Review Article
Prognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non–muscle-invasive bladder cancer (NMIBC): A systematic review and meta-analysis

https://doi.org/10.1016/j.urolonc.2018.05.014Get rights and content

Highlights

  • NLR was associated with disease recurrence and progression in NMIBC.

  • NLR predicted disease recurrence and progression in BCG treated patients.

  • NLR could be used to improve clinical decision-making.

Abstract

Objective

The aim of this study was to summarize and analyze the current evidence regarding the prognostic and predictive value of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients undergoing transurethral resection of bladder tumors (TURBT) for non–muscle-invasive bladder cancer (NMIBC).

Material and methods

A systematic search of Web of Science, Medline/PubMed, Google Scholar, and Cochrane library was performed on the 1st of March, 2018. Studies were deemed eligible if they compared NMIBC patients with high vs. low NLR before TURBT to determine its value for prognosticating disease recurrence and progression using multivariable analysis. We performed a formal meta-analysis for both recurrence-free (RFS) and progression-free survival (PFS).

Results

Six studies encompassing 2,298 patients (477 [20.7%] females) assessed the prognostic value of NLR in NMIBC patients treated with TURBT. NLR predicted worse RFS (pooled HR = 1.78; 95% CI: 1.32–2.4, P<0.001) and PFS (pooled HR = 2.14; 95% CI: 1.59–2.87, P<0.001). In 4 studies encompassing 599 patients, high pretreatment NLR was associated with decreased RFS (pooled HR = 2.31; 95% CI: 1.27–4.22, P = 0.006) and in 3 of them high pretreatment NLR was associated with decreased PFS (pooled HR = 2.54; 95% CI: 1.36–4.71, P = 0.003) in high-risk NMIBC patients treated with BCG.

Conclusion

In this meta-analysis, peripheral blood levels of NLR were associated with an increased risk of disease recurrence and progression in patients who underwent TURBT for NMIBC. Furthermore, NLR was an independent predictor of disease recurrence and progression in NMIBC treated with BCG patients. NLR could be used to improve clinical decision-making regarding treatment and follow-up scheduling.

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)

  • G. Sonpavde et al.

    Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer

    Clin Genitourin Cancer

    (2014)
  • S.F. Shariat et al.

    Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

    Mod Pathol

    (2007)
  • M.R. Galdiero et al.

    Tumor associated macrophages and neutrophils in cancer

    Immunobiology

    (2013)
  • Z.G. Fridlender et al.

    Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN

    Cancer Cell

    (2009)
  • S.F. Shariat et al.

    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

    (2005)
  • K. Bensalah et al.

    Challenges of cancer biomarker profiling

    Eur Urol

    (2007)
  • R.L. Siegel et al.

    Cancer statistics, 2018

    CA Cancer J Clin

    (2018)
  • E. Xylinas et al.

    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

    (2013)
  • H. Fajkovic et al.

    Impact of gender on bladder cancer incidence, staging, and prognosis

    World J Urol

    (2011)
  • D. D Andrea et al.

    Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: a clinical decision-making tool

    Urol Oncol

    (2018)
  • R.J. Sylvester et al.

    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

    (2006)
  • M.D. Vartolomei et al.

    Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients

    World J Urol

    (2018)
  • X. Tang et al.

    The clinical use of neutrophil-to-lymphocyte ratio in bladder cancer patients: a systematic review and meta-analysis

    Int J Clin Oncol

    (2017)
  • Cited by (78)

    • Role of Serum Lymphocyte-derived Biomarkers in Nonmetastatic Muscle-invasive Bladder Cancer Patients Treated with Trimodal Therapy

      2022, European Urology Open Science
      Citation 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].

    View all citing articles on Scopus

    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.

    View full text