Third Prize: The Role of Endoscopic Nephron-Sparing Surgery in the Management of Upper Tract Urothelial Carcinoma

Abstract

Upper tract urothelial carcinoma (UT-UC) is an uncommon disease with pronounced difference in 5-year survival for noninvasive (96%) versus invasive (17%) disease. High survival rate of early disease questioned the accepted norm of using radical nephroureterectomy (RNU) for all stages. This review assesses effectiveness of endoscopic management for UT-UC.
A review of 131 UT-UC patients seen between January 1999 and October 2009 was performed. Demographic, clinicopathologic, and outcomes data were collected and compared between patients initially managed with RNU versus those initially managed with nephron-sparing surgery (NSS). The chi-square or Fisher's exact tests for categorical variables and the Wilcoxon-Mann-Whitney test for continuous variables were used. Clinical and pathologic stages of RNU patients were evaluated with chi-square testing, whereas difference in length of stay was detected using linear regression. Recurrence rates were compared using multivariate Cox regression.
The two arms had similar distributions of age, sex, frequency of medical comorbidities, American Society of Anesthesiologists (ASA), and Charlson scores. Mean-adjusted length of stay was 2.1 (95% confidence interval [1.6, 2.5]) and 5.5 days (95% confidence interval [5.3, 6.4]) for the NSS and RNU groups, respectively (p < 0.001). Comparison of clinical and pathologic stages of RNU patients showed a difference (p < 0.001), with under-staging noted in 32%. Men (Hazards Ratio = 2.9 [1.5-5.5], p = 0.001) and NSS patients (hazards ratio [HR] = 3.5 [1.7-7.3], p < 0.001) had threefold increased recurrence risk.
NSS offered shorter hospital stay but had increased risk of recurrence. Therefore, extreme care should be made to rule out occult invasive tumors preoperatively. Patients being managed endoscopically must be informed of the necessity for close follow-up.

Full text

Clinical Science: Third Prize
The Role of Endoscopic Nephron-Sparing Surgery
in the Management of Upper Tract Urothelial Carcinoma
Eliza M. Raymundo, M.D.,*Michael E. Lipkin, M.D., Lionel B. Ban˜ ez, M.D., John G. Mancini, M.D.,
Dorit E. Zilberman, M.D., Glenn M. Preminger, M.D., and Brant A. Inman, M.D.
Abstract
Introduction: Upper tract urothelial carcinoma (UT-UC) is an uncommon disease with pronounced difference in
5-year survival for noninvasive (96%) versus invasive (17%) disease. High survival rate of early disease ques-
tioned the accepted norm of using radical nephroureterectomy (RNU) for all stages. This review assesses
effectiveness of endoscopic management for UT-UC.
Methods: A review of 131 UT-UC patients seen between January 1999 and October 2009 was performed.
Demographic, clinicopathologic, and outcomes data were collected and compared between patients initially
managed with RNU versus those initially managed with nephron-sparing surgery (NSS). The chi-square or
Fisher’s exact tests for categorical variables and the Wilcoxon–Mann–Whitney test for continuous variables were
used. Clinical and pathologic stages of RNU patients were evaluated with chi-square testing, whereas difference
in length of stay was detected using linear regression. Recurrence rates were compared using multivariate Cox
regression.
Results: The two arms had similar distributions of age, sex, frequency of medical comorbidities, American
Society of Anesthesiologists (ASA), and Charlson scores. Mean-adjusted length of stay was 2.1 (95% confidence
interval [1.6, 2.5]) and 5.5 days (95% confidence interval [5.3, 6.4]) for the NSS and RNU groups, respectively
(p<0.001). Comparison of clinical and pathologic stages of RNU patients showed a difference ( p<0.001), with
under-staging noted in 32%. Men (Hazards Ratio ¼2.9 [1.5–5.5], p¼0.001) and NSS patients (hazards ratio
[HR] ¼3.5 [1.7–7.3], p<0.001) had threefold increased recurrence risk.
Conclusion: NSS offered shorter hospital stay but had increased risk of recurrence. Therefore, extreme care
should be made to rule out occult invasive tumors preoperatively. Patients being managed endoscopically must
be informed of the necessity for close follow-up.
Introduction
Upper tract urothelial carcinoma (UT-UC) is an un-
common disease that occurs predominantly in men in
their seventh decade.
1–3
The 5-year disease-specific survival
rate is *75%,
1
but is strongly stage and grade dependent.
4,5
Although radical nephroureterectomy (RNU) has long been
considered the standard of care for treatment, it has to be
recognized that majority of UT-UCs are low-stage, low-grade
tumors that are potentially curable with less invasive thera-
pies.
6–8
Advances in endoscopy have allowed less invasive
options to be used in select patients, like those with severe
medical comorbidities or with absolute indications for neph-
ron-sparing surgery (NSS).
9
UT-UCs can be treated ureter-
oscopically by basketing and electrical=laser fulguration,
whereas the percutaneous approach affords electrical resec-
tion and treatment of larger renal pelvic tumors inaccessible
by ureteroscopy. Endoscopic modalities have also been cited
as a means to provide adjuvant therapy for UT-UC managed
conservatively.
10–13
Prior publications have shown divergent
outcomes for NSS for UT-UC.
9,14–16
Herein we compare the
oncologic efficacy of NSS and RNU for UT-UC at a single
tertiary institution.
Materials and Methods
After obtaining Institutional Review Board (IRB) approval,
data were abstracted for UT-UC patients managed at our in-
stitution from January 1999 to October 2009. Candidates were
identified using International Classification of Diseases (ICD)
codes corresponding to neoplasms of the renal pelvis, calices,
and ureter corroborated by an imaging study demonstrating
the lesions, and urine cytology or tissue diagnosis confirming
urothelial origin. Patients found to have neoplasms that were
nonurothelial in origin were excluded (n¼5), resulting in a
final cohort of 131 patients. Of these, 11 did not undergo
Department of Surgery-Urology, Duke University Medical Center, Durham, North Carolina.
*Current affiliation: Philippine General Hospital, Manila, Philippines.
JOURNAL OF ENDOUROLOGY
Volume 25, Number 3, March 2011
ªMary Ann Liebert, Inc.
Pp. 377–384
DOI: 10.1089=end.2010.0276
377

either RNU or NSS because of personal choice (n¼2), ex-
tensive comorbidities (n¼5), or metastatic disease (n¼4).
NSS was defined as percutaneous and=or ureteroscopic re-
section and=or fulguration, or basketing of UT-UC. Clinico-
pathologic characteristics were compared between patients
initially managed with RNU versus those initially managed
with NSS using chi-square or Fisher’s exact tests for cate-
gorical variables and Wilcoxon–Mann–Whitney test for
continuous variables. The chi-square test was also employed
to detect if a difference between the clinical and pathologic
stages of patients under the RNU cohort existed. Length of
stay (LOS) was compared using linear regression, adjusting
for age, sex, race, stage, American Society of Anesthesiolo-
gists (ASA) score, Charlson comorbidity index score, and
Clavien complication severity score. Because of non-normal
distribution, LOS was log-transformed before analysis and
mean-adjusted values were calculated for each subgroup;
back-transformation was then done for ease of interpreta-
tion. Follow-up was calculated using reverse Kaplan–Meier
method, and cumulative incidence functions were used to
assess survival outcomes. Cox modeling of recurrence began
by univariate analysis of candidate predictors using logrank
test. Predictors, with a p-value <0.2 were included in mul-
tivariate proportional hazards model. Analyses were per-
formed using STATA v.11 with an alpha of 0.05.
Results
The baseline characteristics for the entire population and
the two subgroups were summarized in Table 1. The most
common presenting symptoms were gross hematuria (56%)
and flank pain (23%). Synchronous bilateral presentation was
seen in 5% of cases, whereas only a single patient (0.8%) had
bilateral metachronous presentation. Eleven patients pre-
sented with a solitary kidney. Of the unilateral cases, 48%
were on the left and 52% were on the right. Tumors were
identified on imaging in all patients: 76% with computed to-
mography scan and retrograde pyelography in 57%. Uretero-
scopy assisted in the work-up of 55%. Preoperatively,
diagnosis was confirmed with cytology in 65%, biopsy in 30%,
and visual assessment in 29%. A mean number of 2.6 1.1
biopsy cores were needed for a preoperative diagnosis and
grading to be made. The majority of cases were managed with
RNU (74%): open approach in 54% and laparoscopic in 46%.
NSS was used to manage 16% of cases (see Table 2). Patients
initially managed with NSS who experienced recurrence un-
derwent further surgery, ranging in number from 1 to 10 with a
mean of three procedures. The rest were diagnosed as stage IV
or synchronous bilateral disease and either underwent sys-
temic chemotherapy alone or opted for palliative care only.
Eight percent were subjected to local adjuvant therapy for their
UT-UC, with a single patient receiving prophylactic treatment 3
weeks postoperatively. The agents were administered through
a nephrostomy tube (3%), or intravesically with an internal
ureteral (4%), or open-ended ureteral stent (1%) in place.
The overall mean postoperative LOS was 5.8 4.4 days.
Mean length of follow-up was 17.9 months (13.2, 24.6). The
mean-adjusted LOS was 2.1 (95% confidence interval [1.6,
2.5]) and 5.5 days (95% confidence interval [5.3, 6.4]) for the
NSS and RNU arms, respectively ( p<0.001) (see Table 3).
Only 28% of the population (n¼37) remained disease-free,
whereas the overall recurrence rate was 63% on the latest date
of follow-up. Recurrence was defined as any recurrent disease
in the bladder, ipsilateral UT, bladder and UT simultaneously,
or distant metastases. The cumulative incidences for recur-
rence in the RNU versus the NSS arms were plotted in
Figure 1. Comparison of clinical and pathologic stages of RNU
patients showed a significant difference ( p<0.001), with un-
der-staging noted in 32% (Table 4). After univariate analysis,
predictors included in the multivariate Cox regression
were sex, type of initial intervention, pathologic stage, and
tumor size, wherein sex (hazards ratio [HR] ¼2.9 [1.5–5.5],
p¼0.001) and initial surgical intervention (HR ¼3.5 [1.7–7.3],
p-value <0.001) proved to be positive predictors of recurrence
(Tables 5 and 6). Kaplan–Meier recurrence-free survival
curves were plotted in Figure 2.
Discussion
Although UT-UC is relatively uncommon, interest in the
disease has remained because of increasing incidence
1,17
and
the pronounced difference in 5-year survival for noninvasive
(96%) versus invasive (17%) disease. Other issues associated
with UT-UC, such as its preponderance to occur in older pa-
tients or for synchronous presentation, resulted in exploring
endoscopy to replace RNU.
Demographic parameters of our UT-UC patients mirrored
characteristics noted in earlier publications. A mean age of 70
years confirmed that this disease is commonly diagnosed in
elderly patients.
1,2
The preponderance of UT-UC for men
2,3
was confirmed by this study’s 2:1 male-to-female ratio. More
importantly, sex’s role as a predictor of recurrence has not
been previously noted to our knowledge. Aside from more
men being found to have UT-UC, men were also almost thrice
as likely to develop recurrence. Racial distribution and pre-
senting symptomatology that we noted were similar to earlier
findings.
2,3,13,18
Previous studies have estimated that 52% of
UT-UC occurred in the renal pelvis and 25% in the lower
ureter.
2,19
We found approximately the same distribution,
with 60% of the tumors in our cohort located in the renal
pelvis and 22% located in the distal ureter.
Part of the impetus for performing NSS in patients with UT-
UC is the tendency for these patients to present with syn-
chronous or metachronous bilateral lesions. This has been
reported to occur in up to 72%.
3
In our population, we found
synchronous bilateral lesions in <5%. Other indications for
NSS in the current study included concomitant renal disease
in 15% and a solitary kidney in 8% of patients. In addition,
significant medical comorbidities are often cited as a reason
for performing NSS. High survival rate in early stage disease
led investigators to consider percutaneous and ureteroscopic
approaches for patients with early stage tumors and signifi-
cant comorbidities precluding RNU. Confounding medical
problems can prevent many patients from undergoing taxing
surgical procedures, such as open RNU. There were no dif-
ferences in the incidence of medical comorbidities, ASA level,
and Charlson index in patients of either arm of our series.
However, there were increased complications in patients
who underwent RNU compared with NSS (30% vs. 14%,
p¼0.137). Although this finding did not reach statistical sig-
nificance, it is clinically relevant. Patients with significant
comorbidities may in fact benefit from less invasive ap-
proaches. With the increasing use of laparoscopy to perform
RNU, this difference in complications may change.
378 RAYMUNDO ET AL.

Table 1. Comparison of Patients in the Nephron-Sparing Surgery
Versus the Radical Nephroureterectomy Cohorts
Overall population
(n¼131)
Untreated patients
(n¼11)
NSS
(n¼21)
RNU
(n¼99) p-Value
Sex 0.800
Male 86 (65%) 5 (45%) 15 (71%) 66 (67%)
Female 45 (34%) 6 (55%) 6 (29%) 33 (33%)
Age (Mean SD) 69.6 11.4 (37–98) 68.81 11.4 72.9 10.9 0.266
Race 0.104
Caucasian 119 (91%) 9 (82%) 14 (74%) 80 (95%)
African American 11 (8%) 2 (18%) 4 (21%) 4 (8%)
Native American 1 (0.8%) 0 1 (5%) 0
HTN 71 (54%) 12 (63%) 45 (54%) 0.450
DM 25 (19%) 6 (32%) 13 (15%) 0.104
CAD 49 (37%) 6 (32%) 34 (40%) 0.474
Pulmo disease 21 (16%) 3 (16%) 11 (13%) 0.758
Renal disease 20 (15%) 3 (16%) 11 (13%) 0.867
BMI (mean SD) 28.2 5.8 28 5.97 26.88 5.77 28.85 5.84 0.269
ASA score 3 (2, 3) 3 (2, 3) 3 (2, 3) 0.735
Charlson score index 6 (5, 8) 6 (5, 8) 6 (5, 8) 0.939
Histologic grade (n¼119) 0.042
Grade 1 31 (26%) 2 (18%) 9 (45%) 20 (21%)
Grade 2 35 (29%) 2 (18%) 5 (25%) 28 (30%)
Grade 3 53 (45%) 1 (9%) 6 (30%) 46 (49%)
Unknown 12 6 (55%) 1 5
Tumor diameter (mean SD) 3.9 3.8 (0.3–20) 2.89 4.02 4.26 3.48 0.003
Tumor architecture 0.079
Sessile 11 (8%) 1 (0.1%) 4 (19%) 6 (6%)
Papillary 109 (83%) 9 (82%) 16 (52%) 85 (85%)
Unknown 11 2 (18%) 1 0
Tumor location 0.688
Ureter 42 (32%) 10 (48%) 51 (53%)
Pelveocaliceal 67 (51%) 6 (29%) 30 (31%)
Pelveocalix þureter 22 (18%) 5 (24%) 16 (16%)
Indications for NSS (n¼38) 0.547
Renal insufficiency 20 (15%) 2 (18%) 3 (14%) 15 (15%)
Solitary kidney 11 (8%) 1 (9%) 7 (4%) 3 (3%)
Bilateral disease 7 (5%) 1 (9%) 4 (19%) 2 (3%)
Multifocality 19 (15%) 4 (36%) 5 (26%) 10 (12%) 0.110
History of bladder tumor diagnosed
before diagnosis of UT-UC
47 (36%) 7 (64%) 8 (38%) 32 (33%) 0.884
Clinical stage (n¼130) 0.107
I 72 (55%) 5 (45%) 16 (76%) 51 (52%)
II 33 (25%) 2 (18%) 2 (10%) 29 (30%)
III 7 (5%) 0 0 7 (7%)
IV 18 (14%) 4 (36%) 3 (14%) 11 (11%)
Unknown 1
Pathologic stage (n¼115)
I 45 (45%) 45 (45%)
II 12 (12%) 12 (12%)
III 19 (19%) 19 (19%)
IV 23 (23%) 23 (23%)
Adjuvant therapy 0.008
None 94 (72%) 9 (82%) 11 (52%) 74 (74%)
Local 10 (8%) 1 (9%) 6 (29%) 3 (5%)
Systemic 26 (20%) 1 (9%) 3 (14%) 22 (22%)
Systemic þlocal 1 (0.8%) 0 1 (5%) 0
Complications 33 (28%) 3 (14%) 30 (30%) 0.137
Clavien grade 2 2 2
Recurrence 78 (63%)
UT (ipsilateral) 23 (18%) 10 (48%) 13 (13%)
Bladder 18 (14%) 2 (10%) 16 (16%)
UT þbladder 6 (5%) 3 (14%) 3 (3%)
Distant metastases 32 (24%) 5 (24%) 27 (27%)
Mortality 6 (5%) 1 (5%) 4 (5%) 0.934
UT-TC related 5 1 (5%) 4 (4%)
Non-UT-TC related 1 1 (1%)
ASA ¼American Society of Anesthesiologists; BMI ¼body mass index; CAD ¼coronary artery disease; DM ¼diabetes mellitus; HTN ¼hyperten-
sion; NSS ¼nephron-sparing surgery; RNU ¼radical nephroureterectomy; SD ¼standard deviation; UT-UC ¼upper tract urothelial carcinoma;
UT ¼upper tract; TC ¼transitional cell.
379

Tumor diameter and histologic grade distribution between
the two arms varied significantly, with more grade 1 disease
and smaller tumors receiving NSS. This finding is expected as
the larger a tumor becomes, the more difficult it is to treat
endoscopically. In addition, histologic grade has been shown
to affect cancer-specific survival rate by multiple studies, with
chances of survival in well-differentiated UT-UC almost
double that of poorly differentiated cancers.
4,5,20,21
Grade is
felt to be a surrogate for tumor stage as it is often difficult to
obtain muscle in biopsy specimens of the UT. Therefore, pa-
tients with higher grade tumors are often felt to have clinically
higher stage disease. One limitation of our study was the
relatively high incidence of visual diagnosis of the initial
tumor. Previous studies suggest that visual assessment alone
was inaccurate in 30% of the cases.
22
There was a trend toward increased clinical stage in the
RNU cohort in our study. Traditionally, it was assumed that
these patients benefit from RNU compared with NSS. Tumor
diameter was found to affect metastasis-free and disease-free
survival,
23
whereas tumor architecture was noted to be an
independent predictor of recurrence and disease-specific
survival rate.
24
Tumors with sessile architecture were found
to be of higher grade, more advance stage, and more likely to
have lymphovascular invasion.
23,24
In this series, neither
tumor grade nor size were significant predictors of recur-
rence. Most of the previous studies that compared NSS to
RNU had demonstrated similar recurrence rates, with ur-
eteroscopy at 30% to 71%, and 11% to 33% for percutaneous
approach
14–16
; rates for RNU were 23% to 62%.
25–28
Our
overall recurrence rate was comparable at 31%. However, we
found significantly greater recurrence in patients who un-
derwent NSS. In particular, patients undergoing NSS were at
significantly greater risk of recurring in their UT. The risk of
bladderrecurrencewassimilarbetweenthetwo.When
bladder and UT recurrences were combined for overall re-
currence rate, patients who were treated with NSS were still
at a disadvantage and having three times the risk of expe-
riencing recurrence (HR ¼3.5 [1.7–7.3], p-value <0.001). This
was likely because of elimination of more anatomic sites of
possible recurrence by RNU, since majority (48%) of the re-
current tumors managed with NSS returned to their original
sites of growth.
29
Incomplete eradication of primary tumor
or intraoperative seeding may also contribute to higher re-
currence rates. The significance of this is that patients who
undergo NSS must be made aware of the need for lifelong
surveillance and repeat procedures when counseled about
their treatment options. It is unclear if the cumulative peri-
operative risk of these procedures is greater than that for
RNU. In our study, 16 of the 22 patients treated with NSS
underwent multiple procedures because of recurrent disease
and 9 went on to undergo RNU. Five of the 10 NSS patients
who experienced UT recurrence progressed to metastatic
disease, 1 of whom died because of surgical complications.
At most recent follow-up, only 8% of the patients treated
ureteroscopically and 44% of patients treated with percuta-
neous approach were disease-free. The ideal surveillance
regimen for these patients is not known at this time, but it is
clear from our data that they require regular surveillance
likely for an indefinite period of time.
Metastasis rate has been reported to be 17% among patients
managed with percutaneous resection,
30
which was slightly
higher than the 8% to 13% rate in a series of patients who
underwent RNU.
28
In our series, there was no significant
difference in the risk for metastasis, despite the previously
mentioned increased risk of recurrence in patients who un-
derwent NSS; the RNU and NSS arms had 36% and 23% rates
at 3 years postintervention (logrank, p¼0.65). For our entire
study population, the overall survival rate was noted to be
95%, likely a consequence of most cases (55%) being diag-
nosed in the early stages. Moreover, most of the NSS patients
who experienced recurrence eventually underwent RNU,
which could explain the improved figures compared with
earlier publications.
31,32
No percutaneous tract recurrence
was noted in our study, as was previously suggested by
others.
21
Disease-specific survival for locally confined UT-UC
Table 2. Patients Treated
with Nephron-Sparing Surgery
Ureteroscopic Percutaneous
Single treatment 6
Multiple treatment 7 9
Local adjuvant therapy
BCG 6 5
Mitomycin C 3 1
Thiotepa 2
Immunotherapy 2
Gemcitabine 1 2
Underwent RNU 5 4
Disease status
Disease free 1 (8%) 4 (44%)
Local recurrence 4 (31%) 6 (67%)
Bladder recurrence 2 (15%) 1 (11%)
Distant metastases 2 (15%) 4 (44%)
Death 1 (8%)
BCG ¼Bacillus Calmette-Guerin.
Table 3. Clinico-Pathologic Parameters
Predicting Postoperative Length of Stay
Parameters RR p-Value
RNU 3.00 <0.001
Age 1.00 0.724
Race 1.12 0.591
Sex 1.05 0.691
Stage 0.042
I1
II 1.08
III 1.36
IV 1.47
ASA 0.191
1–2 1
3 1.17
Charlson comorbidity index score 1.02 0.443
Clavien morbidity score 0.002
01
1 2.24
2 1.29
3 1.54
4 1.69
RR ¼risk ratio.
380 RAYMUNDO ET AL.

has been reported to be 95% compared with 16% for meta-
static disease.
1
Disease-free survival rates ranged from 35% to
86% for tumors treated endoscopically.
30–33
RNU approach
had so far offered disease-free survival rates between 62% and
95%.
26,28,31,32,34,35
As expected, one of the advantages of NSS over RNU was
the shorter postoperative hospital stay. This had been noted in
almost all surgical treatments that veer toward a less invasive
treatment modality.
26,28,30,36
This advantage may become less
significant as more RNU are performed laparoscopically.
Most publications on adjunctive therapy for UT-UC have
not demonstrated a clinical benefit from treatment with Ba-
cillus Calmette-Guerin (BCG),
10,16
immunotherapy,
10,16
or other
chemotherapeutic
11,36–39
agents.
11,35–38
However, several publi-
cations claimed recurrence-free rates between 43%
40
and 83%
25
with the use of BCG,
25,41–44
but the complication of systemic
BCG infection has remained a major concern. Although the use
of adjuvant radiotherapy has been found to have recurrence
rate of 50% and overall disease-free 5-year survival of 30%,
45
its use at our institution for recurrent and end-stage UT-UC
comprised only a handful of cases and remained mostly ex-
perimental. Adjuvant local and systemic chemotherapy given
to our patients did not significantly affect the risk for recur-
rence (logrank p¼0.4). It was, however, noteworthy that a
higher percentage of RNU patients were given adjuvant sys-
temic chemotherapy ( p¼0.008).
Under-staging was observed in 32% of stage I-II UT-UC
after RNU. This could indicate that a significant number of
stage I-II patients in the NSS cohort were under-staged as
well, and may explain the higher UT recurrence in the NSS
FIG. 1. Cumulative incidence of recurrence in the RNU versus NSS cohorts, broken down into (top left) bladder recurrence,
(top right) UT recurrence, (bottom left) simultaneous bladder and UT recurrence, and (bottom right) distant metastases.
NSS ¼nephron-sparing surgery; RNU ¼radical nephroureterectomy; UT ¼upper tract.
ENDOSCOPY FOR UPPER TRACT UROTHELIAL CARCINOMA 381

arm (Fig. 2). Because there would be no way to determine
pathologic and thus under-staging in patients managed with
NSS, it may be prudent to consider UT irrigation with a che-
motherapeutic agent 24 hours postoperatively to address
possible seeding; this adjunctive treatment has been shown to
decrease recurrence in bladder UC managed with transure-
thral resection.
46
Re-staging transurethral resection had like-
wise been shown to improve recurrence-free survival
47
by
minimizing chances of residual tumors. Conducting second-
look endoscopy 2 to 6 weeks after initial NSS should be con-
templated. Other methods that have been used to improve
detection of residual and=or recurrent bladder tumors could
also be applied to NSS for the UT, such as narrow band im-
aging
48–51
or photodynamic endoscopy.
52,53
With increasing incidence of UT-UC
1
and other diseases
that cause chronic renal insufficiency, use of NSS for this
disease is here to stay. Although this approach offers unde-
niable benefits, there is an increased risk for recurrence related
to its use. Thus, NSS should be undertaken with caution and
great care must be made to rule out occult invasive tumors.
Moreover, uniform protocols for administration of adjunctive
treatment should be developed to help decrease the risk of
recurrence after NSS.
Conclusions
Given that UT-UC is rare, this study was limited by a rel-
atively small sample size. Limited number of events (i.e., re-
currence, metastases, and death) precluded adequate
comparison of outcomes parameters (recurrence, metastases,
and survival rate) between the cohorts. Collaborative, multi-
center research would be of great benefit in producing an
adequately powered study that is necessary to meaningfully
determine if one treatment arm would be better than the other
and offer improved prognosis for UT-UC. Variabilities in
histologic grading nomenclature, surgeons’ skills, and treat-
ment preferences likewise hampered this study, as would be
expected from most retrospective research. A randomized
Table 4. Comparison of Clinical and Pathologic Stage
in the Radical Nephroureterectomy Cohort
Clinical stage
Pathologic stage
I II III IV
I 34 (67%) 2 (4%) 10 (20%) 5 (10%)
II 7 (25%) 10 (36%) 7 (25%) 4 (14%)
III 1 (14%) 0 2 (29%) 4 (57%)
IV 1 (10%) 0 0 9 (90%)
Table 5. Univariate Analysis of Candidate Predictors
Variable nHR 95% CI p-Value
Age 120 0.99 0.97, 1.02 0.468
Sex 0.046
Female 39 1
Male 81 1.69 0.99, 2.89
Surgical procedure 0.047
RNU 99 1
NSS 21 1.80 1.04, 3.11
Grade 0.965
1291
2 33 1.08 0.55, 2.15
3 52 1.07 0.59, 1.95
Clinical stage 0.095
1671
2 31 0.85 0.47, 1.54
3 7 1.59 0.63, 4.04
4 14 2.18 1.13, 4.24
Pathologic stage 0.162
1561
2 15 0.92 0.42, 2.01
3 19 1.01 0.51, 2.01
4 22 2.03 1.09, 3.77
Architecture 0.880
Papillary 101 1
Sessile 10 0.94 0.45, 1.99
Location 0.593
Both 21 1
Ureter 36 1.44 0.69, 3.00
Renal pelvis 63 1.19 0.61, 2.33
Tumor size 108 0.94 0.87, 1.01 0.067
Multifocality 0.999
No 112 1
Yes 19 1.00 0.54, 1.87
CI ¼confidence interval; HR ¼hazards ratio.
0.00
0.25
0.50
0.75
1.00
0 50 100 150
Time from initial Treatment to Recurrence
RNU NSS
FIG. 2. Recurrence-free survival rate: NSS versus RNU.
Table 6. Multivariate Cox Proportional
Hazards Model for Recurrences
Variable nHR 95% CI p-Value
Sex 102 0.001
Female 1
Male 2.89 1.53, 5.45
Surgical procedure <0.001
RNU 1
NSS 3.56 1.73, 7.35
Pathologic stage 0.071
11
2 1.32 0.59, 3.01
3 1.55 0.66, 3.63
4 2.79 1.34, 5.79
Tumor size 0.93 0.86, 1.01 0.074
382 RAYMUNDO ET AL.

design would greatly contribute in producing robust results
and recommendations.
Disclosure Statement
Dr. Eliza M. Raymundo is a recipient of the Industry-
sponsored (Gyrus ACMI Corp=Olympus) Endourology
fellowship.
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Address correspondence to:
Eliza M. Raymundo, M.D.
Dept. of Surgery, Div. of Urology
Philippine General Hospital
Taft Avenue
Manila 1000
Philippines
E-mail: raymundoeliza@gmail.com
Abbreviations Used
ASA ¼American Society of Anesthesiologists
BCG ¼Bacillus Calmette-Guerin
BMI ¼body mass index
CAD ¼coronary artery disease
CI ¼confidence interval
DM ¼diabetes mellitus
HR ¼hazards ratio
HTN ¼hypertension
LOS ¼length of stay
NSS ¼nephron-sparing surgery
RNU ¼radical nephroureterectomy
RR ¼risk ratio
UT-UC ¼upper tract urothelial carcinoma
384 RAYMUNDO ET AL.