Low Pretreatment Neutrophil-to-Lymphocyte Ratio Predicts for Good Outcomes in Patients Receiving Neoadjuvant Chemotherapy Before Radical Cystectomy for Muscle Invasive Bladder Cancer

Abstract

Purpose

The pretreatment neutrophil-to-lymphocyte ratio (NLR) has been associated with cancer prognosis, influencing progression and chemosensitivity. We aimed to define the role of the NLR in predicting the outcomes to neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC).

Patients and Methods

The data from patients treated with NAC and radical cystectomy for MIBC from 2007 to 2015 at a tertiary care center were reviewed. The clinicopathologic pretreatment, including the NLR, and post-treatment predictors were documented. The NLR was evaluated as a continuous variable on uni- and multivariate analysis and dichotomized in Kaplan-Meier curves. The relationships with outcomes (progression-free survival [PFS], cancer-specific survival [CSS], and overall survival [OS]) were analyzed using Cox regression analysis and log-rank tests. The pathologic response (PR) included any downstaging from the baseline clinical stage to the final pathologic stage.

Results

Of 205 patients with MIBC, 75 underwent NAC (median follow-up, 31 months) with a 5-year PFS, CSS, and OS rate of 56%, 60%, and 52%, respectively, and a PR of 38.6%. On multivariate analysis, the PR, PFS, CSS, and OS were predicted by the NLR (hazard ratio > 0.8, 1.25, 1.27, and 1.12, respectively; P < .05 for all). The NLR with age and clinical stage predicted the PR. A NLR threshold of 2.26 better predicted CSS (P < .05) and OS (P = .055). The limitations included the retrospective design and modest number of cases.

Conclusion

We have provided initial evidence that a low NLR helps understand the value of the underlying immune system in predicting a good outcome to NAC. The NLR is a simple and accessible biomarker that is easy to implement in clinical practice. In addition to established prognosticators and newer genomic predictors, the NLR could improve therapeutic algorithms and help in decision-making regarding the need for NAC, which is currently underused, in MIBC patients.

Introduction

The initial treatment for most patients with muscle invasive bladder cancer (MIBC) consists of localized therapy, mainly radical cystectomy (RC), but many patients experience relapse, likely from micrometastases present at surgery.¹ Therefore, consensus guidelines have recommended cisplatin-based neoadjuvant chemotherapy (NAC), followed by RC, as standard treatment.2, 3 The addition of NAC, however, only results in an increased overall survival benefit of 5%.⁴ Because of this limited benefit and the potential toxicity, NAC has remained underused.⁵ The use of NAC has been further impaired by the lack of validated methods to predict the response. Although more robust evidence is available for the use of NAC than for the use of adjuvant chemotherapy for MIBC, multiple post-RC nomograms are available to identify patients who might benefit from adjuvant therapy.6, 7, 8 This is because most prediction models include pathologic features found in RC specimens. In contrast, in the prelocalized treatment setting, little information is available for risk stratification. Thus, the indication for NAC is currently determined using a risk-adapted approach that relies on clinicopathologic parameters.⁹

Identifying biologic pretreatment factors to improve pre-RC risk stratification and predict chemotherapy benefit would contribute to the development of better nomograms for this setting.¹⁰ Recent genomic studies have provided data informing about the value of mutations in DNA repair genes to predict the response to cisplatin-based chemotherapy in the neoadjuvant setting.11, 12 The prospectively designed Co-expression Extrapolation (COXEN; program to predict chemotherapy response in patients with bladder cancer) trial¹³ will provide additional value of genomic surrogates, and the MD Anderson Cancer Center has recently reported a potential link between the chemotherapy response and the basal genotype.¹⁴ Also, the relevance of the immune system has emerged with the appearance of effective immunotherapy for MIBC.15, 16 However, our understanding of the contributing factors to good outcomes to NAC is still incomplete. The correlation between the findings in peripheral blood samples and the expression signatures in tumors has not yet been explored but could be of high interest.

The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an easily available, reproducible, and inexpensive marker of systemic inflammation that has lately been linked to prognosis across multiple tumor types. A high NLR, reflecting an increased inflammatory response (dependent on neutrophils) and a suboptimal lymphocyte-mediated antitumor immune response, has been associated with decreased OS in patients with MIBC.17, 18, 19 We hypothesized that lower NLRs might be related to an increased response to NAC in MIBC. To address this, we analyzed the pretreatment NLRs in our series of RC patients who had undergone NAC.