
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364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403
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[20] T.J. Walton, B.T. Sherwood, R.J. Parkinson, O. Obakponovwe, S.A. Thomas, M.C. Taylor, et al., Comparative outcomes following endoscopic ureteral detachment and formal bladder cuff excision in open nephroureterectomy for upper urinary tract transitional cell carcinoma, J. Urol. 181(2) (2009) 532-539. [21] W.M. Li, J.T. Shen, C.C. Li, H.L. Ke, Y.C. Wei, W.J. Wu, et al., Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma, Eur. Urol. 57(6) (2010) 963-969. [22] S.F. Matin, I.S. Gill, Recurrence and survival following laparoscopic radical nephroureterectomy with various forms of bladder cuff control, J. Urol. 173(2) (2005) 395-400. [23] T. Saika, J. Nishiguchi, T. Tsushima, Y. Nasu, A. Nagai, Y. Miyaji, et al., Comparative study of ureteral stripping versus open ureterectomy for nephroureterectomy in patients with transitional carcinoma of the renal pelvis, Urology 63(5) (2004) 848-852. [24] A. Carrion, J. Huguet, E. García-Cruz, L. Izquierdo, L. Mateu, M. Musquera, et al., Intraoperative prognostic factors and atypical patterns of recurrence in patients with upper urinary tract urothelial carcinoma treated with laparoscopic radical nephroureterectomy, Scand J Urol 50(4) (2016) 305-312. [25] H.L. Luo, C.H. Kang, Y.T. Chen, Y.C. Chuang, Y.T. Cheng, W.C. Lee, et al., Oncological impact of endoscopic bladder cuff management during nephroureterectomy varies according to upper urinary tract tumor location, Int. J. Urol. 21(4) (2014) 366-369. [26] T. Kakizoe, J. Fujita, T. Murase, K. Matsumoto, K. Kishi, Transitional cell carcinoma of the bladder in patients with renal pelvic and ureteral cancer, J. Urol. 124(1) (1980) 17-19. [27] D.W. Strong, H.D. Pearse, Recurrent urothelial tumors following surgery for transitional cell carcinoma of the upper urinary tract, Cancer 38(5) (1976) 2173-2183. [28] D.W. Strong, H.D. Pearse, E.S. Tank Jr, C.V. Hodges, The ureteral stump after nephroureterectomy, J. Urol. 115(6) (1976) 654-655. [29] G. Cai, X. Liu, B. Wu, Treatment of upper urinary tract urothelial carcinoma, Surg Oncol 20(1) (2011) 43-55. [30] M.C. Hall, S. Womack, A.I. Sagalowsky, T. Carmody, M.D. Erickstad, C.G. Roehrborn, Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients, Urology 52(4) (1998) 594-601. [31] T. Habuchi, R. Takahashi, H. Yamada, Y. Kakehi, T. Sugiyama, O. Yoshida, Metachronous multifocal development of urothelial cancers by intraluminal seeding, Lancet 342(8879) (1993) 1087-1088. [32] A. Ito, I. Shintaku, M. Satoh, N. Ioritani, T. Tochigi, I. Numata, et al., Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the THPMG trial, Jpn. J. Clin. Oncol. 43(11) (2013) 1139-1144. 14 / 16
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[33] T.F. Chromecki, K. Bensalah, M. Remzi, G. Verhoest, E.K. Cha, D.S. Scherr, et al., Prognostic factors for upper urinary tract urothelial carcinoma, Nat Rev Urol 8(8) (2011) 440-447. [34] M. Remzi, A. Haitel, V. Margulis, P. Karakiewicz, F. Montorsi, E. Kikuchi, et al., Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients, BJU Int. 103(3) (2009) 307-311. [35] C.B. Allard, A. Alamri, S. Dason, F. Farrokhyar, E.D. Matsumoto, A. Kapoor, The method of bladder cuff excision during laparoscopic radical nephroureterectomy does not affect oncologic outcomes in upper tract urothelial carcinoma, World J Urol 31(1) (2013) 175-181. [36] R. Ko, B.H. Chew, D.R. Hickling, H. Razvi, P.P. Luke, J.L. Chin, et al., Transitional-cell carcinoma recurrence rate after nephroureterectomy in patients who undergo open excision of bladder cuff v transurethral incision of the ureteral orifice, J. Endourol. 21(7) (2007) 730-734. [37] C.C. Li, T.H. Chang, W.J. Wu, H.L. Ke, S.P. Huang, P.C. Tsai, et al., Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients, Eur. Urol. 54(5) (2008) 1127-1134. [38] G. Novara, V. De Marco, F. Gottardo, O. Dalpiaz, V. Bouygues, A. Galfano, et al., Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multi-institutional dataset from 3 European centers, Cancer 110(8) (2007) 1715-1722. [39] S. Ni, W. Tao, Q. Chen, L. Liu, H. Jiang, H. Hu, et al., Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies, Eur. Urol. 61 (2012) 1142-1153.
468 469
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470 471 472 473
Figure legends
474
Figure 2. Forest plot comparing survival and subgroup analysis of different distal ureter
475
management techniques. (A) CSS in patients receiving NIVBC versus IVBC; (B) CSS in patients
476
receiving EVBC versus TUBC; (C) OS in patients receiving NIVBC versus IVBC; (D) RFS in
477
patients receiving NIVBC versus IVBC; (E) RFS in patients receiving EVBC versus
478
TUBC.(CSS=cancer-specific survival; EVBC=extravesical incision of the bladder cuff;
479
IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical recurrence-free survival；
480
NIVBC=non-intrasvesical incision of the bladder cuff; OS=overall survival; RFS=recurrence-free
481
survival；TUBC=transurethral incision of the bladder cuff)
Figure 1.
Flowchart of study selection.
482 483
Figure 3.
484
excluding prior bladder tumour history; Forest plot comparing IRFS between EVBC and TUBC:
485
(C) in all patients, (D) excluding prior bladder tumour history. (EVBC=extravesical incision of the
486
bladder cuff; IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical recurrence-free
487
survival；NIVBC=non-intrasvesical incision of the bladder cuff; TUBC=transurethral incision of
488
the bladder cuff)
Forest plot comparing IRFS between NIVBC and IVBC: (A) in all patients, (B)
489 490
Figure 4. Funnel plot for the evaluation of potential publication bias: (A) CSS between NIVBC
491
and IVBC; (B) CSS between TUBC and EVBC; (C) OS between NIVBC and IVBC; (D) RFS
492
between NIVBC and IVBC;(E) RFS between TUVBC and EVBC; (F) IRFS between NIVBC and
493
IVBC;(G) IRFS between TUVBC and EVBC. (CSS=cancer-specific survival; EVBC=extravesical
494
incision of the bladder cuff; IVBC=intrasvesical incision of the bladder cuff；IRFS = intravesical
495
recurrence-free survival； NIVBC=non-intrasvesical incision of the bladder cuff; OS=overall
496
survival; RFS=recurrence-free survival；TUBC=transurethral incision of the bladder cuff)
497
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Table 1. Study characteristics Study
Study design
NOS
Region/
Number of patients (n)
Country
Total
IVBC
NIVBC EVBC
Mean/Median
Gender
age (year)
(F/M)
Tumor location
Tumor grade
Pathologic
History of
Perioperative
Open/
Follow-up
Low
tumor
bladder
chemotherapy
Laparoscopic
median
stage
cancer
(n, %)
High
TUBC
Outcome
(month)
(n, %) Carrion et
Retrospective,
al 2016
single center
7
Spain
117
49
68
(41.9%)
(58.1%)
70.26
32/85
Renal pelvis 74
23
94
≤pT1 47
Ureter 38
pT2 26
Both 5
pT3 33
37 (31.6)
0 (0%)
0/117
20
CSS
NA
91 (11.1%)
382/438
24.6
ORFS;
pT4 11 Kapoor et
Retrospective,
al 2014
multi center
8
Canada
820
406
316
98
(49.5%)
(38.5%)
(12%)
69.6
300/520
Renal pelvis 432
295
525
≤pT1 376
Ureter 198
pT2 126
Both 176
pT3 181
IRFS
pT4 40 Krabbe et
Retrospective,
al 2014
single center
8
USA
122
76(62%)
46(38%)
69
45/77
Renal pelvis 88
27
95
Ureter 34
≤pT1 81
41 (34%)
19 (19.6%)
26 /96
32
pT2 6
CSS; IRFS
pT3 31 pT4 4 Luo et al
Retrospective,
2013
single center
7
Taipei, China
396
240
156
(60.6%)
(39.4%)
66.41
206/190
Renal pelvis 263
39
357
Ureter 133
≤pT1 208
94 (23.7%)
NA
NA
40.65
CSS
770 (28.7%)
0 (0%)
2170 /511
57.5
OS;
pT2 81 pT3 107 pT4 0
Xylinas et
Retrospective,
al 2012
multi center
Li et al
Retrospective,
2010
single center
8
USA, Austria, Italy, Canada,
8
2681
Germany,
1811
785
85
(67.5%)
(29.3%)
(3.2%)
68.4
873/1808
Renal pelvis 1730
415
2242
pT2 519
RFS;
UK, France, Spain,
pT3 810
IRFS
Japan
pT4 131
Taipei, China
301
81
129
91
(27%)
(43%)
(30%)
Ureter 951
≤pT1 1221
65.4
170/131
Renal pelvis 105
130
171
≤pT1 122
Ureter 142
pT2 88
Multifocal 54
pT3 77
0 (0%)
0 (0%)
246 /55
33
CSS; IRFS
pT4 14 Walton et
Retrospective,
al 2009
multi center
8
UK
138
48
90
IVBC 66.5
(35%)
(65%)
TUBC 66.4
51/87
Renal pelvis 56
100
38
≤pT1 88
Ureter 57
pT2 21
Multifocal 25
pT3 29
29(21%)
NA
138 /0
43
CSS; RFS
pT4 0 Matin and
Retrospective,
Gill 2005
single center
6
USA
48
12
36
TUBC 68.8
(25%)
(75%)
EVBC 72.4
15/33
Renal pelvis 29
19
29
≤pT1 26
Ureter 14
pT2 3
Multifocal 4
pT3 13
21 (44%)
0 (0%)
0 /48
TUBC 22
OS;
EVBC 19
RFS
IVBC 42
CSS;
TUBC 32
IRFS
pT4 5 Saika et al
Prospective
2004
nonrandomized, single center
6
Japan
60
32
28
IVBC 69.8
(53%)
(47%)
TUBC 65.2
20/40
NA
45
15
≤pT1 32 pT2 3 pT3 22
0 (0%)
NA
60/0
pT4 6 CSS=cancer-specific survival； ；EVBC=extravesical incision of the bladder cuff; F= female; IVBC=intrasvesical incision of the bladder cuff； ；IRFS = intravesical recurrence-free survival； ；M=male; NIVBC=non-intrasvesical incision of the bladder cuff; NA =not available; NOS= Newcastle-Ottawa Scale; OS=overall survival; RFS=recurrence-free survival； ；TUBC=transurethral incision of the bladder cuff;
Table 2. Chi-squared test results Variable
TUBC (n, %)
EVBC (%)
p value
TUBC(%)
Renal pelvic
314（63.1）
863（55.8）
0.02
Ureteral
166（33.3）
Both
18 （3.6）
Yes
110（23.6）
373（25.2）
No
356（76.4）
1109（74.8）
Low grade or ≤G2
141（30.1）
497（33.5）
High grade or >G2
327（69.9）
985（66.5）
≤pT1
247（53.8）
621（43.2）
pT2
79（17.2）
pT3 pT4
IVBC (%)
EVBC (%)
IVBC (%)
211（64.3） 1391（60.1） 0.06
721（59.9）
1382（60.8） 0.05
615（39.7）
99 （30.2） 835 （36.1）
414（34.4）
804（35.3）
69 （4.5）
18 （5.5） 89 （3.8）
69 （5.7）
89 （3.9）
289（23.5）
546（32.7）
941（76.5）
1122（67.3）
276（22.4）
494（21.5）
189（48.2） 1831（77）
954（77.6）
1804（78.5）
215（55.9） 1125（48.3） 0.02
496（41.8）
1085（48.2） ＜0.01
314（21.8）
69 （17.9） 432（18.5）
255（21.5）
423（18.8）
120（26.1）
433（30.1）
91 （23.6） 662（28.4）
366（30.9）
636（28.2）
13 （2.9）
70 （4.9）
10 （2.6） 112（4.8）
69 （5.8）
107（4.8）
Yes
7
41
41 （3.4）
43 （2.6）
No
303（97.8）
p value
p value
Tumor location
Multifocal 0.50
77 （21.2） 554（32.3）
＜0.01
287（78.8） 1162（67.7）
＜0.01
Tumor grade 0.17
203（51.8） 547 （23）
＜0.01
0.52
Tumor stage
＜0.01
Perioperative chemotherapy （2.2）
（3.3）
1201（96.7）
0.34
7
（2.6） 43
（2.6）
267（97.4） 1625（97.4）
0.98
1181（96.6） 1625（97.4）
0.22
History of bladder cancer Yes
54 （16.3）
255（22.1）
no
278（83.7）
899（77.9）
0.02
41 （3.9） 565（42.1） 253（86.1） 777（57.1）
＜0.01
193（21.1）
555（44.0）
721（78.9）
707（56.0）
EVBC=extravesical incision of the bladder cuff; IVBC=intrasvesical incision of the bladder cuff；TUBC=transurethral incision of the bladder cuff.
＜0.01
Highlights Findings suggest intravesical incision of the bladder cuff (IVBC) during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial carcinoma (UTUC) is associated with a better overall outcome. IVBC also appears to be associated with better intravesical recurrence-free survival (IRFS) when directly compared to extravesical incision of the bladder cuff (EVBC) and transurethral incision of the bladder cuff (TUBC). IVBC is the superior approach, however, meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences among the three different surgical techniques.
Data statement All the data were presented in the manuscript. No additional data are available.
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This study was registered with the Research Registry and the unique identifying number is: reviewregistry741. https://www.researchregistry.com/register-now#registryofsystematicreviewsmetaanalyses/registryofsystematicreviewsmetaanalysesdetails/5d6f2c292339cc00117a5f97/
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Contribution: Shicong Lai and Runqi Guo designed and conducted the systematic search to identify all relevant studies. Shicong Lai and Samuel Seery then assessed eligibility and the quality of each study, before extracting data and conducting statistical analysis. Pengjie Wu, Jianyong Liu and Yaoguang Zhang coordinated the study and performed data acquisition. Shengcai Zhu, Xiaoguang Li and Shicong Lai participated in data interpretation and drafting this article. Samuel Seery, Ming Liu and Jianye Wang reviewed and revised this report for critical content and scientific rigour. All authors read and approved the final manuscript.
Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. In this meta-analysis, the guarantors are Shicong Lai and Jianye Wang
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