Urologic Oncology: Seminars and Original Investigations
Review ArticlePrognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non–muscle-invasive bladder cancer (NMIBC): A systematic review and meta-analysis☆
Introduction
Bladder cancer (BC) is a highly prevalent disease affecting an estimated 81,190 new cases in 2018 and resulting in the demise of 17,240 in the US only [1]. Worldwide these numbers are estimated to more than 400,000 new cases and 165,000 deaths yearly [2], [3]. Approximately, 75% of patients diagnosed with BC present with non–muscle-invasive (NMIBC) disease in western countries [3], [4]. Transurethral resection of the bladder tumors (TURBT) followed by adjuvant intravesical instillation therapy is the therapeutic standard of care for NMIBC [5], [6]. To improve personalized care, prognostic models have been developed to help in the daily clinical decision-making. These models are based on standard clinico-pathological features such as T stage, grade, multifocality, sex, tumor diameter, recurrence rate, and concomitant carcinoma in situ [7], [8], [9]. Despite efforts, the predictive accuracy of these models is suboptimal for care delivery [10].
The role of inflammation in cancer is studied increasingly, to help uncover mechanisms of carcinogenesis, resistance, and progression/metastasis [11]. Among prognostic inflammation markers the neutrophil-to-lymphocyte ratio (NLR) is the most widely studied [12]. A recent meta-analysis supported the negative prognostic effect of high pretreatment NLR on outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy [13]. Similarly, in BC, preoperative NLR was found to be associated with disease recurrence-free (RFS) (hazard ratio, HR = 1.58) and progression-free survival (PFS) (HR = 1.33) in a recent meta-analysis that included 4 studies with NMIBC and 14 with muscle-invasive bladder cancer (MIBC) patients [14].
High-grade T1 (HGT1) represents a subtype of NMIBC with an increased risk of recurrence and progression [15]. The standard treatment of patients with HGT1 considered for bladder preservation is a re-TURBT followed by adjuvant intravesical Bacillus Calmette Guerin (BCG) therapy with maintenance [5], [16]. However, up to 40% of patients with HGT1 will experience disease recurrence within 5 years after treatment [16]. Altered markers of systemic inflammation such as NLR may influence BCG therapy as its effect depends on an intact immune system [17].
To date, no meta-analysis assessed the effect of pre-TURBT NLR on outcomes of NMIBC patients. Thus, the aim of this study was to summarize and analyze the current evidence regarding the prognostic and predictive significance of preoperative NLR in patients undergoing TURBT for NMIBC.
Section snippets
Protocol
The protocol has been registered in the International Prospective Register of Systematic Reviews database (PROSPERO: CRD42018089304). A systematic search of Web of Science, Medline/PubMed, Google Scholar, and Cochrane library was performed using the terms [NLR OR (neutrophil-to-lymphocyte ratio)] AND [(bladder cancer) BC OR (non-muscle invasive bladder cancer) NMIBC] on 1st March 2018.
Inclusion and exclusion criteria
The PICOS (Population, Intervention, Comparator, Outcome and Study design) approach was used to define study
Evidence synthesis
Three hundred and five abstracts and titles were initially identified. After removal of duplicates, reviews, and conference abstracts, 101 full-text original articles were assessed. Ten studies were included for final evaluation with 9 of them being deemed fully eligible [21], [22], [23], [24], [25], [26], [27], [28], [29]. The PRISMA flow chart summarizing the process of study selection is shown in Fig. 1.
Six studies (a total of 2,298 patients with 20.7% females) assessed the importance of NLR
Preoperative NLR as a predictor for disease recurrence
Five of the 6 studies found that high preoperative NLR was independently associated with disease recurrence after TURBT. High preoperative NLR predicted worse RFS with a pooled HR of 1.78 (95% CI: 1.32–2.4, P<0.001) in multivariable analysis (Fig. 2). The Cochrane Q test (χ2 = 14.1; P = 0.014) and I2 test (I2 = 64.7%) revealed a significant heterogeneity. The funnel polts identified 2 studies over the pseudo 95% CI (Fig. 3A). In patients with high-risk NMIBC treated with BCG, high preoperative
Preoperative NLR as predictor for disease progression
Two of the 6 studies failed to show an association between high preoperative NLR and disease progression after TURBT. High preoperative NLR predicted poor PFS; the pooled HR was 2.14 (95% CI: 1.59–2.87, P<0.001) in multivariable analysis (Fig. 5). The Cochrane Q test (χ2 = 4.28; P = 0.5) and I2 test (I2 = 0%) did not detect significant heterogeneity. The funnel plots identified all studies to be within the pseudo 95% CI (Fig. 3C). In patients with high-risk NMIBC treated with BCG, high
Discussion
In this meta-analysis, pretreatment blood-based NLR was associated with an increased risk of disease recurrence and progression in patients with NMIBC who underwent TURBT followed by intravesical therapy. Similarly, in MIBC and in NMIBC (4 studies), pretreatment NLR was shown to be predictive of RFS and PFS in a recent meta-analysis [14]. Although is important the prediction of RFS and PFS in MIBC, identification of NMIBC patients who are at risk of developing disease recurrence and progression
Conclusion
Pre-TURBT NLR is associated with an increased risk of disease recurrence and progression in patients with NMIBC. Moreover, it is an independent predictor of disease recurrence and progression in patients treated with BCG for high-risk NMIBC. Pre-TURBT NLR could be a useful blood-based biomarker to improve patients’ risk-stratification facilitating clinical decision-making regarding therapy and follow-up scheduling.
Author’s contribution
Protocol/project development: M.D. Vartolomei, D. Porav Hodade, M. Ferro, R. Mathieu, M. Abufaraj, B. Foerster, S. Kimura, and S.F. Shariat.
Data collection or management: M.D. Vartolomei, D. Porav Hodade, M. Ferro, R. Mathieu, M. Abufaraj, B. Foerster, S. Kimura, and S.F. Shariat.
Manuscript writing/editing: M.D. Vartolomei, D. Porav Hodade, M. Ferro, R. Mathieu, M. Abufaraj, B. Foerster, S. Kimura, and S.F. Shariat.
References (46)
- et al.
Bladder cancer incidence and mortality: a global overview and recent trends
Eur Urol
(2017) - et al.
ICUD-EAU international consultation on bladder cancer 2012: screening, diagnosis, and molecular markers
Eur Urol
(2013) - et al.
Epidemiology and risk factors of urothelial bladder cancer
Eur Urol
(2013) - et al.
EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016
Eur Urol
(2017) - et al.
Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline
J Urol
(2016) - et al.
Cancer-related inflammation and treatment effectiveness
Lancet Oncol
(2014) - et al.
European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2017 update
Eur Urol
(2018) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Int J Surg Lond Engl
(2010) - et al.
Prognostic and prediction tools in bladder cancer: a comprehensive review of the literature
Eur Urol
(2015) - et al.
Prognostic value of neutrophil-to-lymphocyte ratio in advanced oesophago-gastric cancer: exploratory analysis of the REAL-2 trial
Ann Oncol
(2016)
Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer
Clin Genitourin Cancer
Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness
Mod Pathol
Tumor associated macrophages and neutrophils in cancer
Immunobiology
Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN
Cancer Cell
Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder
J Urol
Challenges of cancer biomarker profiling
Eur Urol
Cancer statistics, 2018
CA Cancer J Clin
Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder
Br J Cancer
Impact of gender on bladder cancer incidence, staging, and prognosis
World J Urol
Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: a clinical decision-making tool
Urol Oncol
Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials
Eur Urol
Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients
World J Urol
The clinical use of neutrophil-to-lymphocyte ratio in bladder cancer patients: a systematic review and meta-analysis
Int J Clin Oncol
Cited by (78)
Circulating Basophils as a Prognostic Marker for Response to Bacillus Calmette-Guérin
2024, Clinical Genitourinary CancerRole of Serum Lymphocyte-derived Biomarkers in Nonmetastatic Muscle-invasive Bladder Cancer Patients Treated with Trimodal Therapy
2022, European Urology Open ScienceCitation Excerpt :Furthermore, an increase in NLR of ≥75% during TMT (post-NLR being ≥1.75 times than pre-NLR) was found to be prognostic for worse OS. Previous meta-analyses on retrospective data have consistently shown the prognostic value of the NLR in both the non–muscle-invasive and the metastatic setting [3,12–15]. Specifically for nonmetastatic MIBC, most studies on NLR included patients treated with RC [16–18].
Pan-immune-inflammation value as a prognostic tool for overall survival and disease-free survival in non-metastatic muscle-invasive bladder cancer
2024, International Urology and NephrologyMetabolomic Biomarkers for Prognosis in Non-Muscle Invasive Bladder Cancer: A Comprehensive Systematic Review and Meta-Analysis
2024, Indian Journal of Clinical Biochemistry
- ☆
M.D.V. had a EUSP laboratory/clinical fellowship awarded by EAU (European Association of Urology) and an Ernst Mach Grant awarded by OeAD, Austria.
- 1
Equal contribution as first author.