Original Study

Prognostic Role of Neutrophil-to-Lymphocyte

Ratio in Primary Nonemuscle-invasive
Bladder Cancer
David D’Andrea,1 Marco Moschini,1,2 Kilian Gust,1 Mohammad Abufaraj,1
Mehmet Özsoy,1 Romain Mathieu,3 Francesco Soria,4 Alberto Briganti,2
Morgan Rouprêt,5 Pierre I. Karakiewicz,6 Shahrokh F. Shariat1,6,7,8,9
Abstract
The neutrophil-to-lymphocyte ratio is associated with poor outcomes in patients with muscle-invasive bladder
cancer. We found that the neutrophil-to-lymphocyte ratio is independently associated with disease recurrence
and progression in patients with nonemuscle-invasive bladder cancer.
Introduction: The purpose of this study was to assess the role of pretreatment neutrophil-to-lymphocyte ratio (NLR)
as a predictor of clinical outcomes in patients treated with transurethral resection (TURB) for primary nonemuscle-
invasive bladder cancer (NMIBC). Patients and Methods: Data from 918 patients treated with TURB for primary
NMIBC were retrospectively collected. NLR was evaluated as binary variable with the cut-point of 3 based on the
visual best correlation of the receiver operating curve analyses focusing on disease recurrence. The median follow-up
was 62 months. Cox regression analyses were used to evaluate associations with recurrence (RFS) and progression-
free survival (PFS). Subgroup analyses were done according to risk groups and receipt of intravesical bacillus
Calmette-Guérin therapy. Results: Overall, 293 patients had a NLR
3. High NLR was associated with pathologic T
stage and smoking status. The 5-year RFS and PFS for NLR < 3 and NLR
3 were, respectively, 55.5% versus 45.9%
(P ¼ .01) and 94.9% versus 89.9% (P ¼ .004). On multivariable analyses, NLR
3 remained significantly associated
with RFS and PFS. The addition of NLR increased the discrimination of a multivariable model by 0.6% and 2.3% for
RFS and PFS, respectively. Moreover, NLR showed a trend in the association with outcomes in patients treated with
intravesical bacillus Calmette-Guérin therapy. Conclusions: Integration of NLR in a prediction model could be helpful
in predicting RFS and PFS in patients with primary NMIBC and identifying those who are likely to fail therapy and may
benefit from an early radical cystectomy. Limitations are associated to the retrospective design.

Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved.
Keywords: Biomarker, Bladder cancer, Neutrophil-to-lymphocyte ratio, Non-muscle invasive, Prognostic

Introduction the patient’s risk stratification.2 Despite multi-optional therapy,

Approximatively 75% of patients in Western countries with
newly diagnosed urothelial carcinoma of the bladder (UCB) present
with a nonemuscle-invasive (NMIBC) stage.1 The standard treat-
ment for NMIBC is trans-urethral resection of the bladder (TURB)
with or without adjuvant intravesical instillation therapy, based on
recurrence rates are as high as 70% and progression rate as high as
30%, depending on the case-mix of patients.3 Current prognostic
models for NMIBC, relying on pathologic features such as T stage,
grade, focality, tumor diameter, recurrence rate, and concomitant
carcinoma in situ (CIS), do not reach sufficient accuracy to identify

1 8
Department of Urology, Medical University of Vienna, Vienna, Austria Department of Urology, University of Texas Southwestern, Dallas, TX
2 9
Urological Research Institute, San Raffaele Scientific Institute, Vita-Salute San Raffaele Karl Landsteiner Univeristy, Krems an der Donau, Austria
University, Milan, Italy
3
Department of Urology, Rennes University Hospital, Rennes, France Submitted: Dec 30, 2016; Revised: Mar 17, 2017; Accepted: Mar 18, 2017
4
Department of Urology, University of Turin, Turin, Italy
5 Address for correspondence: Shahrokh F. Shariat, MD, Department of Urology and
Department of Urology, Pitié-Salpétrière Hospital, APHP, University Paris VI, Paris, France
6 Comprehensive Cancer Center, Vienna General Hospital, Medical University of
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center,
Montreal, Quebec, Canada Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria
7 E-mail contact: sfshariat@gmail.com
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital,
New York, NY

1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.clgc.2017.03.007 Clinical Genitourinary Cancer Month 2017 -1
 NLR in Primary Non-muscle Invasive Bladder Cancer
those patients most likely to benefit from early radical cystectomy
(RC) to ensure optimal survival. Moreover, ideal candidates for
bacillus Calmette-Guérin (BCG) therapy responders are still not
identified.4 Improving the accuracy of recurrence and progression
prediction could help risk-based individuals’ follow-up scheduling,
consultation regarding early RC, and identification of patients most
likely to benefit from novel therapies in clinical trials. Inflammatory
response markers, like the neutrophil-to-lymphocyte ratio (NLR),
have been reported to be associated with clinical outcomes in
various urologic malignancies such as upper tract urothelial carci-
noma,5 muscle-invasive bladder cancer (MIBC),6 and renal cancer.7
However, only insufficient data in low methodological quality
studies are found for NMIBC.8-13
Therefore, we sought to investigate the role of NLR in patients
with newly diagnosed primary NMIBC in a large multi-institutional
cohort.
Materials and Methods
Patient Population
Following institutional review board approval, we reviewed the
data from 4 centers identifying 1117 patients treated with TURB
for NMIBC. Patients treated for recurrent NMIBC (n ¼ 184) were
excluded from analysis; 15 patients with CIS only were also
excluded, as this group was too small for separate analyses, leaving
918 patients for final analyses.
Transurethral Resection and Instillation Therapy
All patients underwent TURB for primary UCB according to
recommendation guidelines.
A second-look resection was performed 2 to 6 weeks after initial
treatment based on pathologic and intraoperative findings. Imme-
diate single-dose postoperative instillation chemotherapy (40 mg
mitomycin-C or 80 mg epirubicin or 50 mg doxorubicin), adjuvant
intravesical mitomycin-C chemotherapy, or BCG immunotherapy
was administered to 300 (26.8%), 48 (4.3%), and 145 (12.9%)
patients, respectively.
Concomitant upper urinary tract urothelial carcinoma was
excluded using radiologic imaging in all patients.
Pathologic Evaluation and Risk Stratification
All surgical specimens were processed according to standard
pathologic procedures and staged based on the 2009 TNM classi-
fication. Tumor grade was assigned according to the 1973 World
Health Organization system. Based on pathologic T stage, patho-
logic grade, concomitant CIS, tumor diameter (< 3 cm vs.
3 cm),
and focality (single vs. multifocal), patients were stratified into low-,
intermediate-, and high-risk groups, in accordance with 2016 Eu-
ropean Association of Urology (EAU) guidelines, European Orga-
nization for Research and Treatment of Cancer (EORTC) risk
tables, and American Urological Association guidelines.2,3,14
All laboratory tests were done within 30 days before TURB. No
patient had a urinary tract infection or known systemic inflamma-
tory pathology at the time of laboratory testing.
NLR was evaluated as binary variable with the cut-point of 3
based on the visual best correlation of the receiver operating curve
analyses focusing on disease recurrence (data not shown) and on
previous literature.8
2 - Clinical Genitourinary Cancer Month 2017
Follow-up
Owing to the retrospective nature of the study, there was no
standardized follow-up. Patients received clinical and radiologic
follow-up based on final pathology, guidelines at that time, and
physician discretion. Generally, patients underwent a physical
examination, cytology, and cystoscopy every 3 months within the
first 2 years, semiannually from the second to the fifth year, and
then annually.2 In case of suspicious lesions in the cystoscopy,
patients underwent re-biopsy. If urinary cytology was positive but
cystoscopy was unremarkable, bladder and prostatic urethra bi-
opsies, in addition to the upper urinary tract workup, were per-
formed. Disease recurrence was defined as the first tumor relapse
in the bladder regardless of tumor stage. Progression was defined as
a tumor relapse at tumor stage T2 or higher in the bladder. Early
recurrence or progression was defined within a year after TURB.
The cause of death was attributed through chart or death record
reviews.15 Tumor recurrence in the upper urinary tract was not
considered tumor recurrence but rather as a second primary
tumor.
Statistical Analysis
Descriptive statistics of categorical variables focused on fre-
quencies and proportions. Means, medians, and interquartile ranges
(IQRs) were reported for continuously coded variables. The Mann-
Whitney test and c2 test were used to compare the statistical sig-
nificance of differences in medians and proportions, respectively.
Follow-up time was calculated from the date of TURB. Patients still
alive were considered at the date of their last follow-up.
Kaplan-Meier curves were applied to evaluate the correlation
between NLR and the time to recurrence and progression. The log-
rank test was used to determinate the statistical difference between
the NLR < 3 and NLR
3 groups with respect to disease recur-
rence and progression. A multivariable Cox proportional hazard
model was used to test the association of NLR with outcomes, after
adjusting for the effects of all available confounders. Discrimination
was evaluated using the Harrell concordance index.
In exploratory analyses, we investigated the recurrence and pro-
gression rate for patients stratified by the EAU risk stratification and
for patients undergoing adjuvant intravesical BCG therapy
depending on their initial NLR.
Statistical significance was considered at P < .05. All tests were 2-
sided. Statistical analyses were performed using SPSS v.22.0 (IBM
Corp, Armonk, NY) and STATA v.14.1 (StataCorp LP, College
Station, TX).
Results
Overall, 933 (83.5%) patients had primary diagnosed NIMBC,
89 (7.9%) had 1 prior recurrence, and 95 (8.5%) had 2 or more
prior recurrences.
The median NLR was 2.56  109 per liter (IQR, 2.1-3.7  109
per liter). The median patient age was 67 years (IQR, 58-74 years),
and 361 (32.3%) patients had an NLR
3.
With a median follow-up of 62.6 months (IQR, 25-110
months), 469 (42%) patients experienced disease recurrence, 103
(9.2%) disease progression, and 50 (4.5%) patients died secondary
to their disease. Overall, 274 (29.8%) patients had early recurrence,
and 27 (2.9%) had early progression.
 David D’Andrea et al
The association of clinicopathologic features with NLR are progression-free survival (PFS) (5-year PFS, 94.9% vs. 89.9%; HR,
shown in Table 1. Patients with pT1 stage and smokers were more 1.9; 95% CI, 1.2-3; P ¼ .004) rates (Figure 1A and B, respectively).
likely to have a NLR
3 (all P  .02). On multivariable analyses, NLR remained independently associated
Patients with NLR
3 had a significant lower recurrence-free with outcomes (Table 2).
survival (RFS) (5-year RFS, 55.5% vs. 45.9%; hazard ratio [HR], The addition of NLR to a base model including pathologic T
1.3; 95% confidence interval [CI], 1.1-1.6; P ¼ .01) and stage, grade, concomitant CIS, tumor diameter, and tumor focality
increased its discrimination for prediction of RFS from 67.2% to
67.8% and of PFS from 67% to 69.3%, respectively. Moreover, we
Table 1 Association of NLR With Clinicopathologic found that patients with NLR
3 were more likely to experience
Characteristics in 918 Patients Treated With TURB for early recurrence (35.1% vs. 27.4%; P ¼ .02) and early progression
Primary NMIBC (5.1% vs. 1.9%; P ¼ .007).
NLR <3, NLR ‡3, Based on the EAU risk table, patients with high-risk cancer and
N (%) N (%) P NLR
3 had a significantly lower RFS and PFS rates (HR, 2; P ¼
Gender .7 .02 and HR, 1.8; P ¼ .001, respectively) (Figure 2). After adjusting
for possible confounders on multivariable analyses, NLR remained
Female 140 (22.4) 62 (21.2)
independently associated with outcomes (Table 3).
Male 485 (77.6) 231 (78.8)
In further subgroup analyses according to the EORTC risk ta-
Median age, y (IQR) 66 (58-74) 67 (59-74) .8
bles, a high NLR was independently associated with RFS in the
Pathologic T stage .02
intermediate-risk group (HR, 1.7; P ¼ .002) and with PFS in the
pTa 395 (63.2) 161 (54.9)
low- and intermediate-risk groups (HR, 2.3; P ¼ .02 and HR, 2.6;
pT1 230 (36.8) 132 (54.1) P ¼ .02, respectively) (Figure 3, Tables 4 and 5). No association
Grade .07 with the high-risk group could be found.
G1 136 (21.8) 47 (16)
G2 232 (37.1) 106 (36.2) Correlation With Intravesical BCG Therapy
G3 257 (41.1) 140 (47.8) In a subpopulation of 110 patients who received adjuvant
Concomitant CIS 24 (3.8) 10 (3.4) .7 intravesical BCG therapy, the median follow-up was 68 months.
Smoking status <.001 During this period, 17 (15%) patients experienced recurrence and
Non-smoker 170 (27.2) 49 (16.7) 10 (9%) progression. Overall, 82 (75.5) patients had NLR < 3, and
Ever smoker 455 (72.8) 244 (83.3) 28 (25.5%) had NLR
3. On univariable analyses, patients with
Tumor size .3 NLR
3 had a significant lower RFS rate (HR, 2.9; 95% CI, 1.1-
7.6; Log-rank P ¼ .03). PFS rates were also lower in patients with
<3 cm 440 (70.4) 196 (66.9)
NLR
3 compared with those with NLR < 3, but this was not

3 cm 185 (29.6) 97 (33.1)
statistically significant (5-year PFS, 79% vs. 94%; HR, 3.1; 95%
Number of tumors .3
CI, 0.9-10.7; Log-rank P ¼ .07) (Figure 4). On multivariable Cox
1 424 (67.8) 198 (67.6)
regression analyses, this association disappeared (Table 6).
2-7 166 (26.6) 71 (24.2)

8 35 (5.6) 24 (8.2) Discussion
Immediate single-shot postoperative .5 Despite adequate TURB and optimal adjuvant intravesical
intravesical chemotherapy
instillation therapy with BCG, the 5-year recurrence and progres-
Yes 364 (70) 181 (72.1)
sion probabilities of NMIBC patients are up to 67% and 33%,
No 156 (30) 70 (27.9)
respectively.16 Prognostic models used in these patients to influence
EORTC risk groups for recurrence .3 clinical decision-making rely on gender, age, recurrent tumor,
Low 423 (67.7) 184 (62.8) number of tumors, T stage, grade, and concomitant CIS.3,16
Intermediate 190 (30.4) 101 (34.5) Because their accuracy still remains suboptimal, the inclusion of
High 12 (1.9) 8 (2.7) other readily available markers associated with the biological and
EORTC risk groups for progression clinical behavior of the tumor could further improve the prediction
Low 374 (59.8) 155 (52.9) .1 accuracy of these models.
Intermediate 204 (32.7) 110 (37.5) Neutrophils and lymphocytes play a central role in the tumor
High 47 (7.5) 28 (9.6) microenvironment. Low lymphocyte levels result in a deficient
EAU risk groups .1 cytotoxic mechanism and impaired anti-tumor activity; high
Low 96 (15.4) 34 (11.6) neutrophil levels, on the other hand, reflect an inflammatory reac-
Intermediate 272 (43.5) 119 (40.6)
tion with increased production of growth factors, cytokines, and
chemokines.17-19 The immunocompetence has been reported to
High 257 (41.1) 140 (47.8)
correlate with the stage and grade of UCB.20 The prognostic role of
Abbreviations: CIS ¼ carcinoma in situ; EAU ¼ European Association of Urology; EORTC ¼ NLR in patients undergoing RC for UCB and the association
European Organization for Research and Treatment of Cancer; IQR ¼ interquartile range;
NLR ¼ neutrophil-to-lymphocyte ratio; NMIBC ¼ nonemuscle-invasive bladder cancer;
with biologically and clinically aggressive UCB has been investi-
TURB ¼ transurethral resection of the bladder. gated.6,21-24 If NLR improves the prognostication of outcomes in

Clinical Genitourinary Cancer Month 2017 -3

 NLR in Primary Non-muscle Invasive Bladder Cancer
Figure 1 Recurrence- (A) and Progression-free Survival (B) Estimates for 918 Patients Treated With TURB for Primary
Nonemuscle-invasive Bladder Cancer Stratified by NLR

A 1.00
B

1.00
Progression−free survival (%)
Recurrence−free survival (%)
0.75

0.75
0.50

0.50
0.25

0.25
HR: 1.3 (95% CI: 1−1.6) HR: 1.9 (95% CI: 1.2−3)
Log−rank = 0.01 Log−rank = 0.004
0.00

0.00
0 20 40 60 80 100 0 20 40 60 80 100
Months after TURB Months after TURB
Number at risk Number at risk
NLR < 3 625 321 227 163 113 76 NLR < 3 625 489 391 321 236 176
NLR ≥ 3 293 136 93 70 51 37 NLR ≥ 3 293 233 192 158 120 85

NLR < 3 NLR ≥ 3 NLR < 3 NLR ≥ 3

Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio; TURB ¼ transurethral resection of the bladder.

patients undergoing RC for MIBC, it could also help identify pa-
tients with aggressive NMIBC who are likely to experience early
recurrence and/or potentially progression.
We investigated the pretreatment NLR in a large cohort of pa-
tients undergoing TURB for primary NMIBC and found that
NLR
3 was significantly associated with higher pathologic stage,
RFS, and PFS. We believe that this reflects the tumor
microenvironment and is therefore associated with more aggressive
disease and higher tumor burden.
Two previous studies reported on the association of NLR with
tumor invasiveness at TURB. Ceylan et al found, in a series of 198
patients, an association between higher pathologic stages and NLR
> 3.96.11 Kaynar et al retrospectively investigated 291 patients but
did not find a significant association in multivariable analyses.13

Table 2 Multivariable Regression Analyses for Prediction of RFS and PFS in 918 Patients Treated With TURB for Primary NMIBC

RFS PFS
HR (95% CI) P Value HR (95% CI) P Value
Age 1.03 (1.02-1.04) <.001 1.03 (1.01-1.05) .003
Gender (ref. female) 0.9 (0.7-1.2) .6 0.9 (0.6-1.7) .9
pT1 vs. pTa 0.6 (0.5-0.8) <.001 0.6 (0.4-0.8) .006
Grade (ref. G1)
G2 1.3 (0.9-1.8) .06 2.4 (0.9-6.3) .07
G3 1.8 (1-2.9) .02 8 (2.5-25) <.001
Concomitant CIS 1 (0.6-1.7) .8 1.1 (0.4-2.9) .8
Number of tumors (ref. single)
2-7 1.3 (1.1-1.7) .01 1.3 (0.8-2.2) .3

8 0.9 (0.6-1.4) .7 1.6 (0.7-3.5) .2
Tumor
3 cm 2.3 (1.9-2.8) <.001 1.3 (0.8-2.1) .2
Ever smoker 0.9 (0.8-1.2) .7 2.2 (1.1-4.5) .03
NLR
3 1.3 (1.1-1.6) .004 1.9 (1.2-3) .006

Abbreviations: CI ¼ confidence interval; CIS ¼ carcinoma in situ; EAU ¼ European Association of Urology; EORTC ¼ European Organization for Research and Treatment of Cancer; HR ¼ hazard ratio;
IQR ¼ interquartile range; NLR ¼ neutrophil-to-lymphocyte ratio; NMIBC ¼ nonemuscle-invasive bladder cancer; PFS ¼ progression-free survival; ref. ¼ reference; RFS ¼ recurrence-free survival;
TURB ¼ transurethral resection of the bladder.

4 - Clinical Genitourinary Cancer Month 2017

 David D’Andrea et al
Figure 2 Recurrence- and Progression-free Survival Estimates for 918 Patients Treated With TURB for Primary Nonemuscle-invasive
Bladder Cancer, According to the EAU Risk Table and Stratified by NLR

Abbreviations: CI ¼ confidence interval; EAU ¼ European Association of Urology; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio; TURB ¼ transurethral resection of the bladder.

Both studies are limited to a case mix of MIBC and NMIBC as well
as to small cohorts.
Although association with stage is important for primary treat-
ment, association with recurrence is more important for clinical
decision-making. The strongest outcome predictors for NMIBC
remain tumor size, focality, recurrence rate, concomitant CIS,
pathologic stage, and grade.3,16 The idea that NLR alone can
predict recurrence and progression is naive, as there are too many
conditions that can influence a patient’s own immune status.
Nevertheless, we found that NLR was an independent outcome
predictor, and its integration in a preoperative model could further
improve its discrimination by a small margin. This is in accordance
with previous reports. Indeed, Mano et al found higher recurrence
rates in patients with NLR > 2.41 and higher progression rates in

Clinical Genitourinary Cancer Month 2017 -5

 NLR in Primary Non-muscle Invasive Bladder Cancer
Table 3 Multivariable Regression Analyses for Prediction of RFS and PFS in 397 Patients Treated With TURB for Primary High-risk
NMIBC, According to the EAU
RFS
HR (95% CI)
Age 1.03 (1.02-1.04)
Gender (ref. female) 1.2 (0.8-1.8)
pT1 vs. pTa 0.6 (0.5-0.7)
Concomitant CIS 0.8 (0.4-1.6)
Number of tumors (ref. single)
2-7 1.3 (0.9-1.9)

8 1 (0.6-1.8)
Tumor >3 cm 2.7 (1.9-3.8)
NLR
3 1.9 (1.4-2.7)
Grade omitted as per definition all patients had G3 tumor.
Abbreviations: CI ¼ confidence interval; CIS ¼ carcinoma in situ; EAU ¼ European Association of Urology; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio; NMIBC ¼ nonemuscle-invasive
bladder cancer; PFS ¼ progression-free survival; ref. ¼ reference; RFS ¼ recurrence-free survival; TURB ¼ transurethral resection of the bladder.
those with NLR > 2.43 (3-year, 61% vs. 84%; P ¼ .004 and 27%
vs. 56%; P ¼ .016, respectively).8 The cut-off point was set using a
validated web-based software.25 The main limitation of this study is
the lack of report on adjuvant instillation therapy. In a smaller
prospective series including 86 patients, Albayak et al performed a
multiple linear regression model and found an association of high
NLR levels with patient age, disease recurrence, and progression
(P ¼ .001, r ¼ 0.4 and P ¼ .004, r ¼ 0.4, respectively). No
multivariable analyses were performed to prove the value of their
findings.12 Defining the ideal cut-off value that could be easily used
in daily routine is a big challenge, and the actual evidence, mainly
because of the case mix and limited patient numbers included, could
not deliver this information.
We expanded upon previous studies in a large cohort of patients
with a long follow-up. Moreover, we investigated the association of
NLR with early recurrence and progression and could prove a sta-
tistically significant association, adding new evidence to the litera-
ture. Nevertheless, the absolute number of patients, particularly
those with early recurrence, is fairly small. Therefore, the clinical
value of pretreatment NLR in this subgroup of patients remains
questionable.
In our series, multivariable analyses showed that not all predictors
were significantly associated with RFS and PFS. This results could
be influenced by the adjuvant intravesical BCG therapy that almost
60% of the patients received. Further, the absolute number of
observations plays a major role. For example, concomitant CIS was
not statistically associated with disease recurrence and progression,
but it represents only 3.7% of the overall population.
Based on our first analyses, high NLR is expected to be more
frequent in unfavorable NMIBC.
We wanted to investigate if a further risk stratification was possible.
Therefore, we divided our population into 3 groups based on the
EAU risk tables and found an independent association of NLR with
outcomes in the high-risk group. In further subgroup analyses based
on EORTC risk tables, the results were mixed. Indeed, NLR was
independently associated with PFS in all risk groups, but with RFS
only in the intermediate-risk group. Nevertheless, these results have
6 - Clinical Genitourinary Cancer Month 2017
PFS
P Value HR (95% CI) P Value
<.001 1.04 (1.01-1.07) .008
.4 1.2 (0.6-2.7) .6
<.001 0.5 (0.3-0.7) .002
.6 0.1 (0.02-1.1) .07
.1 1.8 (0.9-3.7) .08
.9 3.2 (1.3-7.7) .009
<.001 1.7 (0.9-3.1) .1
<.001 2.4 (1.2-4.6) .008
to be carefully interpreted for many seasons. First, these are 2
different risk classification systems; the EORTC is based on a point
scale and estimates disease recurrence (range, 0-17 points) and pro-
gression (range, 0-23 points) separately, whereas the EAU delivers an
overall risk stratification. Second, the EORTC risk tables have been
shown to overestimate the risk of RFS and PFS in the high-risk
group.4 Lastly, numbers in the subgroups are fairly small, not
allowing further analyses. Therefore, the discrimination of these risk
tables needs to be further improved with readily available markers like
the NLR and to be validated in large cohorts.
A major issue in patient consulting is to identify those with very
high-risk NMIBC who will not respond to intravesical immune
therapy, but will instead recur or progress, and would therefore
benefit from an early cystectomy.26 Indeed, patients treated with
RC for recurrent NMIBC have significantly worse outcomes when
compared with those undergoing immediate cystectomy.27
BCG acts as an immunemodulator, inducing antitumor in-
flammatory response, and its efficacy could therefore be corre-
lated with NLR levels. We conducted a subgroup analysis to
investigate the correlation of NLR with BCG and its ability to
identify nonresponders to the therapy. We found that NLR levels
were low in the majority of patients treated with BCG therapy.
Univariable analysis showed a significant association of high NLR
with RFS. On multivariable analysis that adjusted for the vari-
ables present in EORTC and EAU tables, this association dis-
appeared. However, 2 things must be taken into account. First,
these models do not have sufficient accuracy for the prediction of
BCG response.3,4 Second, UCB is a heterogeneous disease with
disparate genetic and epigenetic mutation patterns resulting in a
BCG response related to the single tumor characteristics. For
example, histologic variants like micropapillary showed low
response rates to BCG and even progression to metastatic disease
during therapy.28 Histologic variants were not assessed in our
study but would have been of great value for building a solid
BCG prediction model.
Patients with recurrence of high-grade NMIBC after BCG
therapy are considered at very high risk and are mainly advised to
 David D’Andrea et al
Figure 3 Recurrence- and Progression-free Survival Estimates for 918 Patients Treated With TURB for Primary Nonemuscle-invasive
Bladder Cancer, According to the EORTC Risk Tables and Stratified by NLR

Abbreviations: CI ¼ confidence interval; EORTC ¼ European Organization for Research and Treatment of Cancer; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio; TURB ¼ transurethral
resection of the bladder.

Clinical Genitourinary Cancer Month 2017 -7

 NLR in Primary Non-muscle Invasive Bladder Cancer
Table 4 Multivariable Regression Analyses for Prediction of RFS and PFS in Patients Treated With TURB for Primary Low-risk NMIBC,
According to the EORTC

RFS (n [ 607) PFS (n [ 529)

HR (95% CI) P Value HR (95% CI) P Value
Age 1.02 (1.01-1.03) <.001 1.02 (0.99-1.05) .07
Gender (ref. female) 0.8 (0.6-1.1) .2 1 (0.5-2.2) .9
pT1 vs. pTa 0.3 (0.1-0.9) .04 e e
Grade (ref. G1)
G2 1.4 (1-1.9) .02 2.5 (0.9-6.8) .06
G3 1.3 (0.5-3.6) .6 16 (3.7-70) <.001
Concomitant CIS 1.3 (0.5-3.4) .7 17 (4-66) .001
Number of tumors (ref. single)
2-7 1.3 (0.8-1.9) .2 0.8 (0.3-2.1) .6

8 e e e e
Tumor >3 cm 1.4 (1.1-1.7) .001 1.1 (0.7-1.7) .7
NLR
3 1.1 (0.8-1.4) .4 2.3 (1.2-4.4) .02

Abbreviations: CI ¼ confidence interval; CIS ¼ carcinoma in situ; EORTC ¼ European Organization for Research and Treatment of Cancer; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio;
NMIBC ¼ nonemuscle-invasive bladder cancer; PFS ¼ progression-free survival; ref. ¼ reference; RFS ¼ recurrence-free survival; TURB ¼ transurethral resection of the bladder.

undergo cystectomy. Identifying these patients prior to intravesical
therapy would be a breakthrough in the management of NMIBC.
NLR shows a trend, helping in this quest. Nevertheless, the number
of this subgroup is fairly small. Further studies with larger numbers
and more information on tumor biology are needed to confirm
these findings. Moreover, monitoring of NLR during and after
therapy would be of interest to investigate whether BCG can affect
the ratio and if this is of prognostic value.
Lastly, an aspect that should be taken in account is the smoking
status. Indeed, Rink et al29 reported an independent association of
decreased RFS and PFS (P < .001) in patients with NMIBC who
smoked.
In our series, NLR
3 was strongly associated with smoking
status. Arguably, smoking could have influenced the immune status
of the patients. We therefore conducted multivariable analyses and
found that smoking did not influence the association of NLR with
outcomes (Table 2).
The major limitations of our study are inherent to its retro-
spective and multicentric nature. We did not control for TURB
quality, surgeon performance and experience, and factors such as
treatment delay. Owing to the different adjuvant treatment patterns
offered in the single centers, it is difficult to find out whether pa-
tients completed the instillation therapy within the allocated time.
Moreover, histology specimens were not reviewed by a central

Table 5 Multivariable Regression Analyses for Prediction of RFS and PFS in Patients Treated With TURB for Primary Intermediate-risk
NMIBC, According to the EORTC

RFS (n [ 291) PFS (n [ 314)

HR (95% CI) P Value HR (95% CI) P Value
Age 1.03 (1.01-1.05) <.001 1.04 (1-1.08) .03
Gender (ref. female) 1.2 (0.7-1.8) .4 0.9 (0.3-3.3) .9
pT1 vs. pTa 0.4 (0.2-0.7) .001 0.5 (0.1-1.9) .3
Grade (ref. G1)a e e
G2 1.2 (0.4-3) .7 e e
G3 1.6 (0.6-4.8) .3 e e
Concomitant CIS 0.9 (0.4-1.8) .8 e e
Number of tumors (ref. single)
2-7 0.9 (0.6-1.5) .9 2.7 (0.9-7.9) .07

8 0.8 (0.3-1.9) .6 6 (1.9-19) .002
Tumor
3 cm 1.6 (1.1-2.2) .006 2 (1-4.2) .03
NLR
3 1.7 (1.2-2.4) .002 2.6 (1.1-5.9) .02

Abbreviations: CI ¼ confidence interval; CIS ¼ carcinoma in situ; EORTC ¼ European Organization for Research and Treatment of Cancer; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio;
NMIBC ¼ nonemuscle-invasive bladder cancer; PFS ¼ progression-free survival; ref. ¼ reference; RFS ¼ recurrence-free survival; TURB ¼ transurethral resection of the bladder.
a
Grade not included in PFS analyses as only 1 patient had G1 and 2 patients had G2.

8 - Clinical Genitourinary Cancer Month 2017

 David D’Andrea et al
Figure 4 Recurrence- and Progression-free Survival for 110 Patients Treated With Intravesical Instillation Therapy With BCG for
Primary High Risk Nonemuscle Invasive Bladder Cancer Stratified by NLR

Abbreviations: BCG ¼ bacillus Calmette-Guérin; CI ¼ confidence interval; HR ¼ hazard ratio; NLR ¼ neutrophil-to-lymphocyte ratio; TURB ¼ transurethral resection of the bladder.

pathology, and relevant prognostic factors like lymphovascular in- Conclusion

vasion and variant histology were not assessed. Comorbidities may In conclusion, our study proved an independent association of
have influenced the decision-making of further surgery or instilla- NLR
3 with unfavorable clinical outcomes, particularly in pa-
tion therapy, leading to a selection bias. We did not assess immu- tients with high-risk NMIBC. Moreover, NLR showed a trend
nologic diseases or previous chemotherapy, immunotherapy, or identifying patients failing intravesical immune therapy. The clinical
radiotherapies for other malignancies. All these conditions could relevance of NLR in NMIBC has still to be proved and externally
have influenced the immunologic status of our patients. Finally, we validated.
acknowledge the optimized NLR cut-off used for the analyses; using
a different cut-off for recurrence and progression could further
Clinical Practice Points
improve its clinical use.
 NLR is independently associated with recurrence and progres-
sion of NMIBC.
Table 6 Multivariable Regression Analysis for Prediction of  The integration of NLR into a panel of biomarkers could help
RFS in 110 Patients Treated With Intravesical Instil- selecting patients who are likely to benefit from an early RC.
lation Therapy With Bacillus Calmette-Guérin for
Primary High-risk NMIBC
Disclosure
HR (95% CI) P Value
The authors have stated that they have no conflicts of interest.
Age 1.02 (0.9-1) .5
Gender (ref. female) 0.7 (0.1-3.8) .6
pT1 vs pTa 0.09 (0.01-0.5) .005
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