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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 909-916

Prognostic value of the neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 in estimating survival in patients with metastatic pancreatic cancer


1 Department of Biostatistics, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
2 Department of Medical Oncology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey

Date of Submission25-May-2019
Date of Acceptance26-Nov-2019
Date of Web Publication14-Sep-2020

Correspondence Address:
Sirin Cetin
Faculty of Medicine, Department of Biostatistics, Tokat Gaziosmanpasa University, Tokat
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_366_19

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 > Abstract 


Background: The predictive value of different prognostic biomarkers has been studied in various cancer types.
Aims and Objectives: The purpose of this study was to examine the degree of risk and prognostic significance of pretreatment neutrophil-to-lymphocyte ratio (NLR) and carbohydrate antigen (CA) 19-9 levels in patients with metastatic pancreatic cancer (PC) and reveal its relevance with survival.
Materials and Methods: Clinical and laboratory data of 118 patients with metastatic PC at the time of diagnosis were retrospectively analyzed. The overall survival (OS) was estimated according to the Kaplan–Meier method. To determine the prognostic factors affecting PC, the Cox regression analysis was performed.
Results: The average age of the patients was 67 ± 9.57 years. The patients were analyzed during the follow-up period, and their average OS was 12 months (95% confidence interval [CI] = 9.73–14.26). The cutoff value was 3.54 (area under the curve [AUC] = 0.653, 95% CI = 0.56–0.73, P = 0.006) for NLR and 437 (AUC = 0.670, 95% CI = 0.57–0.75, P = 0.002) for CA19-9. Statistically significant difference was found between CA19-9 (P < 000.1) and NLR (P < 000.1) and OS. Analysis of multivariate Cox regression showed that NLR (hazard ratio [HR] = 2.17, 95% CI = 1.17–4.03, P = 0.013) and CA19-9 (HR = 1.81, 95% CI = 1.08–3.03, P = 0.022) were important prognostic factors in OS analysis.
Conclusion: Pretreatment NLR and CA19-9 levels were found to be reliable estimative markers for poor prognosis in patients with metastatic PC. Our findings revealed that NLR and CA19-9 levels can be used to estimate the survival of patients with PC. We believe that our findings will shed light on the management of treatment protocols for patients diagnosed with metastatic PC.

Keywords: Carbohydrate antigen 19-9, metastatic pancreatic cancer, neutrophil-to-lymphocyte ratio, prognostic factor


How to cite this article:
Cetin S, Dede I. Prognostic value of the neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 in estimating survival in patients with metastatic pancreatic cancer. J Can Res Ther 2020;16:909-16

How to cite this URL:
Cetin S, Dede I. Prognostic value of the neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 in estimating survival in patients with metastatic pancreatic cancer. J Can Res Ther [serial online] 2020 [cited 2020 Sep 23];16:909-16. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/909/294949




 > Introduction Top


Pancreatic cancer (PC) is stated as the fourth leading cause of cancer-related mortality and the fifth most common cancer in the worldwide.[1] The incidence rate of PC has increased in recent years. It is estimated that PC may become the second leading cause of cancer-related mortality by 2030.[2],[3] PC is a highly malignant solid tumor with a 1-year overall survival (OS) rate of 26% and a 5-year survival rate of >5%. Its prognosis is poor despite substantial efforts made in its treatment and diagnosis. Above 80% of patients with PC has progressed stage of unresectable or metastatic disease at the moment of diagnosis. The most important factor in this regard is the absence of distinct specific symptoms in the beginning of the disease. A vast number of patients have already missed the opportunity to undergo curative resection at the time of diagnosis. In addition, metastases can develop in later periods in patients who undergo operation.[4],[5],[6]

The median survival for PC is 6–8 months.[7] In many patients diagnosed with advanced-stage PC, treatment options are limited to palliative chemotherapy or some new treatment protocols. Examining prognostic factors is very important while planning optimal treatment for patients with metastatic PC.[8]

The relationship between inflammation and malignant tumors was first discovered by Virchow in 1863 who reported a positive relationship between inflammation and cancer development.[9],[10],[11] Inflammation, invasion, and metastasis play a crucial role in tumor growing and also affect the response to cancer therapy.[12] Because inflammatory response plays a distinctive role during different stages of tumor growth, such as invasion and metastasis, it has been recently stated that the serum neutrophil-to-lymphocyte ratio (NLR) is important in predicting prognosis in cancer patients.[10] In particular, the NLR has been relevant to weak prognosis in patients with advanced pancreatic ductal adenocarcinoma, small-cell lung cancer, and rectal cancer.[13],[14],[15],[16]

Carbohydrate antigen 19-9 (CA19-9), also known as the Sialyl–Lewisa antigen, is the most recognized standard tumor marker widely used in the diagnosis of PC in symptomatic patients and in the following-up treatment of patients with pancreatic adenocarcinoma.[17] CA19-9 shows 80% sensitivity and 82% specificity in the diagnosis of pancreatic adenocarcinoma.[18] Pancreatic adenocarcinoma is more aggressive with the release of CA19-9, which is associated with hematogenous spread and metastatic phenotype. The poor prognosis of CA19-9 may be associated with the binding of CA19-9 to vascular cell adhesion molecule E-selectin. The adhesion of circulating vascular endothelial tumor cells provides an environment for metastasis.[19] Several studies have demonstrated the connection between CA19-9 and the survival of patients with PC.[20]

There are limited studies in the literature emphasizing the prognostic significance levels of CA19-9, NLR, and albumin in patients with metastatic PC. The aim of this study was to demonstrate the prognostic significance of pretreatment NLR, CA19-9, and albumin levels and elucidate their relationship with survival in patients with metastatic PC. Better prognostic predictors are required to determine effective treatment.


 > Materials and Methods Top


One hundred and eighteen patients' data with metastatic PC registered to the Medical Oncology Clinic of Antakya State Hospital between January 2013 and December 2017 were retrospectively analyzed. Albumin and CA19-9 levels as well as neutrophil and lymphocyte counts were recorded using hematological parameters at the time of diagnosis. Furthermore, NLR was assessed by dividing the number of absolute neutrophils to the number of absolute lymphocytes. All data were obtained within 7 days before treatment. The study was approved by the Ethics Committee of Mustafa Kemal University Medical Faculty (2018/57).

To calculate the cutoff values of NLR, CA19-9, and albumin levels in predicting survival, operating characteristic (receiver operating characteristic [ROC]) curve analysis was used. OS obtained by univariate analyses was compared according to the log-rank test. Cox regression analysis was applied in multivariate analyses. The OS rates were assessed based on the Kaplan–Meier method. The log-rank test was applied to determine the difference between survivals based on NLR as well as those based on CA19-9 and albumin levels. The Chi-square test was used to compare the relationship of low and high NLR groups, low and high CA19-9 groups, and albumin levels with clinical characteristics. For survival analysis, the Kaplan–Meier method was used, and survival of the groups was compared using log-rank test. P <0.05 was considered statistically significant. Statistical analyses were done using SPSS software (version 21.0; IBM, Armonk, NY, USA) and MedCalc trial version for Windows (MedCalc Software, Belgium) trial version.


 > Results Top


All patients show metastatic disease. Regarding the number of metastases and metastasis sites, 37 (31.4%) patients had metastases in two or more regions, and 81 (68.6%) patients had liver metastases. A total of 82 of 118 (69.5%) patients were male and 36 (30.5%) were female. The average age at the time of diagnosis was 67 ± 9.57 years (range = 40–86 years). The median age was 66.7 years for male patients and 67.5 years for female patients. The Eastern Cooperative Oncology Group (ECOG) performance scores of the patients were also assessed based on the ECOG performance scale. The ECOG performance score was 0 in 40 of 118 patients (33.89%), 1 in 65 of 118 patients (55.1%), 2 in 10 of 118 patients (8.5%), 3 in 2 of 118 patients (1.7%), and 4 in 1 of 118 patients (0.8%).

The NLR cutoff value was calculated as 3.54 according to the ROC curve analysis based on mortality [Figure 1]. Analysis of ROC curve shows that the NLR cutoff value was 3.54 (area under the curve [AUC] = 0.653, 95% confidence interval [CI] = 0.56–0.73, P = 0.006). The CA19-9 cutoff value was calculated as 437 according to the ROC curve analysis based on mortality [Figure 2]. Analysis of ROC curve displays that the CA19-9 cutoff value was 437. The cutoff value of albumin was calculated as 3.5 according to the ROC curve analysis based on mortality [Figure 3]. Analysis of ROC curve explained that the albumin cutoff value was 3.5 (AUC = 0.643, 95% CI = 0.55–0.72, P = 0.009). ROC analyses were performed for the tumor markers CA19-9, NLR, and albumin as well as their mathematical combinations using the classification variable as OS [Figure 4]; the corresponding variables, AUC, and test performance (sensitivity and specificity) for an optimal cutoff value are shown in [Table 1].
Figure 1: The receiver operating characteristic curve analysis of the neutrophil-to-lymphocyte ratio in patients with pancreatic cancer. The cutoff value of carbohydrate antigen 19-9 was calculated to be 437 according to the receiver operating characteristic curve analysis based on mortality [Figure 2]. Analysis of receiver operating characteristic curve explained that the cutoff value was 437 (area under the curve = 0.670, 95% confidence interval = 0.57–0.75, P = 0.002)

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Figure 2: The receiver operating characteristic curve analysis of carbohydrate antigen 19-9 in patients with pancreatic cancer

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Figure 3: The receiver operating characteristic curve analysis of albumin in patients with pancreatic cancer

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Figure 4: The receiver operating characteristic curve analysis of albumin, carbohydrate antigen 19-9, and neutrophil-to-lymphocyte ratio in patients with pancreatic cancer

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Table 1: The receiver operating characteristic curve variables with optimal cutoff values and test performance using overall survival as a classification variable

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The relationship between NLR, CA19-9, and albumin levels and prognostic factors was analyzed by Chi-square analysis. All prognostic factors were comparable between patients grouped by NLR, CA19-9, and albumin levels as shown in [Table 2]. The NLR was grouped with respect to two different cutoff points (≥3.54 or <3.54). There was no statistically significant difference between NLR and age, sex, or ECOG PS (P > 0.05). However, there was a statistically significant relationship between NLR and albumin (P = 0.003). There was also a significant relationship between NLR and CA19-9 (P = 0.001). This indicates a parallelism between increase in NLR and increase in CA19-9 levels. Similarly, the prognostic factors were comparable between patients grouped by CA19-9. CA19-9 was grouped with respect to two different cutoff points (≥437 or <437). There was no statistically significant difference between CA19-9 and age, sex, albumin, or ECOG PS (P > 0.05). However, there was a statistically significant relationship between CA19-9 and NLR (P = 0.001).
Table 2: Characteristics of patients with metastatic cancer grouped by neutrophil-to-lymphocyte ratio, carbohydrate antigen, and albumin

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Similarly, the prognostic factors were comparable between patients grouped by albumin. Albumin was grouped with respect to two different cutoff points (≥3.5 or <3.5). There was no statistically significant relationship between albumin and age, sex, CA19-9, or ECOG PS (P > 0.05). However, there was a significant relationship between albumin and NLR (P = 0.003). This indicates a parallelism between increase in NLR and decrease in albumin levels.

The median OS of 118 patients with PC who were analyzed in our study was 12 months (95% CI = 9.73–14.26). The Kaplan–Meier survival curve for all patients is shown in [Figure 5]. The median OS in patients with PC with a CA19-9 level of ≥437 was 8 months (CI = 5.49–10.51) [Figure 6]. The median OS in patients with PC with a CA19-9 level of <437 was 15 months (CI = 1.34–28.65) [Figure 6]. There was a statistically significant difference between CA19-9 and OS (P < 000.1) [Table 3]. The median OS in patients with PC with NLR of ≥3.54 was 9 months (CI = 6.23–11.76) [Figure 7]. The median OS in patients with PC with NLR of <3.54 was 17 months (CI = 4.76–29.23) [Figure 7]. There was a significant relationship between NLR and OS (P < 000.1) [Table 3]. According to the Kaplan–Meier curve for OS, a high NLR in patients was related to week prognosis in metastatic PC.
Figure 5: Kaplan–Meier curve for all patients

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Figure 6: Kaplan–Meier curve of patients according to low and high carbohydrate antigen 19-9 levels

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Table 3: Univariate and multivariate analysis to detect prognostic factors

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Figure 7: Kaplan–Meier curve of patients according to low and high neutrophil-to-lymphocyte ratio

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The median OS in patients with PC with an albumin level of ≥3.5 was 17 months (CI = 1.89–32.11) [Figure 8]. The median OS in patients with PC with an albumin level of <3.5 was 10 months (CI = 7.46–12.53) [Figure 8]. There was a significant difference between albumin and OS (P < 000.1) [Table 3]. Curves of the Kaplan–Meier for OS show that high NLR, CA19-9, and albumin levels are related to prognosis in metastatic PC [Figure 6], [Figure 7], [Figure 8], respectively].
Figure 8: Kaplan–Meier curves of patients according to low and high albumin levels

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Univariable and multivariable Cox regression analyses with OS for all prognostic factor variables were performed, and hazard ratios (HRs) with their 95% CIs and the P value were calculated. Univariate Cox regression analysis revealed that albumin (3.5 vs. <3.5 h = 2.30, 95% CI = 1.37–3.86, P = 0.002), NLR (≥3.54 vs. <3.54 h = 3.23, 95% CI = 1.85–5.62, P < 0.001), and CA19-9 (≥437 vs. <437, HR = 2.45, 95% CI = 1.51–3.96, P < 0.001) were important prognostic factors for survival. According to the results of the univariate Cox regression analysis, patients with an albumin level of <3.5 are at 2.3 times higher risk in comparison to patients with an albumin level of ≥3.5, thereby indicating a shorter duration of survival. Patients with NLR ≥3.54 are at 3.2 times higher risk in comparison to patients with NLR <3.54, thereby indicating a shorter duration of survival. Patients with a CA19-9 level of ≥437 are at 2.4 times higher risk in comparison to patients with a CA19-9 level of <437, thereby indicating a shorter duration of survival.

Similarly, multivariate Cox regression analysis explained that albumin (3.5 vs. <3.5 h = 1.74, 95% CI = 1.01–2.99, P = 0.045), NLR (≥3.54 vs. <3.54 h = 2.17, 95% CI = 1.17–4.03, P = 0.013), and CA19-9 (≥437 vs. <437, HR = 1.81, 95% CI = 1.08–3.03, P = 0.022) were important prognostic factors in OS analysis [Table 3]. According to the results of the multivariate Cox regression analysis, patients with an albumin level of <3.5 are at 1.74 times higher risk in comparison to patients with an albumin level of ≥3.5. Patients with NLR ≥3.54 are at 2.17 times higher risk in comparison to patients with NLR <3.54. Similarly, patients with a CA19-9 level of ≥437 are at 1.81 times higher risk in comparison to patients with a CA19-9 level of <437. All of these outcomes indicate a shorter duration of survival.


 > Discussion Top


This study evaluated CA19-9, NLR, and albumin laboratory markers that affect prognosis in patients with metastatic PC. Our results indicated that high NLR and CA19-9 levels were connected with poor prognosis for OS. Chemotherapy is inadequate in the management of tumor progression and metastasis for patients with progressed stage disease who are typically ineligible for surgery.[20]

In our study, the average OS of 118 patients with PC was 12 months. Gao et al. stated a median OS of 10 months (9.73–10.27 months) for 122 patients with unresectable PC following a 25-month follow-up period.[21] Kadokura et al.[22] reported an OS of 9.2 months in 67 patients with unresectable PC aged over 75 years. Montes et al.[23] indicated a median OS of 15 months in 39 cancer patients, including those with locally progressed unresectable and metastatic cancer. Peixoto et al.[24] noticed a median OS of 11.7 months in patients with unresectable locally advanced PC (LAPC). Wu et al.[25] reported an OS of 12.2 months in 128 patients with PC.

Lymphocytes play a crucial role in the response to antitumor immunity; however, they are usually not present in large proportions within pancreatic tumors.[26] Pancreatic tumors are capable of independently activating the release of proinflammatory cytokines.[11] As reported in several studies, high NLR is inversely associated with the duration of survival in patients with PC. High NLR is usually associated with lymphocytopenia and high neutrophil levels which can promote tumor cell progression by upregulating many inflammatory cytokines, and they provide a microenvironment suitable for tumor growth. In addition, lymphocytopenia, which is caused by many inhibitory mediators, released by tumor cells, results in immunosuppression in cancer patients and leads to poorer prognosis.[27],[28],[29] In our study, the cutoff value for NLR was 3.54 based on the ROC analysis. Xiao et al.[30] detected a cutoff value of 3.4 for NLR in 66 patients with advanced-stage pancreatic ductal adenocarcinoma. Asaoka et al.[31] reported a cutoff value of 2.7 in patients with PC. Mowbray et al.[32] reported in their meta-analysis that the NLR cutoff value ranged from 2 to 5 in different studies. The primary problem with NLR is the inability to obtain an optimal cutoff value. In our study, patients with metastatic PC with NLR ≥3.54 had an average OS of 9 months, whereas those with NLR <3.54 had an average OS of 17 months. There was a significant difference between OS and NLR (P < 000.1). Piciucchi et al.[33] reported an OS of 3 months for NLR >5 and an OS of 7 months for NLR <5 in 81 patients with metastatic PC and defined NLR as a prognostic factor. An et al.[34] reported the prognostic significance of NLR for OS in 95 patients with advanced PC. They stated a median OS of 2.4 months for high NLR and a median OS of 7.7 months for low NLR. In a study conducted by Lee et al.[35] in 497 patients with LAPC, high NLR (NLR ≥1.89) was found to be a poor prognostic factor and the median OS was reported as 15.7 months. Xue et al.[36] reported pretreatment high NLR as a poor prognostic factor for OS in patients with advanced PC. They noted an average OS of 6 months for NLR>5 and 12.8 months for NLR ≤5. Kadokura et al.[22] reported NLR ≥3.3 (HR = 1.91, P = 0.01) as a negative prognostic factor in older patients with unresectable PC. Wang et al.[37] determined that pretreatment NLR >5 in 177 patients with pancreatic adenocarcinoma was related with a decrease in survival time (HR, 2.537; 95% CI = 1.313–4.902; P = 0.006).

CA19-9 is a glycolipid that belongs to the Sialyl–Lewis group of blood antigens. It is present in the serum of patients with PC in the form of mucin.[38] It has been reported that CA19-9 promotes metastasis by binding to E-selectin, which is expressed on the endothelial cell surface.[39] CA19-9 has high sensitivity in PC diagnosis.[40] In our study, according to the results of the ROC analysis, the cutoff value was 437 U/mL for CA19-9 in patients with metastatic PC. Patients with metastatic PC with a CA19-9 level of ≥437 had an average OS of 8 months, and patients with a CA19-9 level of <437 had a median OS of 15 months. There was a statistically significant difference between CA19-9 and OS (P < 0000.1). In similar studies, Reitz et al.[41] reported a cutoff value of 931.4 U/mL for CA19-9, and Song et al.[42] reported a value of 626 U/mL. Combs et al.[43] calculated a median OS of 14 months in 289 patients with LAPC. They determined a cutoff value of 269 U/mL for pretreatment CA19-9 and reported that it was a significant predictive and prognostic factor. Asaoka et al.[31] reported high CA19-9 levels (≥230) as a poor prognostic factor in patients with PC. Peixoto et al.[24] stated a median OS of 11.7 months in patients with unresectable LAPC and defined high CA19-9 levels (>1000 U/mL) as a prognostic factor. Usón Junior et al.[44] noticed a cutoff value of 2504 U/ml and an average survival of 11 months in 64 patients with advanced pancreatic adenocarcinoma. Wu et al.[25] reported an OS of 16.5 months for normal CA19-9 levels and 12.2 months for high CA19-9 levels in 128 patients with PC. They found a cutoff value of 39 U/mL for CA19-9 and reported CA19-9 >39 U/mL as a prognostic factor for PC. Tas et al.[45] emphasized the prognostic significance of CA19-9 in 196 patients with metastatic PC. Song et al.[42] reported NLR and CA19-9 as prognostic factors for OS based on multivariate analysis in patients with metastatic PC (CA19-9 ≥ 626 vs. <626, P = 0.007 and NLR ≥3.75 vs. <3.75, P < 0.0001). Asaoka et al.[31] reported pretreatment CA19-9 ≥230 (P = 0.025) and NLR ≥2.7 (P = 0.03) as poor prognostic factors for OS.

It has been reported that CA19-9 directly reflects the malignancy of tumors, has a predictive value in the staging of tumors, and provides information on tumor respectability; additionally, measuring CA19-9 levels at certain intervals during chemotherapy can predict response to chemotherapy.[42] Although CA19-9 is the most useful tumor marker in PC, wrong negative findings in Sialyl–Lewis-negative persons and wrong positive outcomes because of the existence of obstructive jaundice in patients cause the limitations in the interpretation of serum CA19-9 levels.[43] Approximately 5%–10% of the general population shows Lewisab − phenotype and cannot produce the CA19-9 antigen. Therefore, the CA19-9 level does not increase in these patients with PC or other malignancies.[44] The NLR is the result of either a higher number of neutrophils or a lower number of lymphocytes, and a high NLR may indicate relative lymphocytopenia. It is known that lymphocytes play a very important role in tumor defense by decreasing cytotoxic cell death and preventing migration and tumor cell proliferation. Therefore, a low lymphocyte count leads to a poor immunological response to tumor cells.[8],[10]

Poor prognosis in PC is caused by late diagnosis of the disease due to tumor invasion in tissues containing major vessels. In addition, the absence of biomarkers that can identify PC in early stages or identify patients at risk is another cause of poor prognosis. It is important to shed light on the biological metabolism that promotes to tumor formation and understand associated prognostic factors.[17],[45]

Our study has demonstrated that pretreatment NLR and CA19-9 were reliable predictive markers for poor prognosis in patients with metastatic PC. According to the results of our study, NLR and CA19-9 can be used in predicting survival in patients with PC. Our study revealed that these factors may be independent predictive markers for PC and that they can be clinically used in patients with metastatic PC for whom chemotherapy is planned. We believe that our findings will shed light on the management of treatment protocols for patients with metastatic PC.


 > Conclusion Top


Our results support that NLR and CA19-9 levels can be used as prognostic factors in patients with metastatic PC. Further multicenter rewarding studies are required to confirm the suitability of these parameters.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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