Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study

doi:10.1016/j.clgc.2016.10.013

Clinical Genitourinary Cancer

Volume 15, Issue 3, June 2017, Pages e469-e476

https://doi.org/10.1016/j.clgc.2016.10.013 Get rights and content

Abstract

Background

A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and is associated with poor survival in localized or metastatic cancer. This study assessed the prognostic value of NLR after first-line chemotherapy (CT) in patients with metastatic urothelial carcinoma (mUC).

Patients and Methods

Two hundred eighty consecutive patients treated with first-line platinum-based CT at 4 centers in France and Turkey between 2002 and 2014 were included. The association of NLR and Memorial Sloan Kettering Cancer Center (MSKCC) scores with overall survival (OS) and progression-free survival (PFS) was determined by univariate Cox models.

Results

Median OS was 10.6 months (follow-up, 42.8 months). In univariate analysis, high NLR was associated with worse OS (hazard ratio [HR] for death = 1.36; 95% confidence interval [CI], 1.23-1.51; P < .0001); the result was similar after adjustment for MSKCC prognostic group (HR = 1.28; 95% CI, 1.14-1.43; P < .0001). Low NLR was associated with longer PFS (HR = 1.18; 95% CI, 1.05-1.33; P < .005). When NLR was divided in terciles, OS in the lowest tercile (NLR 0.6-2.78) was 12.4 to 16.6 (median, 13.4) months versus 5.3 to 9.9 (median, 7.3) months in the highest tercile (NLR 4.70-48.9) (P = .001). Similar trends were observed for PFS (5.6-8.9 [median, 7.6] months vs. 3.1-5.7 [median, 4.8] months) in patients with NLR values in the lowest versus highest tercile, respectively (P = .021).

Conclusion

High pre-CT NLR was an independent prognostic factor for poor OS and PFS in mUC patients. The prognostic value of NLR, as either a continuous or categorical variable, compared favorably with MSKCC score but was easier to assess and monitor.

Introduction

Platinum-based chemotherapy (CT) is the standard of care for first-line treatment of metastatic urothelial cancer (mUC).1, 2, 3 Overall survival (OS) ranges from 14 to 15.2 months for patients receiving cisplatin-based CT¹ and averages 9.8 months for those receiving carboplatin-based CT,⁴ although there is some heterogeneity between patients with respect to objective response rate and outcome.

The Memorial Sloan Kettering Cancer Center (MSKCC) risk score model is used in clinical practice to predict OS for mUC patients treated with platinum-based CT.⁵ This score is based on 2 prognostic factors: visceral (lung, liver, or bone) metastases and a Karnofsky performance status of < 80%, and it defines 3 prognostic groups (0, 1, or 2 poor prognostic factors). Several studies have investigated approaches to improve the predictive value of prognostic scores. A 4-variable model including hemoglobin levels below normal (< 11.5 g/dL in women and < 13 g/dL in men) and albumin was superior to the MSKCC risk score model.⁶ A 5-variable model has also been investigated that predicts the probability of OS at 1, 2 and 5 years on the basis of primary tumor site, number of visceral metastatic sites, presence of lymph node metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), and leukocyte count.⁷

Other approaches to predicting risk are based on assessment of systemic inflammation, which is widely recognized as playing an important role in tumorogenesis.⁸ A high neutrophil-to-lymphocyte ratio (NLR), used as a simple biomarker of systemic inflammatory response, has been identified as a predictor of poor outcome⁹ in patients with a variety of tumor types, including metastatic lung cancer, breast cancer, or metastatic colorectal cancer10, 11, 12, 13 and urinary cancers including prostate cancer, renal-cell cancer, and bladder cancer.14, 15, 16, 17 In urothelial bladder cancer patients who underwent radical cystectomy for nonmetastatic disease, pretreatment NLR, or lymphocyte-to-monocyte ratio,¹⁸ has been shown to be a prognostic factor and is associated with poor OS, recurrence-free survival, and cancer-specific survival.19, 20, 21 A retrospective study including 26 patients showed that a sustained decrease in NLR before and after neoadjuvant CT was associated with pathologic response, suggesting a link between a reduction in the inflammatory environment and outcome.²²

This study assessed the prognostic value of pretreatment NLR in mUC patients who had undergone first-line platinum-based CT.

Section snippets

Patients

All consecutive patients with histologically confirmed carcinoma of the urinary tract who received first-line platinum-based CT for metastatic disease from 2002 to 2014 at 3 centers in France (Georges Pompidou Hospital, Paris; Saint-Louis Hospital, Paris; La Louvière Private Hospital, Lille) and one in Turkey (Cerrahpaşa Medical Faculty, Istanbul) were included. Most of the fit patients received CT with cisplatin and gemcitabine or methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC),

Patients

A total of 280 mUC patients were evaluated. Patients were older (median age, 65 years), the majority were men, and the primary tumor site was the bladder in 241 patients (86.1%). Full details of patient demographic, clinical, and pathologic data at baseline are shown in Table 1. First-line CT was based on cisplatin in 170 patients (58%) and carboplatin in 123 patients (42%). Median NLR was 3.8 (range, 0.6-48.9), with distribution shown in Figure 1.

Survival

A total of 234 of 280 patients died. Median

Discussion

The results of this study showed that pre-CT NLR was an independent prognostic predictor of OS and PFS in mUC patients. As has been seen in patients with early-stage bladder cancer, pre-CT NLR was significantly correlated with PFS and OS in mUC patients who had received first-line CT. Marked and significant differences in OS were seen between patients with NLR values in the first (lowest) and third (highest) terciles of NLR.

Our results in a large white population support those of previous

Conclusion

The results of this study showed that pre-CT NLR was an independent prognostic predictor of OS and PFS in mUC patients. These results highlight the importance of an inflammatory cancer-related microenvironment and strengthen the necessity to review the decision of a specific treatment, taking into account, in particular, the tumor microenvironment, molecular subtypes, and immune response to offer the best treatment to each patient.

Disclosure

The authors have stated that they have no conflict of interest.

Acknowledgment

English-language editing assistance was provided by Nicola Ryan, independent medical writer.

References (31)

L. Dogliotti et al.
Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial
Eur Urol
(2007)
G.J. Guthrie et al.
The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer
Crit Rev Oncol Hematol
(2013)
A. Linton et al.
Glasgow prognostic score as a prognostic factor in metastatic castration-resistant prostate cancer treated with docetaxel-based chemotherapy
Clin Genitourin Cancer
(2013)
B. Cetin et al.
Is the pretreatment neutrophil to lymphocyte ratio an important prognostic parameter in patients with metastatic renal cell carcinoma?
Clin Genitourin Cancer
(2013)
D. Keizman et al.
The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma
Eur J Cancer
(2012)
T. Gondo et al.
Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy
Urology
(2012)
J.A. Seah et al.
Neutrophil-lymphocyte ratio and pathological response to neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer
Clin Genitour Cancer
(2015)
D. Hanahan et al.
Hallmarks of cancer: the next generation
Cell
(2011)
P.F. Ferrucci et al.
Baseline neutrophils and derived neutrophil-to- lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab
Ann Oncol
(2016)
J.E. Rosenberg et al.
Atezolizumab in patients with locally advanced and metastatic urothelial who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial
Lancet
(2016)

W. Choi et al.

Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy

Cancer Cell

(2014)

H. Von der Maase et al.

Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer

J Clin Oncol

(2005)

A. Bamias et al.

The combination of gemcitabine and carboplatin as first-line treatment in patients with advanced urothelial carcinoma. A phase II study of the Hellenic Cooperative Oncology Group

Cancer

(2006)

M. De Santis et al.

Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II results of EORTC study 30986

J Clin Oncol

(2009)

D.F. Bajorin et al.

Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy

J Clin Oncol

(1999)

Cited by (10)

Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy
2018, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Higher ANC:ALC ratio was associated with increased systemic inflammation and associated with poorer outcomes in a variety of tumor subtypes [26,27]. Indeed, higher ANC:ALC ratio has well-documented poor prognostic implications in UC of the bladder and the upper tract [28–30]. The association between circulating MDSCs and ANC:ALC ratio further suggest potential value as a biomarker to identify poor risk patients.
Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored.
Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR−. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR−/CD15+/CD14-, monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR−/CD15−/CD14−. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR).
85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44–87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes.
Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings.
Real-world Outcomes in Advanced Urothelial Cancer and the Role of Neutrophil to Lymphocyte Ratio
2018, Clinical Genitourinary Cancer
Citation Excerpt :
However, no inflammatory biomarkers have been established to date in this clinical setting. Neutrophil to lymphocyte ratio (NLR) – a biomarker index reflective of the systemic inflammatory state of neoplastic process – has been identified as a prognostic indicator of patients with mUC treated in the first line.24,25 Elevated preoperative NLR has been identified to be associated with worse 5-year OS (HR, 1.69; P < .001) and cancer-specific survival outcomes (HR, 1.57; P < .001), contrasted with low preoperative NLR.26
In the first- and second-line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real-world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR).
A retrospective analysis was performed on patients with mUC treated with systemic therapy. Overall response rates (ORRs), median time to treatment failure (mTTF), and median overall survival (mOS) were calculated. The association between baseline NLR (using a literature-derived cut-off of 3, as well as the best cut-off NLR value of 5.45 as identified by X-Tile software from this dataset) and mTTF and mOS were evaluated using Cox regression analysis.
We evaluated 233 patients. In the first-line, the ORR was 25%. mTTF and mOS were 6.9 months and 9.0 months, respectively. Low baseline NLR was significantly associated with improved 8.3-month mTTF, in contrast to 5.8 months for patients with high NLR (P = .046). Low NLR was significantly correlated with a longer mOS of 13.1 months, compared with high NLR (8.2 months; P = .007). In the second-line, an ORR of 22%, an mTTF of 4.1 months, and an mOS of 8 months were observed. Low NLR in the second-line was significantly associated with improved mTTF at 7.9 months versus high NLR patients (3.3 months; P = .023). Second-line low NLR was significantly associated with a longer mOS of 12.2 months, in comparison to 6.8 months with high NLR (P = .003).
In this real-world analysis of patients with mUC, first-line outcomes were lower than expected. Low NLR in the first- and second-line is associated with improved mTTF and mOS.
Prognostic Value of the Preoperative Platelet-to-leukocyte Ratio for Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer
2017, Clinical Genitourinary Cancer
Citation Excerpt :
Several studies showed that an elevated C-reactive protein level is associated with adverse oncologic outcomes.6,9 Among the most extensively investigated inflammatory markers is the neutrophil-to-lymphocyte (NLR) ratio, although other cells of the immune system such as lymphocytes and monocytes have also been evaluated.10-15 A recent study pioneered the comparison of several previously reported complete blood count-based biomarkers and found the NLR to be superior among the other parameters tested on multivariate analysis.16
Currently, stratification of patients with bladder cancer (BC) mainly relies on histopathologic and clinical staging. Furthermore, inflammation plays an important role in the pathogenesis of BC. With the preoperative platelet-to-leukocyte ratio (PLR), we introduce a novel prognostic marker based on routine hematologic values in patients undergoing radical cystectomy (RC).
In our cohort of 665 patients undergoing RC (2004-2015) for urothelial carcinoma of the bladder (UCB), we analyzed a variety of preoperative hematologic parameters. We investigated the effect of thrombocytosis, leukocytosis, and the PLR on the oncologic outcomes, including cancer-specific survival (CSS), progression-free survival (PFS), and overall survival (OS). Both univariate (log-rank test) and multivariate (Cox regression) analysis were performed. The prevalence of thrombocytosis and leukocytosis and differences in the PLR was assessed using the Mann-Whitney U test. The cutoff levels for leukocytosis, thrombocytosis, and the PLR were defined using receiver operating characteristic curve analysis, with the 5-year CSS as the binary classifier.
A PLR of ≤ 28 (CSS, P = .033; OS, P = .029) and leukocytosis (CSS, P = .01; OS, P = .001; PFS, P = .003) were significantly associated with adverse oncologic outcomes using the log-rank test. On multivariate regression analysis, the PLR (CSS, P = .022; OS, P = .025) remained a significant prognostic marker among the standard staging variables and hemoglobin level. Advanced BC disease was significantly more prevalent in the patient subgroup with a low PLR (pT2-pT4, 35%; vs. pT ≤ 1, 24%; P = .006) and leukocytosis (pT2-pT4, 46%; vs. pT ≤ 1, 30%; P < .001; pN⁺, 49%; vs. pN0, 39%; P < .047).
To the best of our knowledge, the present study is the first report of the preoperative PLR as a prognostic factor in patients undergoing RC for UCB. Compared with other inflammatory markers in BC, the PLR can be assessed without additional effort. External validation and its combination with other parameters might improve current prognostication systems for UCB.
Latest evidence on clinical outcomes and prognostic factors of advanced urothelial carcinoma in the era of immune checkpoint inhibitors: a narrative review
2024, Japanese Journal of Clinical Oncology
A narrative review of peripheral blood parameters for urothelial carcinoma treated with systemic antitumor drugs
2023, Translational Andrology and Urology
Improved survival in real-world patients with advanced urothelial carcinoma: A multicenter propensity score-matched cohort study comparing a period before the introduction of pembrolizumab (2003–2011) and a more recent period (2016–2020)
2022, International Journal of Urology

View all citing articles on Scopus

View full text

Original StudyPrognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patients

Patients

Survival

Discussion

Conclusion

Disclosure

Acknowledgment

Eur Urol

Crit Rev Oncol Hematol

Clin Genitourin Cancer

Clin Genitourin Cancer

Eur J Cancer

Urology

Clin Genitour Cancer

Cell

Ann Oncol

Lancet

Cancer Cell

Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer

J Clin Oncol

The combination of gemcitabine and carboplatin as first-line treatment in patients with advanced urothelial carcinoma. A phase II study of the Hellenic Cooperative Oncology Group

Cancer

Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II results of EORTC study 30986

J Clin Oncol

Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy

J Clin Oncol

Original Study
Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study