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ORIGINAL ARTICLE
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The relation between inflammation-based parameters and survival in metastatic pancreatic cancer


1 Departments of Medical Oncology, SBU Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Hacettepe University Cancer Institute, Ankara, Turkey

Date of Submission30-Sep-2019
Date of Decision21-May-2020
Date of Acceptance22-Jun-2020
Date of Web Publication21-Jan-2021

Correspondence Address:
Sema Turker,
Department of Medical Oncology, SBU Diskapi Yildirim Beyazit Training and Research Hospital, Altindag, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_773_19

 > Abstract 


Aim: We aimed to evaluate whether tumor markers and inflammation parameters effect on survival in patients with metastatic pancreatic cancer (MPC).
Patients and Methods: This retrospective analysis included 170 patients with pancreatic cancer who were admitted to the oncology clinic at the metastatic stage. Basic patient demographic characteristics, chemotherapy (CT) that patients received in the first line, complete blood count, neutrophil/lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), albumin/globulin ratio (AGR), prognostic nutritional index (PNI), tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigen 19-9 [CA19-9]), and survival were analyzed. Receiver operating characteristic analysis was used to determine the optimum cutoff value of NLR, PLR, AGR, PNI, CEA, and CA 19-9, which could predict survival.
Results: The median age of the patients was 63 years (range, 33–87). About 63.5% of the patients were male and 44.5% were female. 161 (94.7%) patients died, and the median overall survival (OS) was 8.0 months (95% confidence interval = 6.6–9.4) for all patients. In univariate analysis, age (P < 0.001), CT regime (P < 0.002), AGR (P < 0.006), PNI (P < 0.017), NLR (P < 0.001), PLR (P < 0.062), and CA19-9 (P < 0.002) were statistically significant. In multivariate analysis, age (hazard ratio [HR] 1.534 95% 1.079–2.182 P < 0.017) CA19-9 (HR1.410 95% 1.001-1.989, P ≤0.005) and, NLR (HR 1.569 95% 1.001–2.463, P < 0.049) were significant.
Conclusion: We determined, age, CA19-9, and basal high NLR as independent adverse prognostic factors for OS in APC. Fluorouracil, leucovorin, irinotecan, and oxaliplatin CT resulted in a significant increase in OS.

Keywords: Inflammation-based parameters, metastatic pancreatic cancer, tumor markers



How to cite this URL:
Turker S, Cilbir E, Guven DC, Karacin C, Yalcin S. The relation between inflammation-based parameters and survival in metastatic pancreatic cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Mar 4]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=307513




 > Introduction Top


Pancreatic cancer is one of the most common and fatal diseases. It is responsible for 4.5% of cancer-related deaths in the world.[1] Although surgical resection is the only curative treatment of choice for pancreatic cancer, very few patients are suitable for curative resection. 80%–85% of patients are diagnosed at an advanced stage, and overall survival (OS) is <5%.[2] The aim of chemotherapy (CT) in metastatic disease is to relieve patients' symptoms and to prolong survival. Recently, the prognosis of unresectable or metastatic pancreatic cancer (MPC) has been improved by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) CT. Prognostic factors are, therefore, essential, and accurate identification of poor prognostic factors may help guide more aggressive treatment protocols in patients with pancreatic cancer.

With the recognition of the prognostic significance of the inflammatory response in cancer, prognostic scores based on inflammation have been developed. Neutrophil-lymphocyte ratio (NLR),[3] platelet lymphocyte ratio (PLR),[4] prognostic nutritional index (PNI),[5] albumin/globulin ratio (AGR)[6] was investigated in various malignancies.

NLR is one of the most frequently studied inflammatory parameters in cancer patients.[7],[8],[9] Neutrophils promote the growth of the tumor through the signal triggered by inflammatory cytokines.[10] In contrast, lymphocytes inhibit tumor growth and invasion. It has been emphasized in several studies that the infiltration of lymphocytes to the tumor is associated with a better response to cytotoxic treatment and tumor progression.[11] NLR has a relative lymphocytopenia. As a result, NLR may exhibit a weaker immune response to malignancy, and thus, high NLR may have a poor prognosis.[12] Platelets are involved in the growth, invasion, and metastasis of cancer.[13] Like NLR, PLR has also shown that increased inflammatory markers are associated with poor prognosis in patients with different malignancies.[14]

In cancer patients, there are various methods of assessing nutritional status, each with its advantages and disadvantages. Serum albumin is a simple marker that provides information on nutritional status.[15] As well albumin plays an essential role in the inflammation process. The relationship between albumin and inflammation is consistent with the concept that the presence of persistent inflammatory response contributes to the progressive loss of these vital protein components of the body and the death of progressive cancer patients.[16] AGR and PNI might be a significant parameter for cancer prognosis.

The carcinoembryonic antigen (CEA) and its family members mainly express in the gastrointestinal epithelium; the serum level of CEA is usually very low in healthy adults. CEA is increased various types of cancer, especially colorectal cancer. Only 30%–50% of pancreatic cancer patients increased CEA.[17] Carbohydrate antigen 19-9 (CA19-9) level is the most frequently used tumor marker in pancreatic cancer. CA19-9, which is typically synthesized from the pancreas, biliary tract ductal cells, stomach, colon, endometrial and salivary epithelium, is present in small amounts in serum and can be expressed in benign gastrointestinal disorders. Importantly, it exhibits a dramatic increase in plasma levels during neoplastic disease.[18] It may not be detected in 5%–10% of patients with Lewis antigens (−).[19] Although we know it has notable limitations, CA 19-9 remains the only pancreatic cancer marker in clinical use.

Prognostic and predictive factors in pancreatic cancer patients are still debated.[20],[21] In this study, we aimed to investigate the usefulness of inflammation parameters and tumor markers (NLR, PLR, AGR, PNI, CEA, CA 19-9) as a prognostic factor affecting survival in metastatic stage pancreatic cancer patients admitted to hospital.


 > Patients and Methods Top


Data from 170 patients diagnosed with MPC at the time of diagnosis in two oncology centers between January 2014 and December 2018 were collected from hospital automation systems and patient files. All patients underwent tomography or positron emission tomography at the time of diagnosis. Histopathological subtypes other than invasive ductal adenocarcinoma were excluded from the study. The local ethical committee approved the study protocol (Date: 06.11.2018, Approval number: GO 18/1049-36). The CT that patients received in the first line was devoted to FOLFİRİNOX (oxaliplatin 85 mg/m2 on day 1+ irinotecan 180 mg/m2 on day 1+ leucovorin 400 mg/m2 on day 1 followed by FU 400 mg/m2 as a bolus on day 1 and 2400 mg/m2 as 46-h continuous infusion biweekly) or gemcitabine-based (gemcitabine at a dose of 1000 mg/m2, on days 1, 8, and 15 every 4 weeks alone or with nab-paclitaxel 125 mg/m2 combination with gemcitabine, or gemcitabine at a dose of 1000 mg/m2, on days 1and 8 every 3 weeks with cisplatin 75 mg/m2) treatment, patients who received first-line CT for at least three months included in the study. Patients with bone marrow infiltration and secondary malignancy at the time of diagnosis were excluded because the laboratory parameters would be affected. Clinicopathological characteristics, treatment methods, basic laboratory parameters, CA 19-9, CEA, NLR, PLR, AGR, PNI and survival rates were evaluated retrospectively. NLR was defined as dividing neutrophil count by lymphocyte count, PLR was defined as dividing platelet count by lymphocyte count. The AGR value was calculated using the following formula (AGR = Basal serum albumin/basal total protein-basal serum albumin). Patients were also evaluated for PNI, a score based on albumin and lymphocyte counts (10 × serum albumin [g/dL]) (0.005 × peripheral lymphocyte count [/mm3]).[22]


 > Results Top


Key characteristics of patients

A total of 170 patients were included in the study. The median age of the patients was 63 (range = 33–87). The majority were male (63.5%). When patients were divided into two subgroups according to tumor location, 94 patients had head tumors, and 76 patients had body and tail tumors. Of the 170 cases of distant metastasis, 91 had liver metastasis, 51 had liver and nonliver metastasis, whereas 28 had nonliver metastasis. Sixty-six patients received FOLFIRINOX, 104 patients received gemcitabine-based CT [Table 1].
Table 1: Key characteristics of patients (n=170)

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Prognostic factors

The median follow-up was 8 months (range: 3–32 months). 161 (94.7%) patients died, and the median OS was 8.0 months (95% confidence interval = 6.6–9.4) for all patients. The OS was 7 months for tumors located in the pancreas head region and 9 months for those found in the body/tail. FOLFIRINOX CT resulted in a significant increase in OS (11 months for those receiving FOLFIRINOX, 6 months receiving CT-containing gemcitabine). There is no standard method for determining the optimal cutoff value of CEA, CA 19-9, NLR, PLR, PNI that can predict survival. Receiver operating characteristic (ROC) analysis was used to identify high and low rate subgroups of these parameters.

OS was 7 months in patients with high NLR (≥2.17) and 12 months for low NLR (<2.17). OS was calculated as 5 months in patients with elevated CA 19-9 (≥1800). For those with low C19-9 (<1800), this value was calculated as 10 months. There was no significant difference in OS between the subgroups with high (≥9) and low (<9) CEA. Patients were also analyzed for survival outcomes, according to PLR, PNI, and AGR. Patients with PLR <145 had significantly higher median OS than those with PLR ≥145 (8 vs. 7 months). Median OS was 6 months for patients with high PNI (≥47.5) while it was Amend 10.9 to read 9 months for patients with low PNI (<47.5). Median OS was 11 months for patients with high AGR (≥1.27), while it was 6 months for patients with low AGR (<1.27).

In univariate analysis, age (P < 0.001) [Figure 1]a, CT regime (P < 0.002) [Figure 1]b, AGR (P < 0.006), PNI (P < 0.017), NLR (P < 0.001) [Figure 1]c, PLR (P < 0.062), CA19-9 (P < 0.002) [Figure 1]d were statistically significant prognostic factors [Table 2]. In multivariate analysis, age (hazard ratio [HR] 1.534 95% 1.079–2.182 P < 0.017) (HR1.410 95% 1.001-1.989, P≤0.005) and, NLR (HR 1.569 95% 1.001–2.463, P < 0.049) were significant prognostic factors [Table 3].
Figure 1: (a) Overall survival analysis based on age, (b) chemotherapy regime, (c) neutrophil/lymphocyte ratio, and (d) carbohydrate antigen 19-9

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Table 2: Univariate analysis of the factors affecting overall survival

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Table 3: Multivariate analysis of the factors affecting overall survival

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 > Discussion Top


Inflammation plays an essential role in the development and progression of cancer. NLR is one of the most studied inflammatory parameters. Several studies have evaluated the prognostic value of NLR in the early stage and the metastatic stage of pancreatic cancer. Stotz et al. evaluated 261 patients with inoperable PC at the time of diagnosis and 110 patients with surgically resected PC. High NLR is associated with poor prognosis operable or inoperable pancreatic cancer.[23] Formica et al. showed that NLR is a predictive and prognostic factor in metastatic pancreatic ductal adenocarcinoma. Furthermore, only patients with high NLR benefit from the addition of oxaliplatin.[24]

Like NLR, the prognostic value of PLR in pancreatic cancer is also being investigated; however, the results are controversial. Zhou has shown that, as in NLR, high PLR is an adverse prognostic factor in pancreatic cancer.[25] Another study showed that in patients who undergo resection for PDAC following or not neoadjuvant CT/chemoradiation pretreatment NLR is an independent adverse prognostic factor, and considered to be superior to the PLR.[26] In the study we performed in unresectable and de novo metastatic patients, OS was 12 months in patients with low NLR and 7 months in patients with high NLR. We determined NLR as an independent adverse prognostic factor; however, high PLR level was not found an independent prognostic factor, although it was associated with shorter OS (7 vs. 8 months).

Hypoalbuminemia shows the level of nutrition and cachexia in cancer patients. Nakagawa et al. had demonstrated that in patients with recurrent pancreatic adenocarcinoma survival times were significantly shorter in patients with low PNI compared to higher ones.[27] Feng et al. study was about serum biomarkers in predicting the prognosis for advanced pancreatic cancer. They did not find a correlation between AGR and prediction.[28] In our study, we found that OS was longer in patients with high AGR (11 months vs. 6 months) and high PNI values (6 months vs. 9 months) in patients with advanced pancreatic cancer, but they were not significant in multivariate analysis.

CA19-9 was used as a tumor marker for epithelial tumors such as pancreatic and gastrointestinal cancers. It has prognostic importance for an advanced stage of pancreatic cancer.[29] Chen et al. reported that high CA19-9 was associated with poorly differentiated tumor characteristics, a massive tumor size, and clinical stage.[30] Tingle et al. showed that neutrophil albumin ratio (NAR) and CA19-9 were independent predictors of survival in unresectable pancreatic cancer. 145 advanced pancreas cancer patients NLR, PLR, NAR, CA19-9 ve fibrinojen values were classified about their medians for Kaplan–Meier and Cox regression analysis. When combining these using Cox regression analysis adjusting for other prognostic indicators, only NAR and Ca19-9 were independent predictors of surival.[31] In our study, we found “CA19-9 cut off value” as 1800 by ROC analysis. Survival was shorter in patients with high levels of CA19-9. (5 months vs. 10 months), and it was an independent prognostic factor for our patients.

In MPC, FOLFIRINOX and combinations with gemcitabine chemotherapies have been tested in recent years.[32],[33] In the ANICE-PAC study, a patient who receives gemcitabine + nab-paclitaxel at the first-line treatment, the effect of essential characteristics on survival was analyzed. It was found that the Eastern Cooperative Oncology Group (ECOG), NLR, and CA 19.9 significantly affected OS and progression-free survivor progression-free survival (PFS).[34] Vivaldi et al. showed that patients with advanced pancreatic cancer treated with the GONO FOLFOXIRI regimen NLR, ECOG Performance Statüs (ECOG PS), and liver metastasis were associated with more inferior OS.[35] We also used Gemcitabine-based CT and FOLFIRINOX most frequently as CT agents. OS in patients receiving FOLFIRINOX was 11 months.FOLFIRINOX CT regime has significantly prolonged the OS.

The limitation of this study was that the information such as ECOG PS and patient history could not be accessed because some of the patient data were retrieved from the automation system. Furthermore, since the patients were able to continue their treatment in other centers after the procedure was planned, healthy information about PFS rates could not be obtained. Hence, performance score is not used, and PFS is not involved in this analysis. Because the CT regimen choice depends on the physician's discretion, this may have led to bias. Studies done in patients treated with only one regimen may be more significant.


 > Conclusion Top


In summary, we determined, age, basal high NLR and CA19-9 as independent adverse prognostic factors for OS in APC. FOLFIRINOX CT resulted in a significant increase in OS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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