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ORIGINAL ARTICLE
315
Can Neutrophil-to-Lymphocyte ratio predict the response
to BCG in high-risk non muscle invasive bladder cancer?
_______________________________________________
Marco Racioppi 1, Luca Di Gianfrancesco 1, Mauro Ragonese 1, Giuseppe Palermo 1, Emilio Sacco 1, Pier
Francesco Bassi 1
1 Department of Urology, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS - Università
Cattolica del Sacro Cuore di Roma
Vol. 45 (2): 315-324, March - April, 2019
doi: 10.1590/S1677-5538.IBJU.2018.0249
ABSTRACT
Objectives: To evaluate the neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor
for response of high risk non muscle invasive bladder cancer (HRNMIBC) treated with
BCG therapy.
Materials and Methods: Between March 2010 and February 2014 in a tertiary center
100 consecutive patients with newly diagnosed HRNMIBC were retrospectively ana-
lyzed. Patients were divided according to NLR value: 46 patients with NLR value less
than 3 (NLR < 3 group), and 54 patients with NLR value more than 3 (NLR ≥ 3 group).
At the end of follow-up 52 patients were high grade disease free (BCG-responder
group) and 48 patients underwent radical cystectomy for high grade recurrence or pro-
gression to muscle invasive disease (BCG non-responder group). The average follow-up
was 60 months. Intervention: analysis and correlation of preoperative NLR value with
response to BCG in terms of recurrence and progression.
Results: The optimal cut-off for NLR was ≥ 3 according to the receiver operating char-
acteristics analysis (AUC 0.760, 95% CI, 0.669-0.850). Mean NLR value was 3.65 ± 1.16
in BCG non-responder group and 2.61 ± 0.77 in BCG responder group (p = 0.01). NLR
correlated with recurrence (r = 0.55, p = 0.01) and progression risk scores (r = 0.49, p
= 0.01). In multivariate analysis, NLR (p = 0.02) and EORTC recurrence risk groups (p
= 0.01) were associated to the primary endpoint. The log-rank test showed statistically
significant difference between NLR < 3 and NLR ≥ 3 curves (p < 0.05).
Conclusions: NLR value preoperatively evaluated could be a useful tool to predict BCG
response of HRNMIBC. These results could lead to the development of prospective
studies to assess the real prognostic value of NLR in HRNMIBC.
ARTICLE INFO
Keywords:
Urinary Bladder Neoplasms;
Neutrophils; Lymphocytes
Int Braz J Urol. 2019; 45: 315-24
_____________________
Submitted for publication:
April 04, 2018
_____________________
Accepted after revision:
September 29, 2018
_____________________
Published as Ahead of Print:
November 03, 2018
INTRODUCTION
Worldwide, bladder cancer is the ninth
most commonly diagnosed malignancy and the
13th cause of cancer deaths in 2015 (1).
Bladder cancer is the second most frequent
genitourinary tumor. At first diagnosis of 75 -
85% patients have a mucosal (stage Ta, Carcinoma
in situ) or submucosal neoplasia (stage T1) (2).
The challenge in treating non - muscle - in-
vasive bladder cancer (NMIBC) is to preserve the bla-
dder and its function, accepting the risk of recurren-
ce (up to 78% of cases) and the risk of progression to
muscle - invasive disease (up to 45% of cases).
The identification of patients with higher
risk of recurrence and progression is mandatory
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316
in order to predict oncological outcomes and for
optimal tailored therapeutic decision - making.
The gold standard treatment for NMIBC is
represented by transurethral resection of bladder
tumor (TURBT) and a re - TURBT when indicated
(any high grade disease except Cis, any T1, in-
complete TURBT or absence of muscle in the spe-
cimen), followed by adjuvant intravesical chemo
- or immunotherapy.
European Organization of Research and
Treatment of Cancer (EORTC) risk tables (3) sug-
gested a stratification of patients in low, medium
and high risk of recurrence and progression, and a
relative treatment strategy.
The treatment of high-risk patients is ba-
sed on the induction course of intravesical immu-
notherapy with BCG (Bacillus Calmette-Guerin)
followed by maintenance course for at least one
year (4).
Many predictor tools have been analyzed
in the context of cancer development and pro-
gression. A high neutrophil - to - lymphocyte ra-
tio (NLR) was already consistently associated with
locally advanced disease and worse general and
cancer-specific survival rates in several solid tu-
mors (5).
A high NLR seems to represent an inde-
pendent prognostic factor of recurrence and pro-
gression of disease in patients with NMIBC (6).
NLR may be helpful to better identify patients
who would be optimally treated and cured with
BCG and patients in whom conservative treatment
would probably be ineffective.
The purpose of this study is to evaluate
whether preoperative NLR measurement may add
useful information for the best disease manage-
ment and for prediction of response to BCG in
high risk non muscle invasive bladder cancer (HR
- NMIBC).
MATERIALS AND METHODS
We retrospectively analyzed 100 consecu-
tive patients treated in our Clinic for a first diag-
nosis of high - risk NMIBC (according to EORTC
and EAU guidelines) between March 2010 and Fe-
bruary 2012. We excluded patients with previous
history of low risk NMIBC.
All these patients underwent an intravesi-
cal BCG schedule consisting of one induction cour-
se (6 weekly instillations) followed by one year of
monthly maintenance course.
In all patients, the histological specimen
documented a pure urothelial cancer with detru-
sor muscle included in the resection; we did not
analyzed patients with other histological variants.
All high grade pTa and pT1 patients un-
derwent reTURBT according EAU guidelines.
For all patients the follow-up was 60 months.
At the end of follow-up 52 patients were
high grade disease free (BCG - responder group)
and 48 patients underwent radical cystectomy for
high grade recurrence or progression to muscle in-
vasive disease) (BCG non - responder group).
Patients were divided according to their
NLR value (Table-1): 46 patients with NLR value
less than 3 (NLR < 3 group), and 54 patients with
NLR value more than 3 (NLR ≥ 3 group).
Three patients developed a solitary or con-
current upper tract urothelial carcinoma (UTUC)
disease: two patients (4.3%) in NLR < 3 group and
1 patient (1.8%) in NLR ≥ 3 group; two patients
(3.8%) in BCG - responder group and 1 patient
(2.1%) in BCG - non responder group.
In all patients, the BCG strain used was
Seed RIVM by Medac® (derived from seed 1173
- P2, 2 x 10 to 3 x 10 viable units). The Medac®
- BCG powder was re - suspended with 50 mL of
0.9% normal saline and introduced into the blad-
der via a 10-12 French urethral catheter. Patients
were instructed to hold the drug in the bladder for
two hours.
Four experienced urologists performed all
the diagnostic cystoscopies and all the TURBTs.
All specimens were analyzed by an expe-
rienced dedicated uropathologist.
The 2009 TNM classification (7) and the
2004 WHO grading system (8) were used for his-
tologic reports.
Recurrence was defined as the first histo-
logically confirmed high grade NMBIC recurrence;
progression was defined as the development of
muscle - invasive bladder cancer (MIBC).
Diagnostic cystoscopies, TURBTs and even-
tual reTURBTs were performed using NBI (Narrow
Band Imaging) technology.
IBJU | NEUTROPHIL-TO-LYMPHOCYTE RATIO AND BCG RESPONSE IN NON MUSCLE INVASIVE BLADDER CANCER?
317
All the analyzed patients completed the
induction six - weekly BCG instillation schedule
(in order to avoid bias related to the intravesical
immunotherapy toxicity).
At the end of the induction course all pa-
tients underwent endoscopic evaluation, voiding
and washing urinary cytology, transurethral re-
section (TUR) of any suspected area. Random
biopsies including prostatic urethra for patients
were performed if indicated.
In case of high grade tumor recurrence
or progression to muscle invasive disease during
follow-up, patients were considered as BCG fai-
lure according to EAU guidelines and underwent
radical cystectomy. We excluded all cases of BCG-
-intolerance (9). Patients with low grade low stage
BCG - relapsing diseases were considered in the
BCG responder group considering that they should
not be considered as “BCG failure” according to
EAU guidelines (3).
Patients with complete response after in-
duction course underwent BCG maintenance
course for at least 1 year and subsequent endos-
copic follow-up every 3 months for the first two
years and then every 6 months according the EAU
guidelines (3).
All the analyzed patients completed the
induction six - weekly BCG instillation; no event
of therapy discontinuation was reported. We re-
ported 5 cases of therapy discontinuation during
the last instillations of the maintenance cycle (due
to severe BCG - related complications): 3 patients
(6.5%) in NLR < 3 group and 2 patients (3.7%) in
NLR ≥ 3 group; 3 patients (5.8%) in BCG - respon-
der group and 2 patient (4.2%) in BCG - non res-
ponder group; these patients therefore underwent
cystoscopic, cytologic and radiologic evaluations:
all of them were high grade disease - free, so they
continued regular follow-up.
For each patient, we reported the preopera-
tive hematologic and chemical data, including the
total number of white blood cells (WBC), neutro-
phils (N) and lymphocytes (L). Patients underwent
blood sampling the day before the TURBT, in the
morning, after at least 6 hours of fasting. We en-
rolled only patients without hematuria in order to
avoid any sort of bias, especially in terms of total
blood count. The NLR ratio was calculated by di-
viding the value of N by the value of L.
The preoperative NLR measurement col-
lected at the first TURBT was the reference value
for each patient.
We used a receiver operating characteris-
tic (ROC) curve to determine an appropriate cut
- off value.
All patients were classified into two
groups according to the NLR. The X2 test was
used to verify the significance of the correlation
between the NLR and the clinic - pathological
characteristics.
Patients with preoperative diagnosis of
active infection, hematologic neoplasms or unex-
plained leukocytosis, presence of other neoplasms,
prior systemic chemotherapy were excluded from
the study.
The groups were compared according to
the following data: age, sex, stage and grade of
tumor, size and number of tumors, presence of
carcinoma in situ, NLR.
In addition, patients were classified accor-
ding to the EORTC risk tables (3) for the recurrence
risk score (1-4, 5-9, ≥ 10) and for the progression
risk score (2-6, 7-13, and ≥ 13). No patient had a
recurrence or progression risk score of zero and
all patients scored zero regarding “prior recurren-
ce rate” because all of them had newly diagnosed
bladder cancer.
The aim of the study was to identify a
potential role of NLR as an independent prog-
nostic factor for the response to endovesical
BCG therapy.
Categorical variables were summarized
using actual counts and percentages; the conti-
nuous variables using the mean ± standard de-
viation.
Parametric and nonparametric variables
were evaluated using the t - test and the chi squa-
re test, respectively.
Logistic regression was used to determine
independent predictors of BCG response.
The X2 distribution was used for categori-
cal data. Pearson’s test was used for the correla-
tion analysis. Statistical significance was conside-
red at p < 0.05.
IBJU | NEUTROPHIL-TO-LYMPHOCYTE RATIO AND BCG RESPONSE IN NON MUSCLE INVASIVE BLADDER CANCER?
318
Kaplan Meier curves and log rank test were
built in order to evaluate cancer free survival be-
tween the two groups.
All patients provided informed written in-
formed consent with guarantees of confidentiality.
The protocol for the research project was ap-
proved by the local Ethics Committee and it confor-
med to the provisions of the Declaration of Helsinki
(as revised in Fortaleza, Brazil, October 2013).
RESULTS
The baseline patient’s characteristics are
summarized in Table-1. The median age of pa-
tients was 67.5 ± 10.7 years.
The mean value of NLR in all patients was
3.17 ± 1.12.
The mean NLR value was 2.61 ± 0.77 in BCG
- responder group and of 3.65 ± 1.16 in BCG - non
Table 1 - Baseline characteristics based on NLR value.
Variables General NLR < 3 NLR ≥ 3 p value
N° of patients 100 46 54
Median age**, years ± SD 67.5 ± 10.7 68.6 ± 10.8 66.7 ± 10.5 > 0.05
Sex*, nº of pts (%) > 0.05
Male 87 (87%) 39 (84.8%) 48 (89.6%)
Female 13 (13%) 7 (15.2%) 6(10.4%)
NLR**, value ± SD 3.17 ± 1.12 2.32 ± 0.41 3.90 ± 0.88 0.01
Pathological stage***, n° of pts (%) > 0.05
Ta 11 (12%) 3 (6.5%) 8 (14.8%)
T1 73 (73%) 35 (76.1%) 38 (70.4%)
solitary Cis 16 (15%) 8 (17.4%) 8 (14.8%)
Concomitant Cis*, n° of pts (%) 25 (25%) 2 (4.3%) 23 (42.6%) 0.01
No. of tumors*, n° of pts (%) 0.01
1 48 (48%) 35 (76.1%) 13 (24.1%)
≥ 2 52 (52%) 11 (23.9%) 41 (75.9%)
Tumor size (mm)*, n° of pts (%) 0.01
< 30 78 (78%) 42 (91.3%) 36 (66.7%)
≥ 30 22 (22%) 4 (8.7%) 18 (33.3%)
Recurrence risk score**, value ± SD 5.5 ± 2.3 4.2 ± 1.7 6.5 ± 2.2 0.01
Progression risk score**, value ± SD 12.1 ± 3.9 9.7 ± 2.2 14.2 ± 3.9 0.01
EORTC recurrence risk***, class (%) 0.01
1-4 39 (39%) 29 (63.1%) 10 (18.5%)
5-9 55 (55%) 17 (36.9%) 38 (70.4%)
≥ 10 6 (6%) 0 (0%) 6 (11.1%)
EORTC progression risk***, class (%) 0.01
2-6 5 (5%) 3 (6.5%) 2 (3.7%)
7-13 58 (58%) 40 (87%) 18 (33.3%)
≥ 14 37 (37%) 3 (6.5%) 34 (63%)
SD = standard deviation; Pts: patients; NLR = Neutrophil / Lymphocyte Ratio; Cis = Carcinoma In Situ; EORTC = European Organization for Research and Treatment of
Cancer; Test = chi-square*; t-student**, ANOVA***
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319
Figure 1 - Correlation between NLR and recurrence risk score and progression risk score.
responder group (p value: 0.01), and 2.32 ± 0.41
in NLR<3 group and 3.90 ± 0.88 in NLR ≥3 (p
value: 0.01).
After 60 months of follow-up, all patients
in BCG-responder group were cancer-free, while
all patients in BCG-non responder group under-
went radical cystectomy for recurrence of high-
grade NMIBC (n = 31) or for progression to muscle-
invasive disease (n = 17); in 12 cases (70%) with
evidence in the post-operative histopathological
specimen of pT2, in 4 cases (25%) with pT3 and
in 1 patient (5%) with pT4 disease for involving of
prostatic stroma at the level of prostatic urethra.
According to the ROC analysis, the opti-
mal cut-off of NLR was ≥ 3 (area under the curve
[AUC] 0.760, 95% CI, 0.669-0.850, sensitivity
80.0%, specificity 72.0%, PPV 74.0%, NPV 78.0%,
OR 10.29, RR 3.36, +LR 2.85, p value 0.01).
We reported a linear correlation between
NLR value and recurrence risk score (r=0.55, p=0.01)
and progression risk score (r = 0.49, p = 0.01) consid-
ered as continuous variables (Figure-1).
Moreover, we reported a statistically sig-
nificant difference in the value of NLR among
patients with different recurrence (p = 0.01) and
progression risk scores (p = 0.01) considered as
categorical variables.
Recurrence/progression rates increased
with the increase of NLR values: 15.4% in patients
with NLR between 1 and 2, 30.3% in patients with
NLR between 2 and 3, 62.5% in patients with NLR
between 3 and 4, and 78.6% in patients with NLR
higher than 4 (p < 0.05).
We built Kaplan-Meier cancer free sur-
vival curves for patients with NLR < 3 and NLR
≥ 3: the log-rank test showed a statistically sig-
nificant difference between the two curves (p <
0.05) (Figure-2).
In the multivariate analysis, prognostic
factors were analyzed in order to weigh their
role in relation to the primary endpoint; in this
analysis we considered NLR and EORTC risk cat-
egories according relative scores (1-4, 5-9 and
≥ 10 risk groups for recurrence; 2-6, 7-13, ≥ 14
risk groups for progression): NLR (p = 0.02) and
EORTC recurrence risk groups (p = 0.01) were
associated, while EORTC progression (p = 0.11)
risk groups were not associated (Table-2).
At the end of follow-up we reported
higher recurrence/progression rates in case of
higher NLR values. NLR values increased with
the increase in scores: in 1-4, 5-9 and ≥ 10 re-
currence risk groups NLR values were 2.60 ±
0.84, 3.44 ± 1.11, and 3.71 ± 0.38, respectively
(p value: 0.01); in 2-6, 7-13 and ≥ 14 progres-
sion risk groups NLR values were 2.66 ± 0.41,
2.89 ± 1.02 and 3.79 ± 1.26, respectively (p
value: 0.01).
At the end of follow-up in BCG- re-
sponder group there was no cancer-related
death while in BCG-non responder group the
cancer specific survival rate was 96.2%; the 2
patients that died presented an average NLR
value of 4.8, statistically different compared
to disease-free patients (p = 0.01) and patient
treated with radical cystectomy (p = 0.01).
f(x) = 0,26x + 1,66
R
2
= 0,31
f(x) = 0,14x + 1,44
R
2
= 0,25
NLR
Recurrence score Progression score
10
8
6
4
2
0
-2
10
8
6
4
2
0
-2
10 2 3 4 5 6 7 8 9 10 11 4 6 8 10 12 14 16 18 20 22
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320
DISCUSSION
The prognostic role of NLR has already
been extensively analyzed in many solid tumors
but the underlying mechanism explaining the as-
sociation of a high NLR and poor prognosis / poor
outcomes of cancer patients is poorly known (10).
A potential mechanism has been iden-
tified in the association between high NLR and
inflammation. The systemic inflammatory res-
ponse stimulated by the neoplasia involves a
pro-tumor inflammatory state, leading an active
role of systemic inflammation in tumor growth,
recurrence, and progression. Many inflamma-
tory indexes (PCR, Platelet/Lymphocyte ratio
- PLR -, albumin levels, fibrinogen levels, etc.)
obtained from blood tests were associated with
outcomes of many cancers.
Neutrophils and lymphocytes have an inhi-
bitory and activating action, respectively, on the
immune system: that is why they might reflect the
inflammatory and immune response of the host.
Inflammatory response induces neutrophi-
lia, lymphocytopenia and high excretion of pro-
angiogenetic factors, growth factors, anti-apop-
totic factors, all stimulating tumor growth and
progression (11). Neutrophilia as an inflammatory
response inhibits the immune system by suppres-
sing the cytolytic activity of immune cells such as
lymphocytes, activated T cells and natural killers
cells (12, 13).
The increase in tumor lymphocyte infil-
tration has been associated with better responses
to cytotoxic treatments and better prognosis of
cancer patients. Inflammatory cytokines and che-
mokines can be produced by both tumor and host
cells (such as lymphocytes) contributing to tumor
progression.
NLR might therefore represent a systemic
inflammation parameter and efficient biomarker
of the host-tumor interaction (11). A high NLR va-
lue could reflect both an increased neutrophil-de-
pendent inflammatory reaction and a diminished
lymphocyte-dependent immune response (14).
Figure 2 - Kaplan-Meier cancer free survival curves for patients with NLR< 3 and NLR ≥ 3.
Table 2 - Logistic regression analysis for response to BCG.
Factors B S.E. tpB %95 C.I.
Lower Upper
NLR* 0.077 0.035 2.226 0.02 0,008 0,147
EORTC recurrence risk** 0.152 0.048 3.143 0.01 0,056 0.248
EORTC progression risk** 0.202 0.122 1.65 0.10 -0.041 0.444
* continuous variable; ** categorical variable
Cancer-free rates
0 1 2 3 4 5
Long-rank test > 3.84
P<0.05
NLR<3
NLR>3
1
0,5
0
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321
An increase in NLR was associated with
an increase of peritumoral infiltration of macro-
phages and increased interleukins and cytokines
production (IL-1ra, IL6, IL7, IL8, IL9, IL12, IFN-
gamma, etc.). Neutrophils and other cells secrete
tumor growth promoting factors (VEGF, HGF, IL6,
IL8, MMPs, elastanes) thus contributing to micro-
environment of tumor stimulation (for example,
IL6 has been shown to be at higher concentrations
in 13 different types of neoplasia and associated
with higher tumor stage and adverse prognosis).
In vitro and in vivo studies showed that
the systemic and local responses (at the bladder
wall) to BCG are represented by an increase in T
lymphocytes, with a predominance of T helper /
inducer cells.
Although studies demonstrated BCG effi-
cacy (and safety) of immunocompromised patients,
studies on the immunological mechanism of BCG
therapy showed that an intact immune system
(particularly of the cellular system) is required for
anti-tumor activity; clinical and laboratory evi-
dence showed that BCG interaction with immune
system produces a relative systemic immunity to
BCG, necessary for its effectiveness (15).
Previous studies assessed the NLR value
in patients with MIBC undergoing radical cystec-
tomy (16): correlations were found between high
levels of NLR and diagnosis of MIBC at TURBT
and with non-organ confined tumor (17).
In the study of Mano et al. higher NLR va-
lues were associated with unfavorable tumor charac-
teristics (high grade of differentiation, T1 tumor) in
122 patients with new NMIBC diagnosis.
In our study, patients with NLR ≥ 3 presented
statistically significant worse tumor characteristics
(negative prognostic factors) such as concomitant
Cis (p<0.01, OR 16.3), multifocality (p<0.01, OR 10),
tumor size >3 cm (p<0.01, OR 5.2) compared to pa-
tients with NLR <3.
Higher NLR values were associated with
tumor progression and recurrence in univariate
and multivariate analyses adjusted for EORTC risk
groups (16). We observed linear correlations between
NLR value and patient’s EORTC classes (Figure-1).
In a cohort of 86 patients, Albayrak et al.
reported a significant difference in NLR values
between recurrence and progression risk sco-
re groups, with mean NLR values progressively
higher as the risk class increased. In this study,
however, patients’ age was statistically different
between recurrence and progression risk sco-
re groups and, after correcting for the statistical
effect of age on scores, the relationship between
NLR and recurrence and progression risk scores
was no longer significant. Authors suggested to
correct the NLR value according to patients’ age in
order to avoid deceitful results (18). We evaluated
NLR according to EORTC risk score and we repor-
ted their linear correlation. Unlike other studies
(16, 19), patients’ age was not correlated with NLR
values and EORTC risk scores, so our results did
not need correction for the patients’ age.
In the study of Cimen et al. in a cohort of
271 patients the NLR value was associated with
the T1 pathological stage: patients with NLR >1.8
had 1.5 times higher risk to develop a lamina pro-
pria infiltrating tumor. [18] In our study, all pa-
tients with NLR<1.8 had a lamina propria infiltra-
ting cancer, so we could not confirm or compare
these data, maybe due to the specific subgroup of
HRNMIBC patients we considered (Cimen et al. in-
cluded papillary urothelial neoplasm of low ma-
lignant potential – PUNLMP - and low grade low
stage bladder cancer patients).
In a cohort of 178 patients, Favilla et al.
prospectively assessed the role of NLR as bioma-
rker of NMIBC in terms of prognostic marker of
disease recurrence, reporting a statistically signi-
ficant association of higher NLR value (with a cut-
-off ≥ 3) with recurrence (such as in our study)
but not with progression (differently from our re-
sults) (20).
In our study patients with higher NLR
showed higher recurrence/progression rates than
those with lower NLR: 15.4% of recurrence/pro-
gression rate for patients with NLR values between
1 and 2, 32.4% for NLR values between 2 and 3,
83.3% for NLR values between 3 and 4, 85.7% for
NLR value more than 4.
Qzyalvachi et al. reported a statistically
significant correlation between recurrence of pT1
HGNMIBC and NLR with cut-off of NLR ≥ 2.43 in
166 patients. In the multivariate logistic regres-
sion analysis NLR, tumor number and smoking
were determined as independent predictors of re-
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322
currence while no statistically significant correla-
tion was reported between NLR and progression
(18). In our study the multivariate analysis showed
that NLR value (p=0.02) and EORTC recurrence
(p=0.01) risk groups were independent factors of
non-response to BCG (intended as high-grade re-
currence or progression disease); even in our stu-
dy progression risk groups were not independent
factors of non-response to BCG (p=0.10)
D’Andrea et al. evaluated the prognostic
role of NLR in patients with primitive NMIBC. The
optimum cut-off value of NLR was 3. In univariate
and multivariate analysis, NLR≥3 was significan-
tly associated with recurrence free survival (RFS)
and progression free survival (PFS) and with ou-
tcomes in patients treated with BCG. In this retros-
pective study on 918 patients, authors suggested
the integration of NLR into a predictive model to
predict RFS and PFS in patients with NMIBC (19).
Mbeutcha et al. showed a relationship be-
tween oncological outcomes of NMIBC and ma-
rkers of systemic inflammatory response, inclu-
ding NLR. Authors evaluated retrospectively 1.117
patients and reported a statistically significant
association between high NLR values and disease
recurrence and progression; this association was
confirmed in the analysis of a subgroup of 300
patients treated with BCG. Even these authors su-
ggested the introduction of NLR in prognostic mo-
dels (21).
The EAU guidelines for UTUC manage-
ment already considers NLR as a prognostic tool
in the preoperative assessment (22), nevertheless
our results and literature suggest a pivotal role for
this value in bladder cancer management.
In a retrospective study on 1.551 patients,
Kang et al. reported a significant association of
high preoperative NLR with host-related outcomes
(overall and cancer specific survival) but not with
PFS and RFS (23). In this larger series of patients
a linear correlation of NLR with RFS and PFS was
not reported, but authors reported a significant as-
sociation between this factor and overall survival
and cancer specific survival, still validating the
prognostic power of NLR in bladder cancer.
In our cohort of patients the mean higher
values of NLR seemed to be compliant with the spe-
cific population of patients in exam (high grade, pT1,
presence of Cis, etc.). NLR was statistically higher in
patients who underwent radical cystectomy; in fact
patients with NLR ≥3 showed a 2.85 times higher
risk to be treated with radical cystectomy.
Our aim was to add a prognostic factor
for the definition of the particular subgroup of
patients with “highest risk“ NMIBC (3) who, ac-
cording to EAU guidelines (LE: 3, Strength rating:
Strong), could benefit from radical surgery even
after the first diagnosis given the high risk of re-
currence and progression.
In addition to the other already known
prognostic factors, NLR could help to inform pa-
tient, in a shared decision making process, about
the aggressiveness of the neoplasm, providing re-
alistic probabilities of success/failure of the con-
servative treatment.
It is widely known that this group of pa-
tients require the best therapeutic option (BCG)
and a close follow-up since conservative intrave-
sical treatment has a high probability of failure
(up to 62% of recurrence, up to 45% of progres-
sion, in our specific cohort of patients, according
EORTC class risk).
According to our experience the NLR re-
port could allow to better identify patients for
whom radical cystectomy might be the only form
of curative treatment. This could also allow to pre-
cociously begin a psychological support for the
patient in prevision of a major surgery and all re-
lated changes on the quality of life (QoL) (24).
Other advantages of using the NLR value
are: easy applicability, wide availability and low
cost. In the literature, various NLR cutoff values
were evaluated and applied (25). This implies the
need to interpret the results carefully as the cut-off
value was chosen in each specific cohort by tes-
ting different discrimination values with relative
different sensitivities and specificities. In the light
of these considerations, an ideal and generalizable
NLR value is still far from being well defined.
Some limitations of our study were: small
number of patients; individual preoperative sys-
temic inflammatory response tests; retrospective
study performed in a single tertiary center with
relative unavoidable selection biases; the lack of
in vivo and / or in vitro studies in order to validate
our hypotheses.
IBJU | NEUTROPHIL-TO-LYMPHOCYTE RATIO AND BCG RESPONSE IN NON MUSCLE INVASIVE BLADDER CANCER?
323
CONCLUSIONS
Our data showed that a high value of NLR
evaluated preoperatively might be helpful to pre-
dict the BCG response and therefore provide cri-
tical information for the clinical management of
high-risk NMIBC patients together with the prog-
nostic factors already known.
In order to give greater significance to our
results, prospective studies are needed for vali-
dating the NLR as a real prognostic factor of the
high-risk NMIBC and for identifying the ideal and
reproducible NLR cut-off value.
COMPLIANCE WITH ETHICAL STANDARDS
This research study involving human sub-
jects was registered in the publicly accessible Eu-
draCT (European Union Drug Regulating Authori-
ties Clinical Trials) database before recruitment of
the first subject with the number 2018-001276-38.
CONFLICT OF INTEREST
None declared.
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_______________________
Correspondence address:
LUCA Di Gianfrancesco, MD
Department of Urology
“Agostino Gemelli” Foundation Hospital IRCCS, Catholic
University Medical School
L.go A. Gemelli, 8
00168 Rome, Italy
Fax:+3 906 3015-5975
E-mail: luca.digian@libero.it
