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Combined pretreatment serum CA19-9 and neutrophil-to-lymphocyte ratio as a potential prognostic factor in metastatic pancreatic cancer patients

Combined pretreatment serum CA19-9 and neutrophil-to-lymphocyte ratio as a potential prognostic... The aim of this study was to explore the role of combined pretreatment serum carbohydrate antigen 19-9 (CA19-9) and neutrophil-to- lymphocyte ratio (NLR) as potential prognostic factors in metastatic pancreatic cancer patients. We investigated pretreatment serum CA19-9 and NLR in 59 metastatic pancreatic cancer patients, determined the patients’ thresholds by receiver operating characteristic curve analysis, and assessed their prognostic values by Kaplan–Meier curve and Cox regression models. Results of multivariate analysis showed high CA19-9, high NLR, and high score (the scoring system of CA19-9 and NLR) were significantly correlated with overall survival. Area under the curve of the scoring system was higher than that of CA19-9 or NLR. Combined pretreatment serum CA19-9 and NLR is a better prognostic biomarker of metastatic pancreatic cancer patients than CA19-9 or NLR alone. Abbreviations: AUC = area under the curve, CA19-9 = carbohydrate antigen 19-9, CI = confidence interval, NI = not included into multivariate analysis, NLR = neutrophil-to-lymphocyte ratio, OS = overall survival, ROC = receiver operating characteristic. Keywords: CA19-9, metastatic pancreatic cancer, neutrophil-to-lymphocyte ratio, prognostic factor [12] cancer. It is increasingly recognized that survival of cancer 1. Introduction patients was determined not only by tumor characteristics but Pancreatic cancer is an aggressive cancer with a 5-year survival [13] also by systemic inflammatory response of the host. There [1] rate of <7%. It is the seventh leading cause of cancer death have been no studies till date that have reported the prognostic [2] worldwide. Around 80% to 85% of diagnosed patients present role of combined detection of CA19-9 and NLR in metastatic with locally advanced or metastatic disease, and <20% of pancreatic cancer patients and compared the combination with [3] patients can proceed with radical resection. The carbohydrate CA19-9 or NLR alone. Hence, the present study analyzes the antigen 19-9 (CA19-9) is the most commonly used and best prognostic utility of CA19-9 or NLR alone in metastatic validated serum tumor marker for pancreatic cancer diagnosis in pancreatic cancer patients. Further, this study determines the symptomatic patients and for monitoring therapy in patients with prediction ability of combination CA19-9 and NLR in metastatic [4] pancreatic adenocarcinoma. Several previous studies reported pancreatic cancer patients. [5–7] the relationship between the CA19-9 and survival. The link between inflammation and cancer was first exploited by Virchow [8] 2. Patients and methods in 1863. Several systemic inflammatory response markers have been investigated to predict survival in various cancers, such as C- This retrospective analysis included 59 metastatic pancreatic [9] [10] reactive protein, neutrophil-to-lymphocyte ratio (NLR), cancer patients who were treated at Fujian Medical University [11] and platelet-to-lymphocyte ratio. NLR has been reported to be Union Hospital between 2010 and 2015. The medical records associated with the prognosis in patients with pancreatic collected in this study were: age, gender, neutrophil count, lymphocyte count, the primary pancreatic tumor location, site of Editor: Peng Luo. metastasis, levels of CA19-9, type of treatment, follow-up, or The authors have no conflict of interest to disclose. death. NLR was calculated as the neutrophil count divided by Department of Radiation Oncology, Fujian Medical University Union Hospital, lymphocyte count. The data was collected within 7 days before Fuzhou, Fujian Province, China. treatment. Overall survival (OS) was defined as the time from the Correspondence: Ben-Hua Xu, Department of Radiation Oncology, Fujian date of diagnosis to the date of death or the date of last follow-up Medical University Union Hospital, Fuzhou, China (e-mail: benhuaxu@163.com). visit. The study was reviewed and approved by the ethical Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. committee of the Fujian Medical University Union Hospital. This is an open access article distributed under the Creative Commons According to survival time, patients were divided into subgroups Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial to compare patients who have longer survival time than median and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. OS with patients who had not. The receiver operating characteristic (ROC) curve was generated to evaluate the ideal Medicine (2018) 97:4(e9707) cut-off values of CA19-9 and NLR for median OS prediction. The Received: 13 August 2017 / Received in final form: 11 December 2017 / Accepted: 4 January 2018 Youden index was used to determine the cut-off point. On the basis of each cutoff value, patients were dichotomized into 2 http://dx.doi.org/10.1097/MD.0000000000009707 1 Song et al. Medicine (2018) 97:4 Medicine Kaplan–Meier curve, the log-rank test, and Cox proportional Table 1 hazard model. All variables with significant prognostic value in Characteristics of metastatic pancreatic cancer patients. the univariate analysis were introduced in the final multivariate Characteristics Values/Counts Cox proportional hazard model. P<.05 was considered statisti- Age, years, median (range) 65 (42–82) cally significant. Statistical analysis was performed using the SPSS Gender (male/female) 40/19 software 13.0 (SPSS Inc, Chicago, IL). Tumor location (head/body/tail) 36/13/10 Metastatic sites (liver/other) 36/23 Serum CA19-9, U/mL, median (range) 935 (86–3640) 3. Results NLR, median (range) 4.7 (0.9–20.2) 3.1. Patient general characteristics Treatment (chemotherapy/other) 23/36 Survival time, months, median (range) 4.5 (1–10) Fifty-nine patients with metastatic pancreatic cancer diagnosis were enrolled. Of the 59 patients, 40 were males, with a median CA19-9= carbohydrate antigen 19-9, NLR= neutrophil-to-lymphocyte ratio. age of 65 years at diagnosis. Detailed baseline characteristics are listed in Table 1. 3.2. ROC curves of CA19-9 and NLR for median OS The median CA19-9 was 935U/mL (86–3640U/mL) and the median NLR reached 4.7 (0.9–20.2). ROC curve analysis was used to evaluate cut-off values of CA19-9 and NLR to predict median OS. ROC curve analysis suggested that the cut-off value of 626U/ mL for CA19-9 and the cut-off value of 3.75 for NLR were chosen as the optimal value for evaluating median OS (area under the curve [AUC]: 0.744, 95% CI [0.614–0.874], P=.001, and AUC: 0.764, 95% CI [0.638–0.889], P=.001, respectively, sensitivi- ty:61.76%, specificity:84.00%, Fig. 1). Furthermore, the scoring system was applied by combining CA19-9 and NLR levels: score 0 was defined as CA19-9 <626U/mL and NLR <3.75; score 1 was defined as “CA19-9 ≥626U/mL with NLR <3.75” or “NLR ≥3.75 with CA19-9 < 626U/mL”; and score 2 was defined as Figure 1. ROC curve analysis of CA19-9, NLR and scoring system for OS in CA19-9 ≥626U/mL and NLR ≥3.75. metastatic pancreatic cancer patients. CA19-9=carbohydrate antigen 19-9, NLR=neutrophil-to-lymphocyte ratio, OS = overall survival, ROC = receiver operating characteristic. 3.3. Correlations of CA19-9 and NLR with characteristics parameters Correlations of CA19-9 and NLR with various characteristics groups. The association between CA19-9 or NLR and other parameters including age, gender, tumor location, and site of parameters was evaluated by the Pearson x test. Survival data metastasis were analyzed. As shown in Table 2, there was no among subgroups classified by each factor were analyzed via the Table 2 Characteristics of metastatic pancreatic cancer patients grouped by CA19-9 and NLR. CA19-9, U/mL NLR Variables Sum <626 ≥626 P value <3.75 ≥3.75 P value Age, years .26 .549 <65 28 14 14 13 15 ≥65 31 11 20 12 19 Gender .248 .248 Male 40 19 21 19 21 Female 19 6 13 6 13 Tumor location .333 .682 Head 36 18 18 16 20 Body 13 4 9 6 7 Tail 10 3 7 3 7 Site of metastasis .687 .138 Liver 36 16 20 18 18 Other 23 9 14 7 16 NLR .453 <3.75 25 12 13 –– ≥3.75 34 13 21 –– CA19-9, U/mL .453 <626 25 –– 12 13 ≥626 34 –– 13 21 CA19-9= carbohydrate antigen 19-9, NLR= neutrophil-to-lymphocyte ratio. 2 Song et al. Medicine (2018) 97:4 www.md-journal.com Figure 2. Kaplan–Meier survival curves for OS in metastatic pancreatic cancer patients according to CA19-9, NLR, and scoring system. CA19-9=carbohydrate antigen 19-9, NLR=neutrophil-to-lymphocyte ratio, OS = overall survival. significant correlation observed between CA19-9 or NLR and metastatic pancreatic cancer, whereas gender, tumor location, other parameters. and site of metastasis were not (Table 3). All available variables significantly associated with survival in univariable analysis were introduced in a multivariate logistic regression. Multivariate 3.4. Correlations of characteristics parameters with OS analysis reveals that CA19-9 (≥626 vs <626, P=.007), NLR To investigate whether CA19-9, NLR, and other characteristics, (≥3.75 vs <3.75, P<.0001), and the scoring system (score 2 vs parameters are associated with OS, univariate and multivariate score 1 vs score 0, P<.0001) were independent prognostic factors Cox proportional models were calculated. The Kaplan–Meier for OS (Table 3). curves for OS reveal that high levels of CA19-9 or NLR are associated with poor prognosis in metastatic pancreatic cancer 3.5. The scoring system of CA19-9 and NLR is a superior (P=.0036, P<.0001, respectively) (Fig. 2A and B). Univariate prognostic factor analysis identified the age of the patients at diagnosis (≥65 vs<65, P=.0457), CA19-9 (≥626 vs <626, P=.0036), NLR (≥3.75 vs To determine the independent prognostic significance of the <3.75, P<.0001), the high score of scoring system (score 1 vs score scoring system of CA19-9 and NLR in a metastatic pancreatic 0, score 2 vs score 0, P=.0077, P<.0001, respectively), and no cancer patient, Cox regression model and Kaplan–Meier method chemotherapeutic treatment (no chemotherapy vs chemotherapy, were performed. The univariate Cox regression and the P=.0012) were significantly associated with worse OS in multivariate Cox regression survival analysis showed that the Table 3 Univariate and multivariate analysis of parameters for the prediction of overall survival in metastatic pancreatic cancer patients. Univariate analysis Multivariate analysis Variables HR 95% CI P value HR 95% CI P value Age, years <65 1 (referent) 1 (referent) ≥65 1.812 1.011–3.247 .0457 1.388 0.784–2.457 .261 Gender NI Male 1 (referent) Female 1.714 0.8879–3.309 .1083 Tumor location NI Head 1 (referent) Body 0.7897 0.4011–1.555 .4946 Tail 0.7825 0.3752–1.632 .4275 Site of metastasis NI Liver 1 (referent) Other 1.344 0.7411–2.437 0.3304 CA19-9, U/mL <626 1 (referent) 1 (referent) ≥626 2.364 1.325–4.218 .0036 2.22 1.240–3.976 .007 NLR <3.75 1 (referent) 1 (referent) ≥3.75 4.214 2.265–7.838 <.0001 3.698 2.044–6.692 <.0001 Scoring system 0 1 (referent) 2.862 1.832–4.471 <.0001 1 2.762 1.309–5.827 .0077 2 7.286 3.051–17.40 <.0001 Treatment Chemotherapy 1 (referent) 1 (referent) No chemotherapy 2.61 1.462–4.660 .0012 1.586 0.900–2.794 1.111 CA19-9= carbohydrate antigen 19-9, CI= confidence interval, HR= hazard ratio, NI= not included into multivariate analysis, NLR= neutrophil-to-lymphocyte ratio. 3 Song et al. Medicine (2018) 97:4 Medicine scoring system was an independent prognostic factor (Table 3). only represents the tumor characteristics but also reflects the The results of Kaplan–Meier method are presented in Figure 2C. inflammatory and immune status of the patient and therefore is The result of ROC showed that AUC of the scoring system was considered as a good prognostic marker. 0.843 (95% CI 0.737–0.949, P<.0001), which was higher than There are some limitations in this study. First, the study is that of CA19-9 and NLR (Fig. 1). These results implied that the subject to selection bias due to retrospective. Second, the data was scoring system as a significant prognostic biomarker that can be from a single institution. Third, the number of patients included is superior to either CA19-9 or NLR alone. relatively small. At last, potential selection bias should not be omitted in this study. In conclusion, combined pretreatment serum CA19-9 and 4. Discussion NLR is a better prognostic biomarker of metastatic pancreatic In this study, based on the results of ROC analysis, the cut-off cancer patients than CA19-9 or NLR alone. Further studies are value of 626U/mL for CA19-9 and the cut-off value of 3.75 for needed to validate the result. NLR were chosen. A cut-off value of CA19-9 <1000U/mL was [14] reported in Chen et al’s study of advanced pancreatic References [15] cancer, and was >230U/mL in Asaoka et al’s study of [15] [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin resectable pancreatic head cancer. Cut-off value of NLR was 2015;65:5–29. [12] <5 was reported in Piciucchi et al’s study of metastatic [2] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA [12] [16] pancreatic cancer, and was >2.5inWatanabeet al’s Cancer J Clin 2015;65:87–108. [16] [3] Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet study of resectable pancreatic cancer. The optimal cut-off (London, England) 2011;378:607–20. values have remained controversial. The differences of cut-off [4] Scara S, Bottoni P, Scatena R. CA 19-9: biochemical and clinical aspects. value are likely due to different stage of pancreatic cancer and Adv Exp Med Biol 2015;867:247–60. the number of patients. The cut-off values of serum CA19-9 [5] Saad ED, Machado MC, Wajsbrot D, et al. Pretreatment CA 19-9 level as and NLR should be validated in a large prospective a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine. Int J Gastrointest Cancer 2002;32:35–41. multiinstitutional study. [6] Maisey NR, Norman AR, Hill A, et al. CA19-9 as a prognostic factor in In pancreatic cancer, CA19-9, the only biomarker currently inoperable pancreatic cancer: the implication for clinical trials. Brit J recommended for clinical use by the National Comprehensive Cancer 2005;93:740–33. Cancer Network guidelines for pancreatic cancer, is recognized [7] Boeck S, Stieber P, Holdenrieder S, et al. Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients as the most clinically useful marker, which fittingly reflects the with pancreatic cancer. Oncology 2006;70:255–64. tumor burden and positively correlates with the malignancy of [8] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? [17] tumor cell. A more previous study reported that CA19-9 Lancet (London, England) 2001;357:539–45. is reliable as a possible prognostic marker of pancreatic [9] Zhou B, Liu J, Wang ZM, et al. C-reactive protein, interleukin 6 and lung [18–20] cancer risk: a meta-analysis. PLoS One 2012;7:e43075. cancer. A change in CA19-9 level between initial and post [10] Tang X, Du P, Yang Y. The clinical use of neutrophil-to-lymphocyte ratio concurrent chemoradiotherapy was a significant prognostic in bladder cancer patients: a systematic review and meta-analysis. Int J marker for overall survival in locally advanced pancreatic cancer Clin Oncol 2017;22:817–25. [18] treated with concurrent chemoradiotherapy. CA19-9 was an [11] Zhao Y, Si G, Zhu F, et al. Prognostic role of platelet to lymphocyte ratio independent prognostic factor for patients with pancreatic cancer in hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2017;8:22854–62. treated by chemotherapy or concurrent chemoradiother- [19,20] [12] Piciucchi M, Stigliano S, Archibugi L, et al. The neutrophil/lymphocyte apy. Preoperative CA19-9 was an independent predictive ratio at diagnosis is significantly associated with survival in metastatic factor for recurrence of resectable pancreatic cancer and poor pancreatic cancer patients. Int J Mol Sci 2017;18:730. [5,15,21] survival of pancreatic cancer. The systemic inflammatory [13] Carruthers R, Tho LM, Brown J, et al. Systemic inflammatory response is response from cancer cells may play an important role in cancer a predictor of outcome in patients undergoing preoperative chemo- [22] radiation for locally advanced rectal cancer. Colorectal Dis 2012;14: progression and malignant transformation. As one of e701–7. inflammatory markers, NLR is getting more attractive, because [14] Chen Y, Shao Z, Chen W, et al. A varying-coefficient cox model for the NLR is readily measurable in peripheral blood and directly effect of CA19-9 kinetics on overall survival in patients with advanced reflects the systemic host inflammatory response. The prognostic pancreatic cancer. Oncotarget 2017;8:29925–34. [23–25] [15] Asaoka T, Miyamoto A, Maeda S, et al. Prognostic impact of significance of NLR was reported by previous study. NLR preoperative NLR and CA19-9 in pancreatic cancer. Pancreatology provided independent prognostic information about patients 2016;16:434–40. with pancreatic cancer, regardless of the undergoing therapeutic [16] Watanabe J, Otani S, Sakamoto T, et al. Prognostic indicators based on [23] [24] modality. Inoue et al’s study showed that NLR had inflammatory and nutritional factors after pancreaticoduodenectomy for pancreatic cancer. Surg Today 2016;46:1258–67. prognostic value in a large Japanese pancreatic cancer cohort. A [17] Xiang JF, Wang WQ, Liu L, et al. Mutant p53 determines pancreatic systematic review and meta-analysis showed that high pretreat- cancer poor prognosis to pancreatectomy through upregulation of cavin- ment blood NLR could be an adverse prognostic indicator for 1 in patients with preoperative serum CA19-9>/=1,000 U/mL. Sci Rep [25] advanced tumor. Our present study verified the results of 2016;6:19222. previous studies and demonstrated that elevated CA19-9 and [18] Kim YJ, Koh HK, Chie EK, et al. Change in carbohydrate antigen 19-9 level as a prognostic marker of overall survival in locally advanced NLR were independent prognostic factors for poor survival of pancreatic cancer treated with concurrent chemoradiotherapy. Int J Clin metastatic pancreatic cancer. These studies together suggest that Oncol 2017;22:1069–75. CA19-9 and NLR offer significant prognostic information [19] Imaoka H, Shimizu Y, Senda Y, et al. Post-adjuvant chemotherapy associated with survival of pancreatic cancer. Furthermore, the CA19-9 levels predict prognosis in patients with pancreatic ductal adenocarcinoma: A retrospective cohort study. Pancreatology 2016;16: role of combined detection of CA19-9 and NLR in the prognosis 658–64. of metastatic pancreatic cancer was assessed. As shown in Table 3 [20] Gu YL, Lan C, Pei H, et al. Applicative value of serum CA19-9, CEA, and Figure 2C, the scoring system of CA19-9 and NLR was an CA125 and CA242 in diagnosis and prognosis for patients with independent prognostic biomarker and a better predictor of pancreatic cancer treated by concurrent chemoradiotherapy. Asian Pac J prognosis than CA19-9 or NLR alone. The scoring system not Cancer Prev 2015;16:6569–73. 4 Song et al. Medicine (2018) 97:4 www.md-journal.com [21] Nishio K, Kimura K, Amano R, et al. Preoperative predictors for early [24] Inoue D, Ozaka M, Matsuyama M, et al. Prognostic value of neutrophil- recurrence of resectable pancreatic cancer. World J Surg Oncol lymphocyte ratio and level of C-reactive protein in a large cohort of 2017;15:16. pancreatic cancer patients: a retrospective study in a single institute in [22] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Japan. Jap J Clin Oncol 2015;45:61–6. Cell 2011;144:646–74. [25] Mei Z, Shi L, Wang B, et al. Prognostic role of pretreatment blood [23] Stotz M, Gerger A, Eisner F, et al. Increased neutrophil-lymphocyte ratio neutrophil-to-lymphocyte ratio in advanced cancer survivors: A is a poor prognostic factor in patients with primary operable and systematic review and meta-analysis of 66 cohort studies. Cancer Treat inoperable pancreatic cancer. Brit J Cancer 2013;109:416–21. Rev 2017;58:1–3. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Medicine Wolters Kluwer Health

Combined pretreatment serum CA19-9 and neutrophil-to-lymphocyte ratio as a potential prognostic factor in metastatic pancreatic cancer patients

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Wolters Kluwer Health
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Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.
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0025-7974
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10.1097/MD.0000000000009707
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Abstract

The aim of this study was to explore the role of combined pretreatment serum carbohydrate antigen 19-9 (CA19-9) and neutrophil-to- lymphocyte ratio (NLR) as potential prognostic factors in metastatic pancreatic cancer patients. We investigated pretreatment serum CA19-9 and NLR in 59 metastatic pancreatic cancer patients, determined the patients’ thresholds by receiver operating characteristic curve analysis, and assessed their prognostic values by Kaplan–Meier curve and Cox regression models. Results of multivariate analysis showed high CA19-9, high NLR, and high score (the scoring system of CA19-9 and NLR) were significantly correlated with overall survival. Area under the curve of the scoring system was higher than that of CA19-9 or NLR. Combined pretreatment serum CA19-9 and NLR is a better prognostic biomarker of metastatic pancreatic cancer patients than CA19-9 or NLR alone. Abbreviations: AUC = area under the curve, CA19-9 = carbohydrate antigen 19-9, CI = confidence interval, NI = not included into multivariate analysis, NLR = neutrophil-to-lymphocyte ratio, OS = overall survival, ROC = receiver operating characteristic. Keywords: CA19-9, metastatic pancreatic cancer, neutrophil-to-lymphocyte ratio, prognostic factor [12] cancer. It is increasingly recognized that survival of cancer 1. Introduction patients was determined not only by tumor characteristics but Pancreatic cancer is an aggressive cancer with a 5-year survival [13] also by systemic inflammatory response of the host. There [1] rate of <7%. It is the seventh leading cause of cancer death have been no studies till date that have reported the prognostic [2] worldwide. Around 80% to 85% of diagnosed patients present role of combined detection of CA19-9 and NLR in metastatic with locally advanced or metastatic disease, and <20% of pancreatic cancer patients and compared the combination with [3] patients can proceed with radical resection. The carbohydrate CA19-9 or NLR alone. Hence, the present study analyzes the antigen 19-9 (CA19-9) is the most commonly used and best prognostic utility of CA19-9 or NLR alone in metastatic validated serum tumor marker for pancreatic cancer diagnosis in pancreatic cancer patients. Further, this study determines the symptomatic patients and for monitoring therapy in patients with prediction ability of combination CA19-9 and NLR in metastatic [4] pancreatic adenocarcinoma. Several previous studies reported pancreatic cancer patients. [5–7] the relationship between the CA19-9 and survival. The link between inflammation and cancer was first exploited by Virchow [8] 2. Patients and methods in 1863. Several systemic inflammatory response markers have been investigated to predict survival in various cancers, such as C- This retrospective analysis included 59 metastatic pancreatic [9] [10] reactive protein, neutrophil-to-lymphocyte ratio (NLR), cancer patients who were treated at Fujian Medical University [11] and platelet-to-lymphocyte ratio. NLR has been reported to be Union Hospital between 2010 and 2015. The medical records associated with the prognosis in patients with pancreatic collected in this study were: age, gender, neutrophil count, lymphocyte count, the primary pancreatic tumor location, site of Editor: Peng Luo. metastasis, levels of CA19-9, type of treatment, follow-up, or The authors have no conflict of interest to disclose. death. NLR was calculated as the neutrophil count divided by Department of Radiation Oncology, Fujian Medical University Union Hospital, lymphocyte count. The data was collected within 7 days before Fuzhou, Fujian Province, China. treatment. Overall survival (OS) was defined as the time from the Correspondence: Ben-Hua Xu, Department of Radiation Oncology, Fujian date of diagnosis to the date of death or the date of last follow-up Medical University Union Hospital, Fuzhou, China (e-mail: benhuaxu@163.com). visit. The study was reviewed and approved by the ethical Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. committee of the Fujian Medical University Union Hospital. This is an open access article distributed under the Creative Commons According to survival time, patients were divided into subgroups Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial to compare patients who have longer survival time than median and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. OS with patients who had not. The receiver operating characteristic (ROC) curve was generated to evaluate the ideal Medicine (2018) 97:4(e9707) cut-off values of CA19-9 and NLR for median OS prediction. The Received: 13 August 2017 / Received in final form: 11 December 2017 / Accepted: 4 January 2018 Youden index was used to determine the cut-off point. On the basis of each cutoff value, patients were dichotomized into 2 http://dx.doi.org/10.1097/MD.0000000000009707 1 Song et al. Medicine (2018) 97:4 Medicine Kaplan–Meier curve, the log-rank test, and Cox proportional Table 1 hazard model. All variables with significant prognostic value in Characteristics of metastatic pancreatic cancer patients. the univariate analysis were introduced in the final multivariate Characteristics Values/Counts Cox proportional hazard model. P<.05 was considered statisti- Age, years, median (range) 65 (42–82) cally significant. Statistical analysis was performed using the SPSS Gender (male/female) 40/19 software 13.0 (SPSS Inc, Chicago, IL). Tumor location (head/body/tail) 36/13/10 Metastatic sites (liver/other) 36/23 Serum CA19-9, U/mL, median (range) 935 (86–3640) 3. Results NLR, median (range) 4.7 (0.9–20.2) 3.1. Patient general characteristics Treatment (chemotherapy/other) 23/36 Survival time, months, median (range) 4.5 (1–10) Fifty-nine patients with metastatic pancreatic cancer diagnosis were enrolled. Of the 59 patients, 40 were males, with a median CA19-9= carbohydrate antigen 19-9, NLR= neutrophil-to-lymphocyte ratio. age of 65 years at diagnosis. Detailed baseline characteristics are listed in Table 1. 3.2. ROC curves of CA19-9 and NLR for median OS The median CA19-9 was 935U/mL (86–3640U/mL) and the median NLR reached 4.7 (0.9–20.2). ROC curve analysis was used to evaluate cut-off values of CA19-9 and NLR to predict median OS. ROC curve analysis suggested that the cut-off value of 626U/ mL for CA19-9 and the cut-off value of 3.75 for NLR were chosen as the optimal value for evaluating median OS (area under the curve [AUC]: 0.744, 95% CI [0.614–0.874], P=.001, and AUC: 0.764, 95% CI [0.638–0.889], P=.001, respectively, sensitivi- ty:61.76%, specificity:84.00%, Fig. 1). Furthermore, the scoring system was applied by combining CA19-9 and NLR levels: score 0 was defined as CA19-9 <626U/mL and NLR <3.75; score 1 was defined as “CA19-9 ≥626U/mL with NLR <3.75” or “NLR ≥3.75 with CA19-9 < 626U/mL”; and score 2 was defined as Figure 1. ROC curve analysis of CA19-9, NLR and scoring system for OS in CA19-9 ≥626U/mL and NLR ≥3.75. metastatic pancreatic cancer patients. CA19-9=carbohydrate antigen 19-9, NLR=neutrophil-to-lymphocyte ratio, OS = overall survival, ROC = receiver operating characteristic. 3.3. Correlations of CA19-9 and NLR with characteristics parameters Correlations of CA19-9 and NLR with various characteristics groups. The association between CA19-9 or NLR and other parameters including age, gender, tumor location, and site of parameters was evaluated by the Pearson x test. Survival data metastasis were analyzed. As shown in Table 2, there was no among subgroups classified by each factor were analyzed via the Table 2 Characteristics of metastatic pancreatic cancer patients grouped by CA19-9 and NLR. CA19-9, U/mL NLR Variables Sum <626 ≥626 P value <3.75 ≥3.75 P value Age, years .26 .549 <65 28 14 14 13 15 ≥65 31 11 20 12 19 Gender .248 .248 Male 40 19 21 19 21 Female 19 6 13 6 13 Tumor location .333 .682 Head 36 18 18 16 20 Body 13 4 9 6 7 Tail 10 3 7 3 7 Site of metastasis .687 .138 Liver 36 16 20 18 18 Other 23 9 14 7 16 NLR .453 <3.75 25 12 13 –– ≥3.75 34 13 21 –– CA19-9, U/mL .453 <626 25 –– 12 13 ≥626 34 –– 13 21 CA19-9= carbohydrate antigen 19-9, NLR= neutrophil-to-lymphocyte ratio. 2 Song et al. Medicine (2018) 97:4 www.md-journal.com Figure 2. Kaplan–Meier survival curves for OS in metastatic pancreatic cancer patients according to CA19-9, NLR, and scoring system. CA19-9=carbohydrate antigen 19-9, NLR=neutrophil-to-lymphocyte ratio, OS = overall survival. significant correlation observed between CA19-9 or NLR and metastatic pancreatic cancer, whereas gender, tumor location, other parameters. and site of metastasis were not (Table 3). All available variables significantly associated with survival in univariable analysis were introduced in a multivariate logistic regression. Multivariate 3.4. Correlations of characteristics parameters with OS analysis reveals that CA19-9 (≥626 vs <626, P=.007), NLR To investigate whether CA19-9, NLR, and other characteristics, (≥3.75 vs <3.75, P<.0001), and the scoring system (score 2 vs parameters are associated with OS, univariate and multivariate score 1 vs score 0, P<.0001) were independent prognostic factors Cox proportional models were calculated. The Kaplan–Meier for OS (Table 3). curves for OS reveal that high levels of CA19-9 or NLR are associated with poor prognosis in metastatic pancreatic cancer 3.5. The scoring system of CA19-9 and NLR is a superior (P=.0036, P<.0001, respectively) (Fig. 2A and B). Univariate prognostic factor analysis identified the age of the patients at diagnosis (≥65 vs<65, P=.0457), CA19-9 (≥626 vs <626, P=.0036), NLR (≥3.75 vs To determine the independent prognostic significance of the <3.75, P<.0001), the high score of scoring system (score 1 vs score scoring system of CA19-9 and NLR in a metastatic pancreatic 0, score 2 vs score 0, P=.0077, P<.0001, respectively), and no cancer patient, Cox regression model and Kaplan–Meier method chemotherapeutic treatment (no chemotherapy vs chemotherapy, were performed. The univariate Cox regression and the P=.0012) were significantly associated with worse OS in multivariate Cox regression survival analysis showed that the Table 3 Univariate and multivariate analysis of parameters for the prediction of overall survival in metastatic pancreatic cancer patients. Univariate analysis Multivariate analysis Variables HR 95% CI P value HR 95% CI P value Age, years <65 1 (referent) 1 (referent) ≥65 1.812 1.011–3.247 .0457 1.388 0.784–2.457 .261 Gender NI Male 1 (referent) Female 1.714 0.8879–3.309 .1083 Tumor location NI Head 1 (referent) Body 0.7897 0.4011–1.555 .4946 Tail 0.7825 0.3752–1.632 .4275 Site of metastasis NI Liver 1 (referent) Other 1.344 0.7411–2.437 0.3304 CA19-9, U/mL <626 1 (referent) 1 (referent) ≥626 2.364 1.325–4.218 .0036 2.22 1.240–3.976 .007 NLR <3.75 1 (referent) 1 (referent) ≥3.75 4.214 2.265–7.838 <.0001 3.698 2.044–6.692 <.0001 Scoring system 0 1 (referent) 2.862 1.832–4.471 <.0001 1 2.762 1.309–5.827 .0077 2 7.286 3.051–17.40 <.0001 Treatment Chemotherapy 1 (referent) 1 (referent) No chemotherapy 2.61 1.462–4.660 .0012 1.586 0.900–2.794 1.111 CA19-9= carbohydrate antigen 19-9, CI= confidence interval, HR= hazard ratio, NI= not included into multivariate analysis, NLR= neutrophil-to-lymphocyte ratio. 3 Song et al. Medicine (2018) 97:4 Medicine scoring system was an independent prognostic factor (Table 3). only represents the tumor characteristics but also reflects the The results of Kaplan–Meier method are presented in Figure 2C. inflammatory and immune status of the patient and therefore is The result of ROC showed that AUC of the scoring system was considered as a good prognostic marker. 0.843 (95% CI 0.737–0.949, P<.0001), which was higher than There are some limitations in this study. First, the study is that of CA19-9 and NLR (Fig. 1). These results implied that the subject to selection bias due to retrospective. Second, the data was scoring system as a significant prognostic biomarker that can be from a single institution. Third, the number of patients included is superior to either CA19-9 or NLR alone. relatively small. At last, potential selection bias should not be omitted in this study. In conclusion, combined pretreatment serum CA19-9 and 4. Discussion NLR is a better prognostic biomarker of metastatic pancreatic In this study, based on the results of ROC analysis, the cut-off cancer patients than CA19-9 or NLR alone. Further studies are value of 626U/mL for CA19-9 and the cut-off value of 3.75 for needed to validate the result. NLR were chosen. A cut-off value of CA19-9 <1000U/mL was [14] reported in Chen et al’s study of advanced pancreatic References [15] cancer, and was >230U/mL in Asaoka et al’s study of [15] [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin resectable pancreatic head cancer. Cut-off value of NLR was 2015;65:5–29. [12] <5 was reported in Piciucchi et al’s study of metastatic [2] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA [12] [16] pancreatic cancer, and was >2.5inWatanabeet al’s Cancer J Clin 2015;65:87–108. [16] [3] Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet study of resectable pancreatic cancer. The optimal cut-off (London, England) 2011;378:607–20. values have remained controversial. The differences of cut-off [4] Scara S, Bottoni P, Scatena R. CA 19-9: biochemical and clinical aspects. value are likely due to different stage of pancreatic cancer and Adv Exp Med Biol 2015;867:247–60. the number of patients. The cut-off values of serum CA19-9 [5] Saad ED, Machado MC, Wajsbrot D, et al. Pretreatment CA 19-9 level as and NLR should be validated in a large prospective a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine. Int J Gastrointest Cancer 2002;32:35–41. multiinstitutional study. [6] Maisey NR, Norman AR, Hill A, et al. CA19-9 as a prognostic factor in In pancreatic cancer, CA19-9, the only biomarker currently inoperable pancreatic cancer: the implication for clinical trials. Brit J recommended for clinical use by the National Comprehensive Cancer 2005;93:740–33. Cancer Network guidelines for pancreatic cancer, is recognized [7] Boeck S, Stieber P, Holdenrieder S, et al. Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients as the most clinically useful marker, which fittingly reflects the with pancreatic cancer. Oncology 2006;70:255–64. tumor burden and positively correlates with the malignancy of [8] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? [17] tumor cell. A more previous study reported that CA19-9 Lancet (London, England) 2001;357:539–45. is reliable as a possible prognostic marker of pancreatic [9] Zhou B, Liu J, Wang ZM, et al. C-reactive protein, interleukin 6 and lung [18–20] cancer risk: a meta-analysis. PLoS One 2012;7:e43075. cancer. A change in CA19-9 level between initial and post [10] Tang X, Du P, Yang Y. The clinical use of neutrophil-to-lymphocyte ratio concurrent chemoradiotherapy was a significant prognostic in bladder cancer patients: a systematic review and meta-analysis. Int J marker for overall survival in locally advanced pancreatic cancer Clin Oncol 2017;22:817–25. [18] treated with concurrent chemoradiotherapy. CA19-9 was an [11] Zhao Y, Si G, Zhu F, et al. Prognostic role of platelet to lymphocyte ratio independent prognostic factor for patients with pancreatic cancer in hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2017;8:22854–62. treated by chemotherapy or concurrent chemoradiother- [19,20] [12] Piciucchi M, Stigliano S, Archibugi L, et al. The neutrophil/lymphocyte apy. Preoperative CA19-9 was an independent predictive ratio at diagnosis is significantly associated with survival in metastatic factor for recurrence of resectable pancreatic cancer and poor pancreatic cancer patients. Int J Mol Sci 2017;18:730. [5,15,21] survival of pancreatic cancer. The systemic inflammatory [13] Carruthers R, Tho LM, Brown J, et al. Systemic inflammatory response is response from cancer cells may play an important role in cancer a predictor of outcome in patients undergoing preoperative chemo- [22] radiation for locally advanced rectal cancer. Colorectal Dis 2012;14: progression and malignant transformation. As one of e701–7. inflammatory markers, NLR is getting more attractive, because [14] Chen Y, Shao Z, Chen W, et al. A varying-coefficient cox model for the NLR is readily measurable in peripheral blood and directly effect of CA19-9 kinetics on overall survival in patients with advanced reflects the systemic host inflammatory response. The prognostic pancreatic cancer. Oncotarget 2017;8:29925–34. [23–25] [15] Asaoka T, Miyamoto A, Maeda S, et al. Prognostic impact of significance of NLR was reported by previous study. NLR preoperative NLR and CA19-9 in pancreatic cancer. Pancreatology provided independent prognostic information about patients 2016;16:434–40. with pancreatic cancer, regardless of the undergoing therapeutic [16] Watanabe J, Otani S, Sakamoto T, et al. Prognostic indicators based on [23] [24] modality. Inoue et al’s study showed that NLR had inflammatory and nutritional factors after pancreaticoduodenectomy for pancreatic cancer. Surg Today 2016;46:1258–67. prognostic value in a large Japanese pancreatic cancer cohort. A [17] Xiang JF, Wang WQ, Liu L, et al. Mutant p53 determines pancreatic systematic review and meta-analysis showed that high pretreat- cancer poor prognosis to pancreatectomy through upregulation of cavin- ment blood NLR could be an adverse prognostic indicator for 1 in patients with preoperative serum CA19-9>/=1,000 U/mL. Sci Rep [25] advanced tumor. Our present study verified the results of 2016;6:19222. previous studies and demonstrated that elevated CA19-9 and [18] Kim YJ, Koh HK, Chie EK, et al. Change in carbohydrate antigen 19-9 level as a prognostic marker of overall survival in locally advanced NLR were independent prognostic factors for poor survival of pancreatic cancer treated with concurrent chemoradiotherapy. Int J Clin metastatic pancreatic cancer. These studies together suggest that Oncol 2017;22:1069–75. CA19-9 and NLR offer significant prognostic information [19] Imaoka H, Shimizu Y, Senda Y, et al. Post-adjuvant chemotherapy associated with survival of pancreatic cancer. Furthermore, the CA19-9 levels predict prognosis in patients with pancreatic ductal adenocarcinoma: A retrospective cohort study. Pancreatology 2016;16: role of combined detection of CA19-9 and NLR in the prognosis 658–64. of metastatic pancreatic cancer was assessed. As shown in Table 3 [20] Gu YL, Lan C, Pei H, et al. Applicative value of serum CA19-9, CEA, and Figure 2C, the scoring system of CA19-9 and NLR was an CA125 and CA242 in diagnosis and prognosis for patients with independent prognostic biomarker and a better predictor of pancreatic cancer treated by concurrent chemoradiotherapy. Asian Pac J prognosis than CA19-9 or NLR alone. The scoring system not Cancer Prev 2015;16:6569–73. 4 Song et al. Medicine (2018) 97:4 www.md-journal.com [21] Nishio K, Kimura K, Amano R, et al. Preoperative predictors for early [24] Inoue D, Ozaka M, Matsuyama M, et al. Prognostic value of neutrophil- recurrence of resectable pancreatic cancer. World J Surg Oncol lymphocyte ratio and level of C-reactive protein in a large cohort of 2017;15:16. pancreatic cancer patients: a retrospective study in a single institute in [22] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Japan. Jap J Clin Oncol 2015;45:61–6. Cell 2011;144:646–74. [25] Mei Z, Shi L, Wang B, et al. Prognostic role of pretreatment blood [23] Stotz M, Gerger A, Eisner F, et al. Increased neutrophil-lymphocyte ratio neutrophil-to-lymphocyte ratio in advanced cancer survivors: A is a poor prognostic factor in patients with primary operable and systematic review and meta-analysis of 66 cohort studies. Cancer Treat inoperable pancreatic cancer. Brit J Cancer 2013;109:416–21. Rev 2017;58:1–3.

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Published: Jan 1, 2018

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