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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 analyzed. 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 progression 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 characteristics 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.
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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
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.
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
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
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
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.
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
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-
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.
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).
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***
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
= 0,31
f(x) = 0,14x + 1,44
= 0,25
Recurrence score Progression score
10 2 3 4 5 6 7 8 9 10 11 4 6 8 10 12 14 16 18 20 22
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
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
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-
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, NLR3 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.
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.
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.
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
... In 43 of these studies (70%), BCG was used in all patients (100% treatment rate). 16,17,19,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][40][41][42][43][44]46,49,51,54,56,57,[61][62][63]65,68,69,[72][73][74][75][76] BCG therapy was an inclusion criterion for some of these studies, which contributed to this high rate. In the remaining 18 studies (30%), the reported use of BCG instillations in HR-NMIBC patients ranged from 3% to 86%.- 18,20,39,45,47,48,50,52,53,55,[58][59][60]64,66,67,70,71 Thirty-five studies reported on the use of BCG induction therapy specifically, 16 Twelve studies reported the use of mitomycin C in high-risk patients. ...
... 16,[18][19][20][21][22][23][27][28][29][30][31][32][33]37,[41][42][43]45,47,[49][50][51][52][53][54][55][56]58,64,69,70,74,77,78,[83][84][85][86][87][88][89][90] Across 27 studies, the use of this procedure varied from 15% to 82%, 16,18,[20][21][22][30][31][32][33]37,[41][42][43]45,47,49,50,52,53,55,58,70,74,77,83,86,87 and in 16 studies, it was used in all patients (100%). 19,23,[27][28][29]49,51,54,56,64,69,84,85,[88][89][90] The use of radical cystectomy in HR-NMIBC was reported in 36 studies and rates likewise varied, ranging from 3% to 48% in 31 studies; [20][21][22]30,32,[41][42][43]50,53,55,57,58,[65][66][67]70,71,76,81,[86][87][88][91][92][93][94][95][96][97][98] in the remaining 5 studies, radical cystectomy was used in 100% of the patients. 47,[99][100][101][102] Excluding these studies, ≤20% of the patients were treated with radical cystectomy in the majority (60%) of studies. ...
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Background: To date, there has been limited synthesis of RWE studies in high-risk non-muscle invasive bladder cancer (HR-NMIBC). The objective of this research was to conduct a systematic review of published real-world evidence to better understand the real-world burden and treatment patterns in HR-NMIBC. Methods: An SLR was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined by the Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. EMBASE, MEDLINE, and Cochrane databases (Jan 2015-Jul 2020) were searched, and relevant congress abstracts (Jan 2018-Jul 2020) identified. The final analysis only included studies that enrolled ≥100 patients with HR-NMIBC from the US, Europe, Canada, and Australia. Results: The SLR identified 634 RWE publications in NMIBC, of which 160 studies reported data in HR-NMIBC. The average age of patients in the studies was 71 years, and 79% were males. The rates of BCG intravesical instillations ranged from 3% to 86% (29-95% for induction and 8-83% for maintenance treatment). Five-year outcomes were 17-89% recurrence-free survival (longest survival in patients completing BCG maintenance), 58-89% progression-free survival, 71-96% cancer-specific survival (lowest survival in BCG-unresponsive patients), and 28-90% overall survival (lowest survival in patients who did not receive BCG or instillation therapy). Conclusion: BCG treatment rates and survival outcomes in patients with HR-NMIBC vary in the real world, with better survival seen in patients completing maintenance BCG, responding to treatment, and not progressing to muscle-invasive disease. There is a need to better understand the factors associated with BCG use and discontinuation and for an effective treatment that improves outcomes in HR-NMIBC. Generalization of these results is limited by variations in data collection, reporting, and methodologies used across RWE studies.
... To our knowledge, this is the first time this biomarker is associated with BCG response. In addition, considering a previous study by Racioppi et al., we investigated also the value of NLR as a prognostic factor in BCG response, without obtaining, however, significant results [32]. Finally, we did although several studies reported a worse prognosis in older patients [33,34]. ...
Introduction Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Materials and methods Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. Results A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05–1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22–2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02–1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P < 0.0001) and at 10 years (44.2% vs. 74.4%, P < 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P < 0.0001) and at 10 years (72.3% vs. 87.2%, P < 0.0001). Conclusion Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes.
... Moreover, increase in NLR correlated significantly with disease recurrence and progression risk scores. 27 In a similar vein, another study also concluded that an optimal cutoff of NLR >2.5 served as an independent predictor of disease recurrence and prognosticated worse recurrence-free survival in NMIBC patients, particularly within the subgroup treated with BCG therapy. 28 A meta-analysis of 15 studies comprising 5354 patients reported that elevated PLR exhibited poorer progression-free survival and disease-free survival. ...
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Within the heterogeneous population of patients with bacillus Calmette-Guérin failure, there are clear differences in prognosis and therapy with regard to the timeline when bacillus Calmette-Guérin failure occurred. There are a variety of classifications which include bacillus Calmette-Guérin refractory disease, relapsing, unresponsive, and intolerant. Further profiling of these patients may help to shed light on other forms of therapy that are less radical. We hereby summarize the different biomarkers that predicts for response to bacillus Calmette-Guérin immunotherapy and bacillus Calmette-Guérin failure for non-muscle invasive bladder cancer.
... Several prognostic blood-or serum-based biomarkers have been reported in mUC including, CRP, LDH, plateletto-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), absolute monocyte count, or absolute eosinophils count. Among those, the present study focused on NLR since it has shown the consistent ability as a prognosticator in a variety of settings, including intravesical recurrence and muscle-invasive or metastatic progression non-muscleinvasive disease [13][14][15], adverse outcomes of radical cystectomy for non-metastatic muscle-invasive disease (MIBC) [16][17][18][19][20][21][22][23][24][25][26]. In addition to surgical treatment, high NLR has been reported to be associated with unfavorable oncological outcomes in patients with surgically unresectable metastatic UC receiving first- [9] or second-line [27][28][29] chemotherapy. ...
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Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.
... To predict oncological outcomes and optimal, tailored therapeutic decision-making, we have found that a high neutrophil-to lymphocyte ratio (NLR) was already consistently associated with locally advanced disease. Also, it represents an independent prognostic factor of recurrence and progression in NMIBC patients (26). For the second issue, the Enhanced recovery after surgery (ERAS) program has been described as an alternative to reduce the perioperative morbidity and mortality in patients undergoing a radical cystectomy (27,28). ...
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Purpose: To describe the current scientific knowledge and clinical experience in low-grade-non-muscle-invasive bladder cancer (LG-NMIBC) patients in challenging scenarios. Materials and methods: Medline, Embase, Google Scholar, and Cochrane Central were searched until March 2021. Results: A total of 841 studies were identified, and abstracts were analyzed. Twenty-one relevant studies were then identified and reviewed. After all, information was gathered from 16 studies, the authors discussed the specific topics, and expert opinions were also included in the discussion. There have been some studies that can help us to have some insights on how to manage these patients. Very distinctive strategies have been reported in the literature, mainly anecdotally or in small randomized studies. Some of these treatments outlined in the present manuscript include repeated TURBTs, chemoablation, BCG immunoablation, partial cystectomy, radical cystectomy, radiotherapy, chemotherapy, and future perspectives. In the current manuscript, we have combined these strategies in a proposed algorithm. Conclusion: For those LG-NMIBC patients in challenging scenarios, we have found repeated TURBTs, chemoablation, BCG immunoablation, partial cystectomy, radical cystectomy, radiotherapy, and chemotherapy are attractive modalities to treat them effectively. Also, the current manuscript proposes an algorithm to overcome these challenges.
... Albayrak et al. emphasized the fact that after adjusting for age NLR lost its prognostic value (27). NLR also predicted progression and recurrence in patients with bladder cancer receiving BCG immunotherapy (13,28). Yuk et al. showed that in patients receiving BCG immunotherapy NLR was a good predictor of overall survival but not progression-free survival (29). ...
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Introduction: Transurethral resection of bladder tumor with subsequent BCG immunotherapy is the current gold standard in the treatment of high risk and some medium-risk non-muscle invasive bladder cancer. Clinical factors like stage, grade, age and gender are well-know predictors of progression to muscle-invasive bladder cancer. In recent years novel hematological biomarkers were shown to be independent predictors of progression. This study aimed to evaluate which of these novel markers has the highest prognostic value of progression in patients with bladder cancer receiving BCG immunotherapy. Materials and methods: We retrospectively analyzed the data of 125 patients with non-muscle invasive bladder cancer who received BCG immunotherapy. Of these, 61 progressed to muscle-invasive disease or had high-grade recurrence. These patients were compared with the group who did not progress (n = 64). Clinical data including stage, grade, age, gender, smoking status and observational time was collected. Besides, information on blood count analysis was obtained from ambulatory digital charts. On this basis neutrophil-to-lymphocyte ratio (NLR), platelet-to lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) was counted and compared between groups. Results: NLR, PLR and LMR were shown to be independent prognostic markers of progression in multivariable analysis. The model with stage, grade, age, gender, smoking status and LMR had the highest prognostic values of all models (area under curve [AUC] = 0.756). The cut-off point according to ROC curves for LMR was 3.25. Adding LMR to the baseline model including clinical variables significantly increased area under curve by 0.08 (p = 0.001). NLR and PLR did not increase areas under curve significantly to baseline model. Conclusions: LMR outperformed NLR and PLR for prediction of progression in patients with non-muscle-invasive bladder cancer receiving BCG immunotherapy. LMR, as an easily obtainable biomarker, should be incorporated to the present risk stratification models.
... Racioppi et al. [24] evaluated the response to BCG therapy in 100 high-risk patients with non-muscle-invasive bladder cancer. They showed a positive correlation between the preoperative NLR values and the recurrence and progression. ...
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We aimed to investigate the relationship between the preoperative neutrophil to lymphocyte ratio (NLR) and the postoperative tumor stage and grade in patients with organ confined urothelial bladder cancer. We examined 308 patients who underwent transurethral resection in our clinic. Our study only included patients whose pathology results were organ-confined urothelial bladder cancer. The patients were classified according to tumor stage (Ta, T1, and T2) and tumor grade (Grade 1 and 2, indicating a low-grade; Grade 3, referring to a high-grade). Then each group was compared within itself based on the NLR evaluated before the surgery. A total of 279 cases (90.6%) were male. The mean age, tumor size, neutrophil and lymphocyte counts of the patients were 69.33±10.92 years, 2.99±2.35 cm, 5.36±1.99 K/uL, and 2.23±0.78 K/uL, respectively. Inflammation parameters regarding the cancer stage were as follows: NLR was 2.08, 2.36, and 3.07, for Ta, T1, and T2 tumors respectively. The relationship between T1 and T2 tumors and Ta and T2 tumors was significant (p <0.001, p <0.001). But there was no significant difference between the Ta and T1 tumors (p: 0.142). NLR was 2.07 and 2.78 for low-and high-grade tumors, respectively. These values were statistically significant (p <0.001). We could not statistically correlate between Ta and T1 tumors. However, based on the other positive correlations we have obtained, we think that NLR evaluated before transurethral resection may be a valuable parameter in predicting the operative pathology result.
... According to our findings and previously published data on the role of granulocyte-colony stimulating factor in progression of bladder cancer [22], we suggest that poor cancer differentiation plays a key role in patients with pyuria. Another inflammatory markers were also shown to be associated with prognosis of bladder cancer patients, including neutrophil-tolymphocyte ratio or C-reactive protein [23][24][25][26][27][28]. Strengths of our study is a multicenter patient enrollment and representative population. ...
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Introduction: Preoperative identification of high-grade bladder cancer presence can optimize patient management. The aim of this study was to assess the association between preoperative pyuria and the pathological features of bladder cancer. Material and methods: This retrospective analysis enrolled 943 patients undergoing transurethral resection of a bladder tumor. Patients were divided into two study groups based on the presence of pyuria in preoperative urine analysis, defined as the presence of >5 leukocytes in the high power field. Pyuria status as a potential predictive factor was then confronted with pathological features based on standard microscopic examination of the surgical specimen. Results: Among 943 recruited patients, 294 (31.2%) presented with pyuria. Patients with pyuria were older (71 vs. 68 years, p <0.05), had higher rates of large (≥3 cm) tumors (37% vs. 26%, p <0.05), and more frequently presented concomitant hematuria (58% vs. 24%, p <0.05). In case of recurrent tumors patients with pyuria more often received intravesical chemotherapy in the past (4.8% vs. 1.4%, p <0.05). Regarding oncological data, patients with pyuria had significantly higher tumor stage and grade. On multivariable analysis pyuria was independently associated with high-grade tumors (OR 1.97, 95% CI 1.45-2.67). Specificity and negative predictive value of pyuria as a biomarker of high-grade tumors were 76% and 68%, respectively. Conclusions: Preoperative pyuria can be regarded as a predictor of the presence of high-grade bladder carcinoma in patients with bladder tumors.
... Ferro et al. [19] demonstrated that NLR was a predictor of residual HG disease at re-TURB at univariate but not at multivariate analysis. Racioppi et al. [20] reported that higher preoperative NLR could be predictive of poor BCG response in multivariate analysis. ...
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Objectives: To evaluate the impact of pre- and post-treatment systemic inflammatory markers on the response to Hyperthermic IntraVEsical Chemotherapy (HIVEC) treatment in a cohort of patients with high-grade non-muscle-invasive bladder cancer with bacillus Calmette–Guérin (BCG) failure or intolerance who were unsuitable or unwilling to undergo early radical cystectomy. As a secondary endpoint, we assessed the influence of some demographic, clinical and pathological factors on the response to chemo-hyperthermia. Patients and methods: Between March 2017 and December 2019, 72 consecutive patients were retrospectively analysed. Patients with diseases or conditions that could interfere with systemic inflammatory status or full blood count were excluded. The HIVEC protocol consisted of six weekly intravesical treatments with 40 mg Mitomycin-C diluted in 50 mL distilled water. The drug was heated to a temperature of 43°C. Association of categorical variables with response to HIVEC was evaluated using Yates’ chi-squared test and differences in continuous variable were analysed using the Mann–Whitney test. Logistic regression analysis was performed to define independent predictors of response to HIVEC. Results: Patients who failed HIVEC were more likely to have multiple tumours (P = 0.039) at transurethral resection of bladder and a recurrence rate of >1/year (P = 0.046). Lower post-HIVEC inflammatory indices [C-reactive protein (P = 0.021), erythrocyte sedimentation rate (P = 0.027)] and lower pre- (P = 0.014) and post-treatment (P = 0.004) neutrophil-to-lymphocyte ratio (NLR) values were significantly associated with the response to the HIVEC regimen (no bladder cancer recurrence or progression). In the multivariate analysis, patients with a recurrence rate of >1/year were eight-times more likely to experience failure of HIVEC (P = 0.007). Higher pre- (P = 0.023) and post-treatment NLR values (P = 0.046) were associated with a worse response to the HIVEC regimen. Conclusions: The recurrence rate and systemic inflammatory response markers could be useful tools to predict the likelihood of obtaining a response with the HIVEC regimen. These markers might help to guide patients about the behaviour of the tumour after BCG failure, predicting failure or success of a conservative treatment.
Introduction . Transurethral resection of bladder tumor (TURBT) is the gold standard treatment for patients with non-muscle invasive bladder cancer (NMIBC). However, the high recurrence rate after TURBT makes necessary not only regular following to reveal recurrence disease timely, but it also talks about a necessity of adjuvant antitumor therapy in some cases, that allows to prevent disease recurrence and progression. In this regard, patients belonging to high- and sometimes intermediate- risk progression groups are shown to undergo postoperative adjuvant intravesical Bacillus Calmette–Guérin (BCG) therapy. Despite the long experience of using BCG therapy for NMIBC treatment the question of the existence of possible prognostic markers and response predictors to intravesical BCG therapy remains open. Objective . To review cutting-edge data on different markers that can be used as predictive response markers to ongoing intravesical BCG therapy in NMIBC-patients. Materials and methods . A literature search was conducted using PubMed/ Medline and Google Scholar databases. We used terms 'bladder cancer', 'non-muscle-invasive bladder cancer' in conjunction with 'recurrence', 'progression', 'BCG', 'intravesical therapy', 'immune response', 'molecular markers' to choose relevant articles published between 2000 and 2022. Results . Clinical and pathological characteristics of the tumor and the patient himself remain leading in predicting the response to intravesical BCG therapy in NMIBC-patients. However, to improve the effectiveness of assessing the risk of developing adverse BC outcomes and choosing the most appropriate strategy for monitoring and treatment in each case, it is necessary to introduce additional assessment parameters. Molecular and genetic markers could be considered as such parameters, make it possible to reveal differences between tumors at a deeper level. Conclusion . Currently, there are no markers that have high-evidence in predicting response to intravesical BCG therapy in NMIBC-patients compared with the cliniсal and pathological characteristics of the tumor and the patient himself. The clearer awareness of molecular genetic pathways of BC pathogenesis, the mechanism of BCG antitumor effect will make it possible to competently select markers that have the highest specificity for BC, which will increase the predictive ability of currently existing tools to assess the risks of BC recurrence and progression.
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Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.
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Objective Recent studies have demonstrated the role of systemic inflammation in the development and progression of cancer. In this study, we evaluated whether preoperatively measured neutrophil-to-lymphocyte ratio (NLR) can predict lamina propria invasion in patients with non-muscle-invasive bladder cancer (NMIBC). Material and Methods We reviewed the medical records of 304 consecutive and newly diagnosed patients with bladder cancer who had been treated with transurethral resection between January 2008 and June 2014. In total, 271 patients were included in the study and the patients were divided into two groups according to the pathological stage (Group 1: Ta, Group 2: T1). NLR was calculated by dividing the absolute neutrophil count (N) by the absolute lymphocyte count (L). Results In total, 271 patients (27 women and 244 men) were enrolled. Mean age was higher in Group 2 than in Group 1 (67.3±10.8 vs. 62.9±10.8, p<0.001). Furthermore, the presence of high grade tumors and tumors ≥3cm in size was statistically higher in Group 2 than in Group 1 (70.9% vs. 9.9%, p=0.0001; 71.8% vs. 36%, p=0.0001, respectively). While the mean white blood cell (WBC) and N counts were statistically insignificant (7.63±1.87 vs. 7.69±1.93, p=0.780; 4.72±1.54 vs. 4.46±1.38, p=0.140; respectively), L was significantly lower and NLR was significantly higher in Group 2 than in Group 1 (2.07±0.75 vs. 2.4±0.87, p=0.001; 2.62±1.5 vs. 2.19±1.62, p=0.029; respectively). Conclusion Our data indicate that high NLR and low L are statistically associated with T1 stage, whereas low L are able to predict lamina propria invasion in patients with NMIBC. These findings suggest that pretreatment measurement of NLR may provide valuable information for the clinical management of patients with NMIBC. Prospective studies are now required to further validate the role of NLR as a risk factor in NMIBC.
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IMPORTANCE Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. OBJECTIVE To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. EVIDENCE REVIEW Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results. FINDINGS In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (−6.1% [95% uncertainty interval (UI), −10.6% to −1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant. CONCLUSION AND RELEVANCE As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.
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Background: Bladder cancer represents one of the most important clinical challenges in urologic practice. In this context, inflammation has an important role in the development and progression of many malignancies. The objective of the present study was to evaluate the prognostic value of pre-treatment Neutrophil to lymphocyte ratio (NLR) on the risk of recurrence and progression in patients with primary non-muscle invasive bladder cancer. Materials and methods: Data obtained from 178 bladder cancer patients who underwent transurethral resection of bladder tumor (TURB) between July 2008 and December 2014 were evaluated prospectively. NLR was obtained from each patient before TURB and defined as the absolute neutrophil count divided by the absolute lymphocyte count. Cox proportional hazards regression model was performed to calculate disease recurrence and progression including NLR. Results: During the follow-up study (median: 53 months), 14 (23.3%) and 44 (37.9%) (p=0.04) patients respectively with NLR<3 and ≥3experienced recurrence and 2 (3.3%) and 14 (11.9%) experienced progression (p=0.06), respectively. At the multivariate Cox regression analysis, NLR ≥3 was associated with worse disease recurrence (HR: 2.84; p<0.01). No association was found regarding disease progression. The 5-year recurrence free survival was 49% and 62% in patients with NLR≥3 and <3 (p<0.01). The 5-year progression free survival was 77% and 93% in patients with NLR≥3 and <3 (p=0.69). Conclusion: NLR predicts disease recurrence but not disease progression in NMIBC patients. NLR alterations may depend of tumor inflammatory microenvironment.
Context: The European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial Carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice. Objective: To provide an overview of the EAU guidelines on UTUC as an aid to clinicians. Evidence acquisition: The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; ureteroscopy; nephroureterectomy; adjuvant treatment; instillation; recurrence; risk factors; and survival. References were weighted by a panel of experts. Evidence synthesis: Owing to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing number of retrospective articles in UTUC. The 2017 tumour, node, metastasis (TNM) classification is recommended. Recommendations are given for diagnosis and risk stratification, as well as for radical and conservative treatment; prognostic factors are also discussed. A single postoperative dose of intravesical mitomycin after radical nephroureterectomy reduces the risk of bladder tumour recurrence. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk tumours and two functional kidneys. Conclusions: These guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours. Patient summary: Urothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis; appropriate diagnosis and management is most important. We present recommendations based on current evidence for optimal management.
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 non-muscle-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 = .01) and 94.9% versus 89.9% (P = .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.
Introduction: The present study investigated the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) in bladder cancer patients undergoing radical cystectomy (RC), with a focus on the conditional survival (CS) estimates over time after surgery. Materials and methods: We analyzed 385 bladder cancer patients who underwent RC from 1999 to 2012. The patients were classified into 2 groups according to the preoperative NLR (< 2.5 vs. ≥ 2.5). The Kaplan-Meier survival analysis was used to calculate the conditional probabilities of cancer-specific survival and overall survival after surgery. Multivariate Cox regression models were used to identify the predictors of 5-year conditional cancer-specific survival and overall survival. Results: Patients with an elevated preoperative NLR (≥ 2.5) had a greater proportion of advanced-stage tumors (≥ pT3), high-grade tumors, and lymphovascular invasion. Patients with an elevated preoperative NLR (≥ 2.5) had poor CS estimates compared with those with a lower NLR (< 2.5) at baseline and 1 year after RC. However, no significant differences in CS probabilities were observed from 2 years after RC onward. In a multivariate Cox regression analysis, the preoperative NLR was identified as a significant predictive factor for 5-year CS at baseline and postoperative 1-year estimation; however, its significance was lost after 2 years postoperatively. Conclusion: Our study results suggest that the dynamic aspect of the NLR should be considered when assessing the prognosis of bladder cancer patients treated with RC over time after the initial estimates, in particular, in patients who have already survived for additional years after surgery.
Background: The neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein (CRP) are markers of systemic inflammatory response, which have been associated with the prognosis of multiple malignancies, but their relationships with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) have not been well studied yet. Patients and methods: We retrospectively reviewed the medical records of 1,117 patients with NMIBC who underwent a transurethral resection of the bladder. Univariable and multivariable competing risk regression models were used to assess the association of preoperative NLR and CRP with disease recurrence and progression to muscle-invasive disease. The median follow-up was 64 months. Results: In total, 360 patients (32.2%) had a high NLR (≥2.5) and 145 (13.0%) had a high CRP (≥5mg/l). On multivariable analyses, a high NLR was associated with both disease recurrence (subhazard ratio [SHR] = 1.27, P = 0.013) and progression (SHR = 1.72, P = 0.007), and high CRP was associated with disease progression (SHR = 1.72, P = 0.031). Adding NLR and CRP to the multivariable model predicting disease progression lead to a relevant change in discrimination (+2.0%). In a subgroup analysis of 300 patients treated with bacillus Calmette-Guerin, both high NLR and high CRP were associated with disease progression (SHR = 2.80, P = 0.026 and SHR = 3.51, P = 0.021, respectively), and NLR was associated with disease recurrence (SHR = 1.46, P = 0.046). There was also an increase in the discrimination of the model predicting progression after bacillus Calmette-Guerin following the inclusion of both markers (+2.4%). Conclusion: In patients with NMIBC, markers of systemic inflammation response are associated with disease recurrence and progression. The inclusion of such markers in prognostic models does enhance their accuracy.
Context: Bladder cancer has become a common cancer globally, with an estimated 430 000 new cases diagnosed in 2012. Objective: We examine the most recent global bladder cancer incidence and mortality patterns and trends, the current understanding of the aetiology of the disease, and specific issues that may influence the registration and reporting of bladder cancer. Evidence acquisition: Global bladder cancer incidence and mortality statistics are based on data from the International Agency for Research on Cancer and the World Health Organisation (Cancer Incidence in Five Continents, GLOBOCAN, and the World Health Organisation Mortality). Evidence synthesis: Bladder cancer ranks as the ninth most frequently-diagnosed cancer worldwide, with the highest incidence rates observed in men in Southern and Western Europe, North America, as well in certain countries in Northern Africa or Western Asia. Incidence rates are consistently lower in women than men, although sex differences varied greatly between countries. Diverging incidence trends were also observed by sex in many countries, with stabilising or declining rates in men but some increasing trends seen for women. Bladder cancer ranks 13th in terms of deaths ranks, with mortality rates decreasing particularly in the most developed countries; the exceptions are countries undergoing rapid economic transition, including in Central and South America, some central, southern, and eastern European countries, and the Baltic countries. Conclusions: The observed patterns and trends of bladder cancer incidence worldwide appear to reflect the prevalence of tobacco smoking, although infection with Schistosoma haematobium and other risk factors are major causes in selected populations. Differences in coding and registration practices need to be considered when comparing bladder cancer statistics geographically or over time. Patient summary: The main risk factor for bladder cancer is tobacco smoking. The observed patterns and trends of bladder cancer incidence worldwide appear to reflect the prevalence of tobacco smoking.
Context: The European Association of Urology (EAU) panel on Non-muscle-invasive Bladder Cancer (NMIBC) released an updated version of the guidelines on Non-muscle-invasive Bladder Cancer. Objective: To present the 2016 EAU guidelines on NMIBC. Evidence acquisition: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines published between April 1, 2014, and May 31, 2015, was performed. Databases covered by the search included Medline, Embase, and the Cochrane Libraries. Previous guidelines were updated, and levels of evidence and grades of recommendation were assigned. Evidence synthesis: Tumours staged as TaT1 or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection of the bladder (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis. If the initial resection is incomplete, there is no muscle in the specimen, or a high-grade or T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour and intermediate-risk patients at a lower risk of recurrence, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy (RC) should be considered. RC is recommended in BCG-refractory tumours. The long version of the guidelines is available at the EAU Web site ( Conclusions: These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary: The European Association of Urology has released updated guidelines on Non-muscle-invasive Bladder Cancer (NMIBC). Stratification of patients into low-, intermediate-, and high-risk groups is essential for decisions about adjuvant intravesical instillations. Risk tables can be used to estimate risks of recurrence and progression. Radical cystectomy should be considered only in case of failure of instillations or in NMIBC with the highest risk of progression.