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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 4  |  Page : 511-515

Prognostic value of neutrophil-to-lymphocyte ratio in castration resistant prostate cancer: Single-centre study of Nigerian men


Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Date of Acceptance29-Jan-2019
Date of Web Publication11-Apr-2019

Correspondence Address:
Dr. J O Bello
Department of Surgery, University of Ilorin Teaching Hospital, Ilorin
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_382_18

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   Abstract 


Background: Elevated neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a useful prognosticator of overall survival (OS) in several cancers including castration resistant prostate cancer. However, its utility in black populations known to have benign ethnic neutropenia is unknown. We evaluated the prognostic value of NLR in Nigerian men with CRPC in terms of OS. Materials and Methods: We retrospectively analysed 58 patients with castration resistant prostate cancer who received androgen deprivation therapy (ADT) and docetaxel chemotherapy at our institution. Baseline NLR was calculated from available complete blood counts. NLR cut-off point value was determined based on receiver operator characteristic (ROC) curves for mortality. A multivariate analysis was performed to investigate the association between NLR and OS. Results: Based on the ROC curves, the NLR (AUC 0.85, 95% CI 0.74-0.97, P = 0.0001) cut-off point was determined to be 1.8. This cut-off point has a sensitivity of 92% and specificity of 70%. Median OS was 20 months (95% CI 14-27 months); the median OS in patients with NLR <1.8 and those with NLR of ≥1.8 was 40 months and 12 months respectively. Kaplan-Meier plots showed that a higher NLR of ≥1.8 correlated significantly with an increased risk of mortality, Log rank P = 0.001. Multivariate Cox regression analyses confirmed NLR as an independent prognostic biomarker for OS (HR = 1.49, 95% CI: 1.18-1.87). Conclusions: This study demonstrated that NLR is a useful prognostic biomarker in Nigerian men with CRPC and that elevated baseline NLR ≥1.8 is associated with poorer OS.

Keywords: Benign ethnic neutropenia, castration resistant prostate cancer, neutrophil-to-lymphocyte ratio


How to cite this article:
Bello J O, Olanipekun O O, Babata A L. Prognostic value of neutrophil-to-lymphocyte ratio in castration resistant prostate cancer: Single-centre study of Nigerian men. Niger J Clin Pract 2019;22:511-5

How to cite this URL:
Bello J O, Olanipekun O O, Babata A L. Prognostic value of neutrophil-to-lymphocyte ratio in castration resistant prostate cancer: Single-centre study of Nigerian men. Niger J Clin Pract [serial online] 2019 [cited 2019 Apr 23];22:511-5. Available from: http://www.njcponline.com/text.asp?2019/22/4/511/255924




   Introduction Top


Prostate cancer is the most common solid cancer seen in Nigerian men.[1] Unfortunately, majority of Nigerian men present late with advanced disease and require androgen deprivation therapy (ADT).[2] Despite the initial response to ADT, most patients progress invariably to castration resistant prostate cancer (CRPC).[2] Treatment of CRPC with docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223 have been shown to prolong overall survival (OS).[3],[4] However, docetaxel is the more common therapy available to Nigerian men with CRPC due to its lower cost and easier accessibility.[2]

The prostate specific antigen (PSA), a glycoprotein secreted by the prostate gland, is the most commonly used biomarker in prostate cancer (PCa) diagnosis, monitoring and prognostication though recent data suggests that there are multiple challenges in the use of PSA particularly in interventions and treatments.[5] Neutrophil-to-lymphocyte ratio (NLR) which is a simple biomarker of systemic inflammation and host immune response derived from a ratio of absolute neutrophil counts to absolute lymphocyte counts has also been found to have prognostic value in PCa.[6],[7],[8] Several clinical studies have found that a higher NLR correlates with poorer prognosis in a variety of cancers including prostate cancer.[6],[7],[8],[9] NLR is easily measured from inexpensive complete blood counts which is routinely available in most clinical settings. Thus, there is a potential benefit in determining its prognostic value in our resource-limited setting.

The prognostic value of NLR particularly in black African men remains unclear. It is unknown if the relative neutropenia widely observed in black populations compared to other racial groups has an effect on the prognostic value of NLR as most of the clinical studies done to evaluate NLR in cancer has been in non-black populations.[6],[7],[8],[10] Since Forbes et al. described leukopenia and neutropenia in an apparently healthy black population in 1941, several subsequent studies have consistently confirmed that a significant difference exists in the white blood cell counts and absolute neutrophil counts of black and Caucasian populations.[10],[11] This finding of a lower absolute neutrophil count in Blacks compared to Caucasians is referred to as benign ethnic neutropenia.[10],[11] The condition has an identified genetic basis; the polymorphism of the Duffy antigen for chemokines which regulates neutrophil production and migration.[12]

In this current study, we evaluated the prognostic value of NLR in Nigerian men with CRPC in terms of overall survival (OS). We hypothesize that the prognostic ability of NLR in this black population may be affected by the well-described benign ethnic neutropenia. This study aims to evaluate the prognostic ability of NLR in our population and could potentially provide for a low-cost, easy to use biomarker of CRPC in our population. This is probably the first study, to our knowledge, to evaluate NLR in this manner in our population.


   Materials and Methods Top


This retrospective study primarily aims to determine the prognostic value of baseline NLR among Nigerian patients newly diagnosed with CRPC. The study population include men earlier diagnosed with advanced PCa at the University of Ilorin teaching hospital, Nigeria and subsequently developed disease progression despite appropriate and adequate treatment to CRPC. The clinical records of consecutive patients with CRPC as defined by the Prostate Cancer Working Group 2 (relative increase of 25% and absolute increase of ≥2 ng/mL of PSA above nadir and castrate level of testosterone <1.7 nmol/L, development of new metastases detected on imaging) diagnosed between January 2013 and June 2017 were retrieved. We included only patients who were followed-up until death occurred and patients who were alive at last follow-up only if they completed at least 12 months of follow-up. This minimum follow-up was based on an earlier finding of median OS of 11 months for CRPC patients in our population.[2]

Patient data retrieved from folders include the complete blood counts (CBC) performed at commencement of treatment for CRPC. Details of absolute neutrophil count, absolute lymphocyte count, NLR, platelet count, platelet to lymphocyte ratio (PLR) and hemoglobin concentration were extracted from the CBC. The additional demographic and clinical information on patient's age, prostate specific antigen (PSA), Gleason grade/score, mode of castration and the number of cycles of DOC received were also retrieved from the records. Overall survival (OS) was calculated from the date of CRPC diagnosis to the date of death from any causes or censure.

The optimal cut-off point of NLR and PLR were determined based on the sensitivity and specificity levels derived from receiver operator characteristic (ROC) curves plotted based on 12-month mortality following the diagnosis of CRPC. Cox proportional hazards regression model including the possible confounders of overall survival-age, PSA, Gleason score—was used to assess the prognostic significance of identified variables in univariable and multivariable analyses. Kaplan-Meier plots were used to depict survival outcomes with significance determined by log rank test. All statistical analyses were performed with the SPSS version 22 software (IBM, Chicago, IL), P < 0.05 was considered significant. The institutional ethics review board approval was obtained for this study.


   Results Top


The baseline characteristics of the 58 CRPC patients included in the study are shown in [Table 1]; eleven patients were excluded due to incomplete data or insufficient follow-up. Twenty-four patients (41.4%) had Gleason score of ≥8 at diagnosis. All the patients received androgen deprivation therapy in the form of either bilateral orchiectomy (45, 77.6%) or medical castration with luteinizing hormone releasing hormone analogues (13, 22.4%). Patients also received docetaxel chemotherapy (65-75 mg/m2) in tri-weekly cycles (median cycles, IQR: 2, 1-6). Thirty-two patients (55.2%) died during a median follow-up of 12 months.
Table 1: Characteristics of study cohort (n=58)

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Based on the ROC curves [Figure 1], the NLR (AUC 0.85, 95%CI 0.74-0.97, P = 0.0001) cut-off point was determined to be 1.8. This NLR cut-off point has a sensitivity of 92% and specificity of 70%. PLR (AUC 0.64, 95%CI 0.47-0.81, P = 0.121) cut-off point was also determined to be 100 with a sensitivity of 72% and specificity of 50%. The PSA (AUC 0.71, 95%CI 0.56-0.86, P = 0.019) cut-point of 15 ng/mL has a sensitivity of 91% and specificity of 52%.
Figure 1: The Kaplan-Meier plots of Overall survival (OS) according to Neutrophil-to-lymphocyte ratio (NLR) dichotomized at 1.8 (dotted lines <1.8, solid line ≥1.8). NLR of ≥1.8 correlated significantly with poorer OS, Log Rank P = 0.001

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The median OS was 20 months (95%CI 14-27 months). When the survival probabilities were compared according to NLR, the median OS in patients with NLR of <1.8 was 40 months (95%CI 29-51 months) and those with NLR of ≥1.8 was 12 months (95%CI 9-16 months). The Kaplan-Meier plots showed that a higher NLR of ≥1.8 correlated significantly with an increased risk of mortality, Log Rank P = 0.001 [Figure 2].
Figure 2: Receiver operator characteristic (ROC) curves for Neutrophil-to lymphocyte ratio (NLR), Platelet-to lymphocyte ratio (PLR) and Prostate specific antigen (PSA)

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The multivariate Cox regression analyses revealed that PSA at CRPC diagnosis and NLR are independent prognostic biomarkers for OS. Age, PLR and Gleason score were not found to be predictors of OS [Table 2].
Table 2: Cox proportional hazards prognostic models for overall survival

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   Discussion Top


Black men are disproportionately impacted by advanced PCa including CRPC.[2] With the increasing options of therapies available for men with CRPC coupled with the resource-limited setting of health-care delivery in our region, there is a need for a suitable, low cost and easily accessible biomarker to assist in the clinical management of our patients. Several studies conducted mainly in Asian and Caucasian men with advanced PCa have fairly consistently shown that an elevated NLR was predictive of poor OS, poor progression-free survival and or poor PSA response rate in the populations.[6],[7],[8] However, little data exist with regards to this association in black men; a knowledge gap which is particularly worrisome in view of higher incidence of PCa in blacks and the well-established observation of a significantly lower white cell count and lower absolute neutrophil count in black men compared to other ethnic groups including Caucasians and Asians.[1],[2],[10] Additionally, NLR which is derived from complete blood counts is inexpensive and widely accessible; and could potentially fill the need for a prognostic biomarker particularly suitable for our resource-limited region.

Cancer-related inflammation is now recognized to play an important role in modulating the tumor microenvironment.[13] A leukocyte infiltrate which include tumor-associated neutrophils and tumor-associated macrophage are the key participants in the tumor microenvironment and they promote or inhibit cancer formation and development.[13],[14] Tumor-associated neutrophils has been associated with poor clinical outcomes in patients with cancer and an increase in NLR has been shown to correlate with worse outcomes in a variety of malignant conditions.[9],[14]

The widely observed benign ethnic neutropenia in people of African descent commonly could potentially impact the usefulness of NLR as a potential biomarker in black men with PCa. In the current study, we reported on the value of NLR as a prognosticator in a sample of Nigerian men with CRPC. We found on ROC curve analysis that NLR out-performs both PSA and PLR with a higher AUC of 0.85, this implies that NLR is the more useful prognostic variable. The AUC for PSA of 0.71 was better than the poor value of 0.64 obtained for PLR. Not surprisingly, the ROC determined cut-off point of 1.8 also had a very good sensitivity of 92% and a respectable specificity of 70% much better than that of PSA and PLR. Our findings are comparable to similar studies in other racial groups which reveal that NLR is a useful prognosticator in advanced PCa.[6],[7],[8],[15] The NLR cut-off point of 1.8 found in this study is much lower than that described in other studies which are often in the 3-5 range.[15] This may be due to the effect of previously described benign ethnic neutropenia. Despite the lower value, the cut-off point correlated significantly with an increased risk of mortality with the OS of an NLR <1.8 being 40 months and NLR ≥1.8 determined to be 12 months. Our finding confirms that though NLR may be lower in blacks it retains its prognostic power.

Multivariate Cox regression analyses in the index study confirmed NLR and PSA as having an independent impact on OS. This is similar to findings in several studies. Buttigliero and colleagues in their study of I79 Caucasian metastatic CRPC patients found that a low pretreatment NLR of ≤3 was associated with better survival which was confirmed on multivariate analysis.[8] A systematic review and meta-analysis of 22 studies mainly conducted in Asian and Caucasian populations confirmed that an elevated NLR was a prognostic predictor of poor progression-free survival in CRPC (HR = 1.42, 95%CI: 1.23-1.61) and poor OS in metastatic CRPC (HR = 1.45,95%CI: 1.32-1.59).[7] Their finding is very similar to that of the index study with NLR independently predicting poor OS (HR = 1.49, 95%CI: 1.18-1.87). Lorente et al. analyzed metastatic CRPC patients treated in the TROPIC trial and similarly found that baseline NLR treated as a continuous variable was associated with OS in multivariable analysis (HR = 1.5, 95%CI: 1.1-2.1).[15]

NLR has shown fairly inconsistent results in terms of prognostic value in some previous studies in which it was investigated;[16] additionally, NLR could be impacted by other common conditions particularly infections and inflammation.[17],[18] These reasons are probably responsible for its low usage compared to the well-established PSA. However, a recent meta-analysis which pooled results from 16 studies with 5,705 CRPC patients provided greater evidence of the value of elevated NLR in predicting poor OS (pooled HR = 1.52, 95% CI: 1.41-1.63).[16] Not surprisingly, the study cohorts included in the meta-analysis came from the mainly non-black populations of Asia, Europe and North America; this makes the current study particularly necessary and timely.

The index study is associated with some limitations. First, it is a retrospective study and selection bias cannot be ruled out. Moreover, eleven patients with incomplete information were excluded from analysis. It is also a single-center study but our institution caters for a large part of North-Central Nigeria and our observation period was fairly adequate. Despite these limitations, we report to our knowledge, the first study to evaluate the prognostic ability of NLR in CRPC in our population. A prospective, multi-center study with the evaluation of a larger patient population over a longer time is being planned to validate our findings.


   Conclusion Top


This study demonstrated that NLR is a useful prognostic biomarker in the study cohort of Nigerian men with CRPC and that an elevated baseline NLR ≥1.8 is associated with poorer OS. The study fills a gap in the growing body of knowledge on the prognostic relevance of NLR in CRPC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ogunbiyi JO, Shittu OB. Increased incidence of prostate cancer in Nigerians. J Natl Med Assoc 1999;91:159-64.  Back to cited text no. 1
    
2.
Bello JO. Natural history of castration-resistant prostate cancer in sub-Saharan African black men: A single-centre study of Nigerian men. Ecancermedicalscience 2018;12:797.  Back to cited text no. 2
    
3.
Lowrance WT, Roth BJ, Kirkby E, Murad MH, Cookson MS. Castration-resistant prostate cancer: AUA Guideline Amendment 2015. J Urol 2016;195 1444-52.  Back to cited text no. 3
    
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Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: Treatment of relapsing, metastatic, and castration-resistant prostate cancer Eur Urol 2017;71:630-42.  Back to cited text no. 4
    
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Thompson IM. PSA: A biomarker for disease. A biomarker for clinical trials. How useful is it? J Nutr 2006;136:2704S.  Back to cited text no. 5
    
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Uemura K, Kawahara T, Yamashita D, Jikuya R, Abe K, Tatenuma T, et al. Neutrophil-to-lymphocyte ratio predicts prognosis in castration-resistant prostate cancer patients who received cabazitaxel chemotherapy. Biomed Res Int 2017;2017:7538647.  Back to cited text no. 6
    
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Cao J, Zhu X, Zhao X, Li XF, Xu R. Neutrophil-to-lymphocyte ratio predicts PSA response and prognosis in prostate cancer: A systematic review and meta-analysis. PLoS One 2016;11:e0158770.  Back to cited text no. 7
    
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Buttigliero C, Pisano C, Tucci M, Vignani F, Bertaglia V, Iaconis D, et al. Prognostic impact of pretreatment neutrophil-to-lymphocyte ratio in castration-resistant prostate cancer patients treated with first-line docetaxel. Acta Oncol 2017;56:555-62.  Back to cited text no. 8
    
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Vano Y-A, Oudard S, By M-A, Têtu P, Thibault C, Aboudagga H, et al. Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients. PLoS One 2018;13:e0195042.  Back to cited text no. 9
    
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Forbes WH, Johnson RE, Consolazio F. Leukopenia in Negro workmen. Am J Med Sci 1941;201:407-12.  Back to cited text no. 10
    
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Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: What is a normal absolute neutrophil count? J Lab Clin Med 1999;133:15-22.  Back to cited text no. 11
    
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Reich D, Nalls MA, Kao WHL, Akylbekova EL, Tandon A, Patterson N, et al. Reduced neutrophil count in people of african descent is due to a regulatory variant in the duffy antigen receptor for chemokines gene. PLoS Genet 2009;5:e1000360.  Back to cited text no. 12
    
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Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7, 211-7.  Back to cited text no. 13
    
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Shen M, Hu P, Donskov F, Wang G, Liu Q, Du J. Tumor-associated neutrophils as a new prognostic factor in cancer: A systematic review and meta-analysis. PLoS One 2014;9:e98259.  Back to cited text no. 14
    
15.
Lorente D, Mateo J, Templeton AJ, Zafeiriou Z, Bianchini D, Ferraldeschi R, et al. Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. Ann Oncol 2015;26:750-5.  Back to cited text no. 15
    
16.
Wang Z, Peng S, Xie H, Guo L, Jiang N, Shang Z, Niu Y. Neutrophil-lymphocyte ratio is a predictor of prognosis in patients with castration-resistant prostate cancer: A meta-analysis. Cancer Manag Res 2018;10:3599-610.  Back to cited text no. 16
    
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Cataudella E, Giraffa CM, Di Marca S, Pulvirenti A, Alaimo S, Pisano M, et al. Neutrophil-to-lymphocyte ratio: An emerging marker predicting prognosis in elderly adults with community-acquired pneumonia. J Am Geriatr Soc 2017;65:1796-801.  Back to cited text no. 17
    
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Chandrashekara S, Mukhtar AM, Renuka P, Anupama KR, Renuka K. Characterization of neutrophil-to-lymphocyte ratio as a measure of inflammation in rheumatoid arthritis. Int J Rheum Dis 2017;20:1457-67.  Back to cited text no. 18
    


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