
==== Front
J Gastrointest Oncol
J Gastrointest Oncol
JGO
Journal of Gastrointestinal Oncology
2078-6891
2219-679X
AME Publishing Company

jgo-15-04-1805
10.21037/jgo-23-893
Original Article
Combination of neutrophil-to-lymphocyte ratio and serum CA 19-9 as a prognostic factor in pancreatic cancer
García-Herrera Juan Sebastián https://orcid.org/0000-0003-0448-3102
1 #
Muñoz-Montaño Wendy R. https://orcid.org/0000-0003-2269-2354
2 #
López-Basave Horacio N. https://orcid.org/0000-0003-0903-0735
1
Morales-Vásquez Flavia https://orcid.org/0000-0001-9298-5617
3
Castillo-Morales Carolina https://orcid.org/0000-0003-0793-858X
1
Rivera-Mogollán Luis G. https://orcid.org/0000-0002-7737-7944
1
Hernández-Castañeda Karla F. https://orcid.org/0000-0001-7444-6468
1
1 Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México;
2 Medical Oncology Department, Hospital Médica Sur, Mexico City, México;
3 Medical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
Contributions: (I) Conception and design: JS García-Herrera, WR Muñoz-Montaño; (II) Administrative support: F Morales-Vásquez; (III) Provision of study materials or patients: HN López-Basave; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

# These authors contributed equally to this work as co-first authors.

Correspondence to: Horacio N. López-Basave, MD. Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Avenida San Fernando 22, Sección XVI, Mexico City 14080, México. Email: lobohnoe@gmail.com.
22 8 2024
31 8 2024
15 4 18051819
09 11 2023
14 6 2024
2024 Journal of Gastrointestinal Oncology. All rights reserved.
2024
Journal of Gastrointestinal Oncology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.
Background

Traditionally, serum carbohydrate antigen 19-9 (CA 19-9) has been used as a key biomarker for pancreatic cancer and recently other biomarkers which reflect the systemic immune and inflammatory responses also have been explored as potential prognostic factors. The study aims to evaluate the significance of pretreatment neutrophil-to-lymphocyte ratio (NLR) and serum CA 19-9 as prognostic factor in pancreatic cancer patients.

Methods

A retrospective analysis was conducted in 153 consecutive patients with pancreatic cancer in Instituto Nacional de Cancerología from 2013 to 2018. Pretreatment NLR and serum CA 19-9 values were recorded as well as survivals.

Results

The cut-off value determined for NLR was 2.4 and for serum CA 19-9 was 553 U/mL. Survival analysis showed that the 5-year overall survival (OS) was 9% in patients with low-NLR compared with 2% for patients with high-NLR (P=0.008), and 5-year progression-free survival (PFS) was 5.7% in patients with low-NLR compared with 1.3% in patients with high-NLR (P=0.007). For patients with low-CA 19.9, 5-year OS was 8.5% compared with 0% for patients with high-CA 19-9 (P=0.002), and 5-year PFS was 4.1% in patients with low-CA 19-9 compared with 0% in patients with high-CA 19-9 (P=0.005). Classification groups created showed that 5-year OS in Group 1 (low-NLR and low-CA 19-9) was 11.8% compared with 1.9% for patients in Group 2 (either one or both high-NLR or CA 19-9) (P<0.001), and 5-year PFS was 8.6% in Group 1 and 0% in Group 2 (P=0.001).

Conclusions

High-NLR and high-CA 19-9 values used separately are both independently associated with worse OS and PFS in patients with pancreatic cancer. The classification groups created combining both biomarkers showed better prognostic significance than when used separately as demonstrated by survival analysis and multivariate analysis.

Keywords:

Neutrophil-to-lymphocyte ratio (NLR)
carbohydrate antigen 19-9 (CA 19-9)
pancreatic cancer
prognostic factors
biomarkers
==== Body
pmcHighlight box

Key findings

• In patients with pancreatic ductal adenocarcinoma high-neutrophil-to-lymphocyte ratio (NLR) and high-carbohydrate antigen 19-9 (CA 19-9) levels at diagnosis are both independent prognostic factors for worse disease-free survival and overall survival. The combination of these two biomarkers (NLR and CA 19-9) seems to be better for predicting prognosis and stratifying patients.

What is known and what is new?

• Some biomarkers of systemic inflammation have been studied as possible prognostic factors in tumors.

• The classification we propose using NLR and serum CA 19-9 levels could be a better prognostic tool to guide and optimize treatment and follow-up strategies than used separately.

What is the implication, and what should change now?

• Identifying appropriate biomarkers to predict recurrence and survival is essential to improve the determination of prognosis and selection of the best treatment strategy in patients with pancreatic cancer.

• Both biomarkers (NLR and CA 19-9) are accessible, inexpensive, and easily measured, which may facilitate and expand their use.

Introduction

Background

Pancreatic cancer incidence is increasing and projected to be the second leading cause of cancer death by 2030 in the U.S. (1). Despite advances in recent years in the oncological management of pancreatic cancer, it remains one of the most lethal neoplasms with a 5-year survival rate from 5% to 15% and an overall survival (OS) rate of 6% (2), mainly due to early recurrence or progression of the disease despite optimal treatment; even in patients undergoing surgical resection the 5-year survival rate is around 20% (3). In general, pancreatic cancer is considered a systemic disease even if diagnosed in early stages, which occurs in only 10–15% of cases, and most cases are diagnosed with unresectable or metastatic disease. Because of poor outcomes in pancreatic cancer patients, biomarkers are necessary to better predict prognosis and improve treatment strategies.

Rationale and knowledge gap

Carbohydrate antigen 19-9 (CA 19-9) is a cell surface glycoprotein complex, produced by the ductal cells of the pancreas and other organs. It is overexpressed in a wide range of benign diseases such as cholestasis and malignant diseases, mainly in pancreatic ductal adenocarcinoma (PDAC) (4,5). It has been used as a useful biomarker in diagnosis, assessment of resectability, monitoring response to treatment, prognosis, and surveillance in pancreatic cancer (6-9). It reflects biological aggressiveness and is a predictor of hematogenous dissemination, micrometastatic, and metastatic disease since this biomarker plays a role in malignant cell-adhesion to endothelial cells and transmigration (10,11). CA 19-9 values are a valuable prognostic marker in patients undergoing curative resection or neoadjuvant chemotherapy. Previous studies have reported the association between CA 19-9 level and survival in pancreatic cancer. Therefore, postoperative follow-up is important since an increase in serum levels of CA 19-9 may predict recurrence of pancreatic cancer (12-14).

Neutrophil-to-lymphocyte ratio (NLR) is one of the most studied indicators of systemic inflammatory response. Neutrophils are known to infiltrate tumors, contributing to the tumor microenvironment for secretion of cytokines, while lymphocytes induce cell death. NLR has been increasingly validated as a fundamental prognostic factor in different stages of the disease, suggesting that high levels of NLR may reflect unresectable disease or progression depending on the case (15,16). NLR has shown to have a prognostic impact in some malignancies (17-22) including pancreatic cancer (23,24), while other studies have not demonstrated NLR to have a prognostic value in pancreatic cancer patients (25-27).

Previous studies and meta-analysis have shown high NLR to be a predictor of poor outcomes in pancreas cancer patients although a definitive cut-off value has not been established (28,29). Therefore, identifying appropriate biomarkers to predict recurrence and survival is essential to improve the determination of prognosis and selection of the best treatment strategy in patients with pancreatic cancer.

Objective

The aim of this study was to evaluate the role of pretreatment NLR and serum CA 19-9 values alone, and the combination of both values as prognostic factors in patients with PDAC of all stages. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-893/rc).

Methods

We conducted a retrospective cohort study in patients with pancreatic cancer at Instituto Nacional de Cancerología. We explored the prognosis impact of NLR, serum CA 19-9, and the combination of both values, with primary endpoints being OS and progression-free survival (PFS). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Research and Ethics Committee of Instituto Nacional de Cancerología (No. 2023/020). Informed consent from patients was waived due to the retrospective nature of this study.

Patients

From 2013 to 2018, all patients diagnosed with pancreatic cancer at our institution regardless of stage at diagnosis were retrospectively screened for inclusion. We included patients with histologically confirmed PDAC, over 18 years, complete files with serum levels of lymphocytes, neutrophils and CA 19-9. Patients with previous treatment at other institution, with metachronous or synchronous malignancies, and with missing data were excluded. A final cohort of 153 patients was analyzed.

Data collection

Clinical and pathological variables of patients were collected from electronic medical records. Serum lymphocyte and neutrophil levels at diagnosis were collected, as well as serum CA 19-9 levels at diagnosis. The NLR was calculated by dividing the absolute blood neutrophil count by the absolute blood lymphocyte count. All patients were staged according to the 8th edition American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) staging system. Information regarding patient status and disease progression was collected. Patients were followed up regularly (every 2 weeks while receiving chemotherapy and every 2 months otherwise). Follow-up included clinical examinations, laboratory testing, and imaging [computed tomography (CT) scan, positron emission tomography-CT (PET-CT), magnetic resonance imaging (MRI)], according to international guidelines. OS was defined as the time from the date of diagnosis to the date of death or last follow-up visit. PFS was defined as the time from the diagnosis to the date of documented recurrence or progression of the disease during follow-up.

Statistical analysis

Continuous variables were presented as median with 95% confidence interval (CI), categorical variables were presented as percentage and compared using Chi-squared or Fisher’s exact test. OS and PFS were calculated using the Kaplan-Meier method and compared with log-rank test. Differences were considered statistically significant when P<0.05. Additionally, multivariate Cox regression analysis was performed to identify association between each variable and survivals; hazard ratios (HRs) and their respective 95% CI were calculated. Only statistically significant variables in the univariate analysis were included in the subsequent multivariate analysis.

To determine the optimal cut-off values of NLR and CA 19-9 we used X-tile software (version 3.6.1, Yale University, U.S.). The cut-off with the lowest P value calculated from the Chi-squared test for OS was selected and patients were classified as having either low- or high-NLR and CA 19-9. The optimal cut-off values were first determined for the entire cohort and later it was identified independently within the subgroups. The best cutoff value of NLR was 2.4, and the cutoff value of CA 19-9 was 553 U/mL. The prognostic value of combined NLR and serum CA 19-9 levels at diagnosis was evaluated by the Cox model and presented as an HR. Statistical analysis was conducted using SPSS software (SPSS 27.0, IBM, Chicago, IL, USA).

Results

Determination of cut-off values for NLR and CA 19-9

The optimal cut-off point value in the whole cohort was set at 2.4 for NLR, and 553 U/mL for serum CA 19-9. Patients were classified as having low-NLR or low-CA 19-9 if their levels were equal to or below the cut-off points and high-NLR or high-CA 19-9 if their levels were above the cut-off points.

According to the cut-off values obtained for NLR and CA 19-9 and in order to explore the combined use of these biomarkers as a prognostic factor, the patients were divided into two groups: Group 1 when both values of NLR and CA 19-9 were low (low-NLR/low-CA 19-9), and Group 2 when either one or both values of NLR and CA 19-9 were high (low-NLR/high-CA 19-9, or high-NLR/low-CA 19-9, or high-NLR/high-CA 19-9).

Patient characteristics and clinical outcomes

One hundred and fifty-three patients were included. The median age was 60 years (95% CI: 28–82) and 52.9% were male. The median tumor size was 4.0 cm (95% CI: 1.6–11.0), the median CA 19-9 was 409 U/mL (95% CI: 2.5–280,000) and the median NLR value was 2.67 (95% CI: 0.12–34.0). Clinicopathologic baseline characteristics and comparisons between groups are shown in Table 1. There was a significant difference between the low-NLR (≤2.4) and high-NLR (>2.4) groups in Eastern Cooperative Oncology Group performance status (ECOG PS), node status, and systemic treatment received. Comparing the low-CA 19-9 (≤553 U/mL) and high-CA 19-9 (>553 U/mL) groups there was a significant difference in age, tumor size, and presence of metastases. According to the classification groups created combining both values of NLR and CA 19-9 there was a significant difference between Group 1 (both low-NLR and low-CA 19-9) and Group 2 (either one or both values of NLR and CA 19-9 high) in ECOG PS, vascular invasion, tumor size, presence of metastases, clinical stage, and global treatment received.

Table 1 Clinicopathologic characteristics and comparison between groups

Characteristic	Total (n=153)	NLR		CA 19-9, U/mL		Groups	
≤2.4 (n=60)	>2.4 (n=93)	P value	≤553 (n=80)	>553 (n=73)	P value	Group 1 (n=40)	Group 2 (n=113)	P value	
Age, n (%)				0.42				0.02*				0.07	
   ≤65 years	107 (69.9)	43 (71.7)	64 (68.8)			62 (77.5)	45 (61.6)			32 (80.0)	75 (66.4)		
   >65 years	46 (30.1)	17 (28.3)	29 (31.2)			18 (22.5)	28 (38.4)			8 (20.0)	38 (33.6)		
Gender, n (%)				0.28				0.51				0.31	
   Female	72 (47.1)	26 (43.3)	46 (49.5)			38 (47.5)	34 (46.6)			17 (42.5)	55 (48.7)		
   Male	81 (52.9)	34 (56.7)	47 (50.5)			42 (52.5)	39 (53.4)			23 (57.5)	58 (51.3)		
BMI (kg/m2), n (%)				0.37				0.56				0.78	
   <18.5	5 (3.3)	1 (1.7)	4 (4.3)			3 (3.8)	2 (2.7)			1 (2.5)	4 (3.5)		
   18.5–24.9	83 (54.2)	32 (53.3)	51 (54.8)			45 (56.2)	38 (52.1)			20 (50.0)	63 (55.8)		
   25–29.9	44 (28.8)	21 (35.0)	23 (24.7)			24 (30.0)	20 (27.4)			14 (35.0)	30 (26.5)		
   ≥30	21 (13.7)	6 (10.0)	15 (16.1)			8 (10.0)	13 (17.8)			5 (12.5)	16 (14.2)		
ECOG-PS, n (%)				0.01*				0.48				0.047*	
   0–1	127 (83.0)	55 (91.7)	72 (77.4)			67 (83.8)	60 (82.2)			37 (92.5)	90 (79.6)		
   ≥2	26 (17.0)	5 (8.3)	21 (22.6)			13 (16.2)	13 (17.8)			3 (7.5)	23 (20.4)		
Tumor location, n (%)				0.32				0.24				0.21	
   Head	134 (87.6)	54 (90.0)	80 (86.0)			72 (90.0)	62 (84.9)			37 (92.5)	97 (85.8)		
   Body-tail	19 (12.4)	6 (10.0)	13 (14.0)			8 (10.0)	11 (15.1)			3 (7.5)	16 (14.2)		
Tumor differentiation, n (%)				0.56				0.96				0.32	
   Well	8 (5.2)	4 (6.6)	4 (4.3)			4 (5.0)	4 (5.5)			3 (7.5)	5 (4.4)		
   Moderate	47 (30.7)	16 (26.6)	31 (33.3)			25 (31.2)	22 (30.1)			15 (37.5)	32 (28.3)		
   Poor	24 (15.7)	7 (11.6)	17 (18.2)			12 (15.0)	12 (16.4)			4 (40.0)	20 (17.7)		
Vascular involvement, n (%)				0.39				0.15				0.01*	
   No	61 (39.9)	26 (43.3)	35 (37.6)			36 (45)	25 (34.2)			21 (52.5)	40 (35.4)		
   Venous	37 (24.2)	16 (26.7)	21 (22.6)			22 (27.5)	15 (20.5)			12 (30.0)	25 (22.1)		
   Arterial	21 (13.7)	9 (15.0)	12 (12.9)			8 (10.0)	13 (17.8)			5 (12.5)	16 (14.2)		
   Both	34 (22.2)	9 (15.0)	25 (26.9)			14 (17.5)	20 (27.4)			2 (5.0)	32 (28.3)		
Tumor size, n (%)				0.17				0.04*				0.009*	
   ≤4 cm	73 (47.7)	32 (53.3)	41 (44.1)			44 (55.0)	29 (39.7)			26 (65.0)	47 (41.6)		
   >4 cm	80 (52.3)	28 (46.7)	52 (55.9)			36 (45.0)	44 (60.3)			14 (35.0)	66 (58.4)		
T, n (%)				0.60				0.43				0.24	
   T1	10 (6.5)	4 (6.7)	6 (6.5)			6 (7.5)	4 (5.5)			4 (10.0)	6 (5.3)		
   T2–T4	143 (93.5)	56 (93.3)	87 (93.5)			74 (92.5)	69 (94.5)			36 (90.0)	107 (94.7)		
N, n (%)				0.04*				0.44				0.052	
   N0	53 (34.6)	28 (46.7)	25 (26.8)			31 (38.8)	22 (30.1)			20 (50.0)	33 (29.2)		
   N+	100 (65.4)	32 (53.3)	68 (73.2)			49 (61.2)	51 (69.9)			20 (50.0)	80 (70.8)		
M, n (%)				0.19				0.03*				0.046*	
   M0	84 (54.9)	36 (60.0)	48 (51.6)			50 (62.5)	34 (46.6)			27 (67.5)	57 (50.4)		
   M1	69 (45.1)	24 (40.0)	45 (48.4)			30 (37.5)	39 (53.4)			13 (32.5)	56 (49.6)		
Clinical stage, n (%)				0.08				0.07				0.01*	
   I–II	48 (31.4)	25 (41.7)	23 (24.7)			31 (38.8)	17 (23.3)			20 (50.0)	28 (24.8)		
   III	38 (24.8)	12 (20.0)	26 (28.0)			20 (25.0)	18 (24.7)			8 (20.0)	30 (26.5)		
   IV	67 (43.8)	23 (38.3)	44 (47.3)			29 (36.2)	38 (52.1)			12 (30.0)	55 (48.7)		
Global treatment, n (%)				0.13				0.06				0.03*	
   Surgery followed by ChT	20 (13.1)	11 (18.3)	9 (9.6)			16 (20.0)	4 (5.5)			10 (25.0)	10 (8.8)		
   Neoadjuvant ChT +/− RT	45 (29.4)	20 (33.3)	25 (26.8)			22 (27.5)	23 (31.5)			12 (30.0)	33 (29.2)		
   Palliative ChT	43 (28.1)	17 (28.3)	26 (28.0)			21 (26.2)	22 (30.1)			11 (27.5)	32 (28.3)		
   Supportive care	45 (29.4)	12 (20.0)	33 (35.5)			21 (26.2)	24 (32.9)			7 (17.5)	38 (33.6)		
Systemic treatment, n (%)				0.04*				0.54				0.06	
   None	50 (32.7)	14 (23.3)	36 (38.7)			26 (32.5)	24 (32.9)			9 (22.5)	41 (36.3)		
   Monotherapy (gemcitabine/capecitabine)	54 (35.3)	29 (48.3)	25 (26.9)			32 (40.0)	22 (30.1)			21 (52.5)	33 (29.2)		
   Doublet (Gemox/Xelox/GemNab)	38 (24.8)	14 (23.3)	24 (25.8)			17 (21.3)	21 (28.8)			8 (20.0)	30 (26.5)		
   Triplet (Folfirinox)	11 (7.2)	3 (5.0)	8 (8.6)			5 (6.2)	6 (8.2)			2 (5.0)	9 (8.0)		
Group 1, both values of NLR and CA 19-9 were low; Group 2, either one or both values of NLR and CA 19-9 were high. *, P<0.05 indicates statistically significant. NLR, neutrophil-to-lymphocyte ratio; CA 19-9, carbohydrate antigen 19-9; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; PS, performance status; cm, centimeters; T, tumor; N, nodes; M, metastasis; ChT, chemotherapy; RT, radiotherapy; Gemox, gemcitabine and oxaliplatin; Xelox, capecitabine and oxaliplatin; GemNab, Gemcitabine and Nab-paclitaxel; Folfirinox, 5-fluorouracil, leucovorin, irinotecan and oxaliplatin.

For the entire cohort the median follow-up was 7.3 months (95% CI: 1.0–78.9), the median PFS was 6.2 months (95% CI: 5.4–7.0) and the median OS was 10.1 months (95% CI: 7.1–13.1). The 1-, 3- and 5-year OS rates were 42%, 11%, and 4.9% respectively, and the 1-, 3- and 5-years PFS were 23.3%, 3.2%, and 2.4% respectively.

The median OS, 1-, 3- and 5-year survival rates were 13.2 months (95% CI: 11.2–15.1) and 58.7%, 15.1%, and 9.0% respectively in low-NLR group (≤2.4), and 6.7 months (95% CI: 5.6–7.8) and 30.8%, 8.1%, and 2.0% respectively in high-NLR group (>2.4) with a significant difference between two groups (P=0.008). According to CA 19-9 value the median OS, 1-, 3- and 5-year survival rates were 13.1 months (95% CI: 8.9–17.4) and 54.3%, 17.0%, and 8.5% respectively in low-CA 19-9 group (≤553 U/mL); 6.8 months (95% CI: 5.1–8.6) and 28.8%, 3.5%, and 0% respectively in high-CA 19-9 group (>553 U/mL) with a significant difference between both groups (P=0.002). According to the classification groups created combining both values of NLR and CA 19-9, the median OS, 1-, 3- and 5-year survival rates were 15.3 months (95% CI: 13.5–17.0) and 69.4%, 19.7%, and 11.8% respectively in Group 1 (both low-NLR and low-CA 19-9); 6.8 months (95% CI: 5.4–8.2), 31.8%, 7.5% and 1.9% respectively in Group 2 (either one or both high-NLR or CA 19-9) also with a significant difference between groups (P<0.001) (Figure 1A-1C).

Figure 1 Comparison of overall survival curves in pancreatic cancer patients based on prognostic biomarkers. Overall survival according to (A) NLR value, (B) CA 19-9 value, and (C) groups using the combination of NLR and CA 19-9 values. Group 1, both values of NLR and CA 19-9 were low; Group 2, either one or both values of NLR and CA 19-9 high. NLR, neutrophil-to-lymphocyte ratio; CA 19-9, carbohydrate antigen 19-9.

The median PFS, 1-, 3- and 5-year survival rates were 9.0 months (95% CI: 5.9–12), 30.6%, 5.7%, and 5.7% respectively in patients with low-NLR (≤2.4); and 5.6 months (95% CI: 4.6–6.5), 18.5%, 1.3%, and 0% respectively in patients with high-NLR (>2.4) with a significant difference between two groups (P=0.007). According to CA 19-9 value the median PFS, 1-, 3- and 5-year survival rates were 6.9 months (95% CI: 4.8–9.0) and 28.7%, 5.5%, and 4.1% respectively in patients with low-CA 19-9 (≤553 U/mL); and 5.0 months (95% CI: 3.9–6.2), 17.4%, 0% and 0% respectively in patients with high-CA 19-9 (>553 U/mL) with a significant difference between two groups (P=0.005). According to the classification groups created combining both values of NLR and CA 19-9, the median PFS, 1-, 3- and 5-year survival rates were 10.9 months (95% CI: 9.0–12.9), 39.9%, 8.6% and 8.6% respectively in Group 1 (both low-NLR and low-CA 19-9); and 5.4 months (95% CI: 4.6–6.3), 17.4%, 1.1%, and 0% respectively in Group 2 (either one or both high-NLR or CA 19-9) with a significant difference between groups (P=0.001) (Figure 2A-2C).

Figure 2 Comparison of progression-free survival in pancreatic cancer patients based on prognostic biomarkers. Progression-free survival according to (A) NLR value, (B) CA 19-9 value, and (C) Groups using the combination of NLR and CA 19-9 values. Group 1, both values of NLR and CA 19-9 were low; Group 2, either one or both values of NLR and CA 19-9 high. NLR, neutrophil-to-lymphocyte ratio; CA 19-9, carbohydrate antigen 19-9.

Univariate and multivariate survival analyses

Cox regression analysis was performed to determine factors associated with OS and PFS. In multivariate analysis ECOG-PS, tumor differentiation, presence of metastases, global treatment received, systemic treatment received, NLR value, serum CA 19-9 value and classification group combining NLR and CA 19-9 values were identified as independent prognostic factors for OS (Table 2).

Table 2 Univariate and multivariate analyses for factors associated with OS

Variable	Total (events)	Median OS (95% CI), months	Univariate analysis, P value	Multivariate analysis	
HR (95% CI)	P value	
Age, n (%)			0.18			
   ≤65 years	107 (69.9)	10.7 (7.6–13.9)				
   >65 years	46 (30.1)	6.5 (1.4–11.6)				
Gender, n (%)			0.91			
   Female	72 (47.1)	9.3 (5.3–13.4)				
   Male	81 (52.9)	10.7 (6.0–15.5)				
BMI (kg/m2), n (%)			0.76			
   <18.5	5 (3.3)	3.7 (0)				
   18.5–24.9	83 (54.2)	10.7 (5.7–15.8)				
   25–29.9	44 (28.8)	9.3 (4.9–13.8)				
   ≥30	21 (13.7)	6.8 (1.4–12.2)				
ECOG-PS, n (%)			0.01	2.008 (1.235–3.265)	0.005	
   0–1	127 (83.0)	10.8 (7.8–13.7)				
   ≥2	26 (17.0)	6.2 (3.0–9.4)				
Tumor location, n (%)			0.24			
   Head	134 (87.6)	10.7 (7.4–14.1)				
   Body-tail	19 (12.4)	8.0 (3.4–12.7)				
Tumor differentiation, n (%)			0.001	1.644 (1.249–2.164)	<0.001	
   Well/moderate	55 (35.9)	12.8 (8.7–17.0)				
   Poor	24 (15.6)	6.5 (3.0–9.9)				
Vascular invasion, n (%)			0.28			
   No	61 (39.9)	10.7 (7.2–14.3)				
   Yes	92 (60.1)	8.6 (5.1–12.2)				
Tumor size, n (%)			0.37			
   ≤4 cm	73 (47.7)	10.5 (5.6–15.5)				
   >4 cm	80 (52.3)	8.6 (4.8–12.5)				
T, n (%)			0.06			
   T1	10 (6.5)	16.7 (9.9–23.6)				
   T2–T4	143 (93.5)	9.4 (6.6–12.3)				
N, n (%)			0.20			
   N0	53 (34.6)	12.8 (9.7–16.0)				
   N+	100 (65.4)	7.1 (3.7–10.4)				
M, n (%)			<0.001	2.492 (1.415–4.389)	0.002	
   M0	84 (54.9)	13.2 (9.3–17.0)				
   M1	69 (45.1)	5.8 (4.1–7.6)				
Global treatment, n (%)			<0.001	2.440 (1.763–3.378)	<0.001	
   Surgery followed by ChT	20 (13.1)	21.6 (8.3–34.8)				
   Neoadjuvant ChT +/− RT	45 (29.4)	16.7 (12.0–21.4)				
   Palliative ChT	43 (28.1)	7.1 (1.4–12.7)				
   Supportive care	45 (29.4)	3.0 (2.4–3.6)				
Systemic treatment, n (%)			<0.001	0.639 (0.507–0.806)	<0.001	
   None	50 (32.7)	3.4 (2.6–4.1)				
   Monotherapy (gemcitabine/capecitabine)	54 (35.3)	14.2 (11.9–16.4)				
   Doublet (Gemox/Xelox/GemNab)	38 (24.8)	11.5 (8.7–14.3)				
   Triplet (Folfirinox)	11 (7.2)	17.8 (7.4–28.1)				
NLR			0.008	1.653 (1.135–2.408)	0.009	
   ≤2.4	60 (39.2)	13.2 (11.2–15.1)				
   >2.4	93 (60.8)	6.7 (5.6–7.8)				
CA 19-9, U/mL			0.002	1.787 (1.237–2.582)	0.002	
   ≤553	80 (52.3)	13.1 (8.9–17.4)				
   >553	73 (47.7)	6.8 (5.1–8.6)				
Groups			<0.001	2.127 (1.383–3.272)	0.001	
   Group 1	40 (26.1)	15.3 (13.5–17.0)				
   Group 2	113 (73.9)	6.8 (5.4–8.2)				
Group 1, both values of NLR and CA 19-9 were low; Group 2, either one or both values of NLR and CA 19-9 were high. OS, overall survival; CI, confidence interval; HR, hazard ratio; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; PS, performance status; cm, centimeters; T, tumor; N, nodes; M, metastasis; ChT, chemotherapy; RT, radiotherapy; Gemox, gemcitabine and oxaliplatin; Xelox, capecitabine and oxaliplatin; GemNab, gemcitabine and Nab-paclitaxel; Folfirinox, 5-fluorouracil, leucovorin, irinotecan and oxaliplatin; NLR, neutrophil-to-lymphocyte ratio; CA 19-9, carbohydrate antigen 19-9.

In multivariate analysis, presence of metastases, global treatment received, systemic treatment received, NLR value, CA 19-9 value and classification group combining NLR and CA 19-9 values were identified as independent prognostic factors for PFS (Table 3).

Table 3 Univariate and multivariate analyses for factors associated with PFS

Variable	Total (events)	Median PFS (95% CI), months	Univariate analysis, P value	Multivariate analysis	
HR (95% CI)	P value	
Age, n (%)			0.40			
   ≤65 years	107 (69.9)	6.2 (5.1–7.4)				
   >65 years	46 (30.1)	6.2 (3.9–8.5)				
Gender, n (%)			0.79			
   Female	72 (47.1)	5.7 (4.5–6.8)				
   Male	81 (52.9)	6.7 (5.0–8.5)				
BMI (kg/m2), n (%)			0.55			
   <18.5	5 (3.3)	3.7 (1.7–5.8)				
   18.5–24.9	83 (54.2)	6.2 (5.4–7.1)				
   25–29.9	44 (28.8)	6.6 (3.6–9.5)				
   ≥30	21 (13.7)	5.3 (4.7–5.8)				
ECOG-PS, n (%)			0.045	1.043 (0.434–2.506)	0.92	
   0–1	127 (83.0)	6.3 (5.1–7.6)				
   ≥2	26 (17.0)	3.8 (0.6–7.0)				
Tumor location, n (%)			0.15			
   Head	134 (87.6)	6.3 (5.5–7.2)				
   Body-tail	19 (12.4)	5.3 (4.7–5.8)				
Tumor differentiation, n (%)			0.002	1.313 (0.977–1.764)	0.07	
   Well/moderate	8 (5.2)	8.6 (5.3–12.0)				
   Poor	47 (30.7)	4.9 (2.7–7.0)				
Vascular invasion, n (%)			0.02	0.823 (0.460–1.475)	0.51	
   No	61 (39.9)	6.9 (3.3–10.5)				
   Yes	92 (60.1)	5.6 (4.3–6.8)				
Tumor size, n (%)			0.02	1.210 (0.669–2.188)	0.52	
   ≤4 cm	73 (47.7)	6.9 (5.2–8.5)				
   >4 cm	80 (52.3)	5.6 (4.5–6.6)				
T, n (%)			0.04	0.923 (0.325–2.616)	0.88	
   T1	10 (6.5)	16.4 (8.7–24.2)				
   T2–T4	143 (93.5)	5.9 (5.1–6.7)				
N, n (%)			0.03	1.092 (0.596–2.000)	0.77	
   N0	53 (34.6)	7.0 (4.2–9.7)				
   N+	100 (65.4)	5.6 (4.6–6.6)				
M, n (%)			<0.001	1.403 (0.991–1.987)	0.049	
   M0	84 (54.9)	8.6 (6.3–10.9)				
   M1	69 (45.1)	4.6 (3.4–5.8)				
Global treatment, n (%)			<0.001		<0.001	
   Surgery followed by ChT	20 (13.1)	14.4 (9.5–19.1)		1.983 (1.573–2.499)		
   Neoadjuvant ChT +/− RT	45 (29.4)	10.6 (8.2–13.0)				
   Palliative ChT	43 (28.1)	5.4 (4.4–6.5)				
   Supportive care	45 (29.4)	2.7 (2.4–3.0)				
Systemic treatment, n (%)			<0.001	1.724 (1.100–2.703)	0.01	
   None	50 (32.7)	2.8 (2.3–3.2)				
   Monotherapy (gemcitabine/capecitabine)	54 (35.3)	8.12 (6.1–10.2)				
   Doublet (Gemox/Xelox/GemNab)	38 (24.8)	7.6 (2.6–12.5)				
   Triplet (Folfirinox)	11 (7.2)	11.8 (2.8–20.7)				
NLR			0.007	1.511 (1.074–2.126)	0.01	
   ≤2.4	60 (39.2)	9.0 (5.9–12.0)				
   >2.4	93 (60.8)	5.6 (4.6–6.5)				
CA 19-9, U/mL			0.005	1.606 (1.149–2.246)	0.006	
   ≤553	80 (52.3)	6.9 (4.8–9.0)				
   >553	73 (47.7)	5.0 (3.9–6.2)				
Groups			0.001	1.961 (1.327–2.897)	0.001	
   Group 1	40 (26.1)	10.9 (9.0–12.9)				
   Group 2	113 (73.9)	5.4 (4.6–6.3)				
Group 1, both values of NLR and CA 19-9 were low; Group 2, either one or both values of NLR and CA 19-9 were high. PFS, progression-free survival; CI, confidence interval; HR, hazard ratio; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; PS, performance status; cm, centimeters; T, tumor; N, nodes; M, metastasis; ChT, chemotherapy; RT, radiotherapy; Gemox, gemcitabine and oxaliplatin; Xelox, capecitabine and oxaliplatin; GemNab, gemcitabine and Nab-paclitaxel; Folfirinox, 5-fluorouracil, leucovorin, irinotecan and oxaliplatin; NLR, neutrophil-to-lymphocyte ratio; CA 19-9, carbohydrate antigen 19-9.

Discussion

Key findings

Pancreatic cancer is one of the leading causes of cancer-related deaths globally, and even in patients who receive optimal treatment for each stage, the prognosis is dismal. Therefore, it is of utmost importance to identify prognostic biomarkers that will help us to select patients who may benefit from more aggressive treatment strategies (neoadjuvant chemotherapy and/or radiation) and closer follow-up to prevent and diagnose early recurrences respectively.

The present study demonstrated that high-NLR (>2.4) and high-CA 19-9 (>553 U/mL) values used separately are both independently associated with poorer OS and PFS in patients with pancreatic cancer of all stages.

The classification of two groups we created by combining both NLR and serum CA 19-9 values showed better prognostic significance on OS and PFS than when both biomarkers are used separately.

Strengths and limitations

Limitations of this study are that it is a retrospective single-center study with a relatively small number of patients. A definitive optimal cut-off value for NLR and CA 19-9 has not been established and differences between studies may be explained by the different stages of pancreatic cancer and the number of patients included in studies. A larger prospective multicenter study is needed to determine and validate the optimal cut-off values of these biomarkers and their prognostic importance used separately and in combination.

Comparison with similar researches

The prognostic significance of NLR in pancreatic cancer was explored by another study and is matching with our cut-off (2.4), different levels in other studies ranged from 2.62 to 3.74. In general, all the results reveal that a high NLR at the time of diagnosis or post-treatment could be an independent indicator of poor prognosis and is associated with metastatic stage in patients with pancreatic cancer (15,16,30). Kim et al. identified a high NLR (>2.8) and CA 19-9 (>70 U/mL) as independent predictors of worse disease-free survival (DFS), but only high CA 19-9 and not high NLR as independent predictor of worse OS, combining both values they found patients with both high-NLR and high-CA 19-9 levels to have worse OS and recurrence rates, however this study only enrolled resected patients with pancreatic head cancer (31). Song et al. also demonstrated that high NLR (>3.75) and CA 19-9 (>626 U/mL) are independently associated with worse OS and that the combined use of both in similar classification groups to ours better predicts OS than when both values used separately, but this study was limited to metastatic patients and only analyzed association with OS and not with PFS (32). Asaoka et al. similarly to us demonstrated the prognostic utility of the combination of these two parameters, showing that when one of these parameters NLR or CA 19-9 was elevated above their cut-off values, OS and DFS were significantly poorer than those in patients with both low CA 19-9 and NLR, however, their analysis was restricted to a small group of surgically resected pancreatic head cancer patients (29).

Explanations of findings

In this study, we evaluated serum CA 19-9 and NLR values at diagnosis and the combination of these two values in a simple classification as prognostic factors for patients with pancreatic cancer of all stages in a single referral center and demonstrated that elevated CA 19-9 and NLR values were independent predictors of worse OS and PFS. Moreover, the combination of these two parameters seems to better predict prognosis according to multivariate analysis, and patients with both low-NLR and low-CA 19-9 (Group 1) showed better OS and DFS when compared with patients with either one or both high-NLR or high-CA 19-9 (Group 2).

The cut-off value obtained in our cohort for CA 19-9 was 553 U/mL, and patients with CA 19-9 above this level were associated with larger tumor size, higher proportion of metastatic disease at diagnosis, and worse PFS and OS. Several studies have demonstrated that high levels of serum CA 19-9 are associated with worse prognosis in pancreatic cancer patients in different clinical settings and with variable cut-off values reported (33,34). However, the main limitations in the use of CA 19-9 alone as a reliable biomarker in patients with pancreatic cancer are that up to 10% of the population does not produce it and the false positive elevation in patients with obstructive jaundice which could lead to a misinterpretation of serum CA 19-9 levels for prognosis purposes.

Regarding NLR, the cut-off value obtained in this study was 2.4 with patients showing worse PFS and OS when NLR was above this level and was also associated with poorer performance status, higher proportion of nodal disease at diagnosis, and lesser likelihood to receive oncologic treatment. Chen et al. reported a cut-off value of 2.78 for NLR in advanced pancreatic cancer, with high-NLR independently associated with worse OS (35). Luo et al. determined an NLR cut-off value of 3.1 as an independent prognostic factor for OS in patients with advanced pancreatic cancer undergoing chemotherapy (36). Similar to our study, Shin et al. reported an NLR cut-off value of 2.6 to have prognostic significance for both PFS and OS, but this study only included patients with advanced pancreatic cancer receiving first-line chemotherapy (15). Also, Dogan et al. reported NRL with a cut-off value of 3.0 to be an independent prognostic factor for OS and PFS but they included only patients with metastatic pancreatic cancer in their study (5). Previous meta-analysis demonstrated that pancreatic cancer patients with low NLR have longer OS and DFS compared to patients with high NLR (16,24,37,38) which is consistent with our results.

Cetin et al. showed that high NLR (>3.5) and CA 19-9 levels (>437 U/mL) are both independently associated with worse OS in patients with metastatic pancreas cancer (39). Similarly, Asaoka et al. demonstrated pretreatment serum CA 19-9 >230 U/mL and NLR >2.7 were independent risk factors for poorer OS and DFS in surgically resected pancreatic cancer patients (29).

Furthermore, the classification of two groups we created by combining both NLR and serum CA 19-9 values showed better prognostic significance on OS and PFS than when both biomarkers are used separately as demonstrated with survival analysis and multivariate analysis. Also using our classification groups, Group 2 patients (either one or both high-NLR or high-CA 19-9 levels) were significantly associated with poorer performance status, higher occurrence of tumor vascular involvement, larger tumor size, higher proportion of metastatic disease at diagnosis, more advanced clinical stage, and less proportion of patients undergoing surgery and more patients receiving best supportive care compared with Group 1 patients (both low-NLR and low-CA 19-9 levels).

Implications and actions needed

Currently CA 19-9 is the most widely used and endorsed biomarker for PDAC, useful for decision of initial treatment, monitoring of treatment response, prognosis and follow-up in PDAC patients (15). Nevertheless, up to 10% of patients do not produce and thus do not elevate CA 19-9 (40) and different biomarkers other than CA 19-9 would be useful and necessary in this group of patients to predict tumor recurrence or progression. Inflammation plays a role in cancer initiation and progression, and tumor suppression by immune cells such as lymphocytes is impaired by inflammatory cascade in addition to cancer cells (41). Moreover, PDAC specially seems to be associated with lymphocytopenia (42). The NLR, a biomarker that reflects the systemic immune and inflammatory responses, has demonstrated a prognostic significance in patients with pancreatic cancer in specific different clinical stages and scenarios (16,43-45). However, few studies have evaluated its prognostic impact in pancreatic cancer patients of all clinical stages regardless of the treatment received (29). NLR and serum CA 19-9 used independently and especially combined are useful as predictors of OS and PFS in patients with pancreatic cancer, the classification we propose using both NLR and serum CA 19-9 levels could be a better prognostic tool to guide and optimize treatment and follow-up strategies than NLR and serum CA 19-9 levels used separately. Also, both biomarkers are accessible, inexpensive and readily measurable which may facilitate and expand their use and the classification we propose is simple, practical and easy to apply.

Conclusions

Our results demonstrated that in patients with PDAC, regardless stage and treatment, high-NLR and high-CA 19-9 levels at diagnosis are both independent prognostic factors for worse DFS and OS when used separately and that the combination of these two biomarkers seems to better predict prognosis and stratify patients to guide treatment and surveillance strategies than when used separately. Although a specific cut-off value has not been established, our study has demonstrated the prognostic utility of the combination of NLR and CA 19-9, when both parameters are elevated, they have worse survival than patients with both parameters below the cut-off point and assume disease in advanced stages. Furthermore, the implementation of these parameters is a great option since they are very practical to calculate in daily clinical practice. Furthermore, the implementation of these parameters is a great option since they are very practical to calculate in daily clinical practice.

Supplementary

The article’s supplementary files as

10.21037/jgo-23-893 10.21037/jgo-23-893

Acknowledgments

Funding: None.

Data Sharing Statement

Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-893/dss 10.21037/jgo-23-893

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Instituto Nacional de Cancerología (No. 2023/020) and individual consent for this retrospective analysis was waived.

Peer Review File
Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-893/prf

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-893/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-893/coif). The authors have no conflicts of interest to declare.
==== Refs
References

1 Rahib L Smith BD Aizenberg R Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74 :2913-21. 10.1158/0008-5472.CAN-14-0155 24840647
2 Puckett Y, Garfield K. Pancreatic Cancer. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 26, 2022.
3 Ferrone CR Pieretti-Vanmarcke R Bloom JP Pancreatic ductal adenocarcinoma: long-term survival does not equal cure. Surgery 2012;152 :S43-9. 10.1016/j.surg.2012.05.020 22763261
4 Lee T Teng TZJ Shelat VG . Carbohydrate antigen 19-9 - tumor marker: Past, present, and future. World J Gastrointest Surg 2020;12 :468-90. 10.4240/wjgs.v12.i12.468 33437400
5 Dogan M Algin E Guven ZT Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, neutrophil-platelet score and prognostic nutritional index: do they have prognostic significance in metastatic pancreas cancer? Curr Med Res Opin 2018;34 :857-63. 10.1080/03007995.2017.1408579 29161926
6 Goonetilleke KS Siriwardena AK . Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33 :266-70. 10.1016/j.ejso.2006.10.004 17097848
7 Sugiura T Uesaka K Kanemoto H Serum CA19-9 is a significant predictor among preoperative parameters for early recurrence after resection of pancreatic adenocarcinoma. J Gastrointest Surg 2012;16 :977-85. 10.1007/s11605-012-1859-9 22411488
8 Hartwig W Strobel O Hinz U CA19-9 in potentially resectable pancreatic cancer: perspective to adjust surgical and perioperative therapy. Ann Surg Oncol 2013;20 :2188-96. 10.1245/s10434-012-2809-1 23247983
9 Humphris JL Chang DK Johns AL The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Ann Oncol 2012;23 :1713-22. 10.1093/annonc/mdr561 22241899
10 Kannagi R. Carbohydrate antigen sialyl Lewis a--its pathophysiological significance and induction mechanism in cancer progression. Chang Gung Med J 2007;30 :189-209.17760270
11 Kishimoto T Ishikura H Kimura C Phenotypes correlating to metastatic properties of pancreas adenocarcinoma in vivo: the importance of surface sialyl Lewis(a) antigen. Int J Cancer 1996;69 :290-4. 10.1002/(SICI)1097-0215(19960822)69:4<290::AID-IJC9>3.0.CO;2-S 8797870
12 Saad ED Machado MC Wajsbrot D Pretreatment CA 19-9 level as a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine. Int J Gastrointest Cancer 2002;32 :35-41. 10.1385/IJGC:32:1:35 12630768
13 Maisey NR Norman AR Hill A CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer 2005;93 :740-3. 10.1038/sj.bjc.6602760 16175188
14 Boeck S Stieber P Holdenrieder S Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer. Oncology 2006;70 :255-64. 10.1159/000094888 16899980
15 Shin K Jung EK Park SJ Neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 as prognostic markers for advanced pancreatic cancer patients receiving first-line chemotherapy. World J Gastrointest Oncol 2021;13 :915-28. 10.4251/wjgo.v13.i8.915 34457195
16 Iwai N Okuda T Sakagami J Neutrophil to lymphocyte ratio predicts prognosis in unresectable pancreatic cancer. Sci Rep 2020;10 :18758. 10.1038/s41598-020-75745-8 33127996
17 Galizia G Lieto E Zamboli A Neutrophil to lymphocyte ratio is a strong predictor of tumor recurrence in early colon cancers: A propensity score-matched analysis. Surgery 2015;158 :112-20. 10.1016/j.surg.2015.02.006 25818659
18 Dong YW Shi YQ He LW Prognostic significance of neutrophil-to-lymphocyte ratio in rectal cancer: a meta-analysis. Onco Targets Ther 2016;9 :3127-34.27307753
19 Azab B Bhatt VR Phookan J Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19 :217-24. 10.1245/s10434-011-1814-0 21638095
20 Zhao QT Yang Y Xu S Prognostic role of neutrophil to lymphocyte ratio in lung cancers: a meta-analysis including 7,054 patients. Onco Targets Ther 2015;8 :2731-8.26491346
21 Kim EY Song KY . The preoperative and the postoperative neutrophil-to-lymphocyte ratios both predict prognosis in gastric cancer patients. World J Surg Oncol 2020;18 :293. 10.1186/s12957-020-02059-4 33172490
22 Li B Xiong F Yi S Prognostic and Clinicopathologic Significance of Neutrophil-to-Lymphocyte Ratio in Esophageal Cancer: An Update Meta-Analysis. Technol Cancer Res Treat 2022;21 :15330338211070140. 10.1177/15330338211070140 35025614
23 Wang DS Luo HY Qiu MZ Comparison of the prognostic values of various inflammation based factors in patients with pancreatic cancer. Med Oncol 2012;29 :3092-100. 10.1007/s12032-012-0226-8 22476808
24 Cheng H Long F Jaiswar M Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: a meta-analysis. Sci Rep 2015;5 :11026. 10.1038/srep11026 26226887
25 Watanabe J Otani S Sakamoto T Prognostic indicators based on inflammatory and nutritional factors after pancreaticoduodenectomy for pancreatic cancer. Surg Today 2016;46 :1258-67. 10.1007/s00595-016-1308-6 26869184
26 Chawla A Huang TL Ibrahim AM Pretherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio do not predict survival in resectable pancreatic cancer. HPB (Oxford) 2018;20 :398-404. 10.1016/j.hpb.2017.10.011 29221789
27 Jamieson NB Denley SM Logue J A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. Ann Surg Oncol 2011;18 :2318-28. 10.1245/s10434-011-1560-3 21267785
28 Garcea G Ladwa N Neal CP Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with reduced disease-free survival following curative resection of pancreatic adenocarcinoma. World J Surg 2011;35 :868-72. 10.1007/s00268-011-0984-z 21312035
29 Asaoka T Miyamoto A Maeda S Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer. Pancreatology 2016;16 :434-40. 10.1016/j.pan.2015.10.006 26852169
30 Onoe S Maeda A Takayama Y The Prognostic Impact of the Lymphocyte-to-Monocyte Ratio in Resected Pancreatic Head Adenocarcinoma. Med Princ Pract 2019;28 :517-25. 10.1159/000501017 31104057
31 Kim WJ Lim TW Park PJ Prognostic impact of the combination of the neutrophil-to-lymphocyte ratio and serum carbohydrate antigen 19-9 in patients with pancreas head cancer. ANZ J Surg 2019;89 :E302-E307. 10.1111/ans.15029 30895709
32 Song JY Chen MQ Guo JH Combined pretreatment serum CA19-9 and neutrophil-to-lymphocyte ratio as a potential prognostic factor in metastatic pancreatic cancer patients. Medicine (Baltimore) 2018;97 :e9707. 10.1097/MD.0000000000009707 29369199
33 Combs SE Habermehl D Kessel KA Prognostic impact of CA 19-9 on outcome after neoadjuvant chemoradiation in patients with locally advanced pancreatic cancer. Ann Surg Oncol 2014;21 :2801-7. 10.1245/s10434-014-3607-8 24916745
34 Reitz D Gerger A Seidel J Combination of tumour markers CEA and CA19-9 improves the prognostic prediction in patients with pancreatic cancer. J Clin Pathol 2015;68 :427-33. 10.1136/jclinpath-2014-202451 25759406
35 Chen Y Yan H Wang Y Significance of baseline and change in neutrophil-to-lymphocyte ratio in predicting prognosis: a retrospective analysis in advanced pancreatic ductal adenocarcinoma. Sci Rep 2017;7 :753. 10.1038/s41598-017-00859-5 28392554
36 Luo G Guo M Liu Z Blood neutrophil-lymphocyte ratio predicts survival in patients with advanced pancreatic cancer treated with chemotherapy. Ann Surg Oncol 2015;22 :670-6. 10.1245/s10434-014-4021-y 25155401
37 Mowbray NG Griffith D Hammoda M A meta-analysis of the utility of the neutrophil-to-lymphocyte ratio in predicting survival after pancreatic cancer resection. HPB (Oxford) 2018;20 :379-84. 10.1016/j.hpb.2017.12.009 29336893
38 Yang JJ Hu ZG Shi WX Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis. World J Gastroenterol 2015;21 :2807-15. 10.3748/wjg.v21.i9.2807 25759553
39 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 Cancer Res Ther 2020;16 :909-16. 10.4103/jcrt.JCRT_366_19 32930139
40 Tempero MA Uchida E Takasaki H Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res 1987;47 :5501-3.3308077
41 Balkwill F Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357 :539-45. 10.1016/S0140-6736(00)04046-0 11229684
42 Fogar P Sperti C Basso D Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas 2006;32 :22-8. 10.1097/01.mpa.0000188305.90290.50 16340740
43 Hasegawa S Eguchi H Tomokuni A Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer. Oncol Lett 2016;11 :1560-6. 10.3892/ol.2015.4057 26893780
44 Alagappan M Pollom EL von Eyben R Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT. Am J Clin Oncol 2018;41 :242-7. 10.1097/COC.0000000000000263 26757436
45 Reddy AV Hill CS Sehgal S High neutrophil-to-lymphocyte ratio following stereotactic body radiation therapy is associated with poor clinical outcomes in patients with borderline resectable and locally advanced pancreatic cancer. J Gastrointest Oncol 2022;13 :368-79. 10.21037/jgo-21-513 35284125
