Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients

Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced... www.nature.com/scientificreports OPEN Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic Received: 29 March 2016 cancer patients Accepted: 25 April 2017 Published: xx xx xxxx 1,2 1,2 2,3 4 1,2 1,2 Junjie Hang , Peng Xue , Haiyan Yang , Shaobo Li , Donghui Chen , Lifei Zhu , Weiyi 1,2 1,2 1,2 1,2,3 Huang , Shujuan Ren , Yue Zhu & Liwei Wang Although previous studies demonstrated that elevated C-reactive protein to albumin ratio (CAR) predicted poor prognosis in various solid tumors, little was known about the prognostic value of CAR in patients with advanced pancreatic cancer (APC). The aim of the present study was to assess CAR as one independent prognostic factor in predicting overall survival (OS) in APC patients who had received palliative chemotherapy. Data of 142 APC patients who received palliative chemotherapy between 2009 and 2014 were retrospectively documented. We classified the patients into two groups based on the optimal cutoff value of CAR identified by generating receiver operating characteristics (ROC) curve. The clinicopathological parameters were compared between two CAR groups. Pearson correlation test showed that the level of C-reactive protein (CRP) was inversely correlated with albumin (r = −0.387; P < 0.001). Kaplan-Meier analysis demonstrated overall survival (OS) was significantly longer in CAR < 0.156 group than CAR ≥ 0.156 group (11.2 vs 5.9 months, P < 0.001). CAR was an independent prognostic factor for OS in the Cox regression model (HR, 1.623; 95% CI, 1.093–2.410; P = 0.016). Furthermore, the discrimination ability of CAR (AUC = 0.648, P = 0.025) was slightly higher than that of other inflammation-based factors. Therefore, pretreatment CAR could be an independent prognostic biomarker for APC patients. Pancreatic cancer is the seventh leading cause of cancer-related mortality among both men and women globally. In more developed regions, the incidence rate of pancreatic cancer is 8.6 per 100,000 in males and 5.9 per 100,000 1 2 in females . Even with curative resection, the 5-year overall survival rate is less than 5% . Most patients with locally advanced or metastatic disease at the first diagnosis can only receive the palliative chemotherapy . The prognosis of advanced pancreatic cancer (APC) remains unsatisfactory. Emerging evidence suggests the cancer-associated inflammation and nutritional status play a critical role in the progress of tumors . Accordingly, previous studies identified several immunologically or nutritionally rele- 5–7 8 vant biomarkers as prognostic factors for survival, such as CRP , Glasgow prognostic score (GPS) , modified 9 10 Glasgow prognostic score (mGPS) , neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) . Among these, both GPS and mGPS are determined based on the serum concentration of CRP and albu- min. As they are qualitative scores in nature, they may have the potential to cause underestimation (a lower CRP level) or overestimation (a lower albumin level) of the prognostic evaluation in cancer patients . Recently, a new prognostic index, CAR, has been reported as an independent prognostic factor in various 12–18 tumors including pancreatic cancer . Although CAR is also calculated based on the serum levels of CRP and albumin, it is a more quantitative parameter when compared with GPS or mGPS. In previous cohort study of the prognostic potential of CAR in pancreatic cancer, a large number of patients with resectable pancreatic Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, New Songjiang Road 650, Shanghai, 201620, China. Shanghai Key laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai, 201620, China. Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pujian Road 160, Shanghai, 200120, China. Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Haining Road 100, Shanghai, 200080, China. Junjie Hang, Peng Xue and Haiyan Yang contributed equally to this work. Correspondence and requests for materials should be addressed to L.W. (email: yzwlw@hotmail.com) Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 1 www.nature.com/scientificreports/ Valuables Category Characteristics Male 92 (64.8%) Gender Female 50 (35.2%) Age Median (Range) 61 (34–86) 0 14 (9.9%) ECOG PS 1 108 (76.1%) 2 20 (14.1%) Head and neck 61 (43.0%) Primary tumor location Body and tail 81 (57.0%) III 41 (28.9%) TNM stage IV 101 (71.1%) Yes 71 (50.0%) Liver metastasis No 71 (50.0%) Gemcitabine monotherapy 50 (35.2%) Chemotherapy Gemcitabine combination therapy 45 (31.7%) Gemcitabine exclusive therapy 47 (33.1%) Albumin (g/L) Median (Range) 39.2 (26.1–48.4) CRP (mg/L) Median (Range) 3.55 (0.2–178.0) CAR Median (Range) 0.099 (0.004–5.266) 0 79 (55.6%) GPS 1 47 (33.1%) 2 16 (11.3%) 0 92 (64.8%) mGPS 1 34 (23.9%) 2 16 (11.3%) AST (IU/L) Median (Range) 25.0 (7.3–1529.0) ALT (IU/L) Median (Range) 20.9 (5.0–1300.0) CA19–9 (U/ml) Median (Range) 430.45 (0.60–2084.00) CEA (ng/ml) Median (Range) 6.57 (0.40–1065.00) Hemoglobin (g/L) Median (Range) 122 (75–168) Table 1. Baseline clinicopathological characteristics of patients with APC. cancer were enrolled . Nevertheless, the prognostic value of CAR in APC patients who can only receive palliative chemotherapy has not been verified. Therefore, this study investigated CAR as an independent prognostic factor for overall survival (OS) in APC patients. Methods Patients. From 2009 to 2014, 142 patients with locally advanced or metastatic pancreatic cancer (ICD, Tenth Revision, codes C25) were enrolled at the Department of Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University (Shanghai, China). The following inclusion criteria were applied: (1) without any concurrent cancer at another organ site; (2) with at least two cycles of palliative chemotherapy after the first diagnosis; (3) without any incomplete records of clinicopathological features; (4) pathologically confirmed pancreatic ductal adenocarcinoma. Baseline clinicopathological characteristics were retrieved from electronic medical charts and summarized in Table 1. In 101 patients with metastatic pancreatic cancer, 71 of them had liver metastasis and 30 of them had metastasis in other organs like lung, kidney and spleen. The CAR was calculated by dividing the serum CRP by the albumin obtained at the time of diagnosis. The GPS was deter - mined as follows: the patients with a high CRP level (>10 mg/L) and a low albumin level (<35 g/L) were scored 2, those with either abnormality were given a score of 1 and those without any abnormal values were given a score of 0 . Likewise, the mGPS is almost the same as that of GPS except that the patients with only a low albumin level were scored 0. Palliative chemotherapy regimens included gemcitabine monotherapy (n = 50) , gemcit- abine combination therapy (n = 45, including gemcitabine and oxaliplatin combination therapy , gemcitabine 22 23 and S-1 combination therapy , gemcitabine and erlotinib combination therapy , gemcitabine and nab-paclitexal 24 25 combination therapy ) and gemcitabine exclusive therapy (n = 47, including S-1 monotherapy , nab-paclitexal 26 27 monotherapy and FOLFIRINOX ). The average treatment cycles of first-line chemotherapy were 3.3. Informed consent was obtained from all subjects and all experimental protocols were approved by the Ethics Committees of Shanghai General Hospital. And the methods were carried out in accordance with the relevant guidelines and regulations. 18, 28 Cutoff values for CAR and other factors. There was no consistent cutoff value of CAR , thus it was identified by generating receiver operating characteristics (ROC) curve. The area under the curve (AUC) was calculated as 0.62 (95% CI, 0.51–0.73) for the CAR (Fig. 1). The CAR of 0.156 corresponded to the maximum sum of sensitivity and specificity on the ROC curve, which was equivalent to the maximization of Youden’s J statistics Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 2 www.nature.com/scientificreports/ Figure 1. Cutoff value of CAR assessed by ROC curve. (J = sensitivity + specificity-1) . For other factors, the cutoff values were their upper limit of normal values (AST, ALT and CEA) or those applied in other large trails (CA19–9 and hemoglobin) which were close to the median values of these factors . Statistical analysis. All statistical analyses were performed with SPSS statistical sowa ft re (version 21.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented as median and 95% confidence interval (95% CI). For the assessment of correlation between CAR and other valuables, patients were stratified into two groups according to different factors including gender (male and female), age (≥60 or <60 years), ECOG PS (0, 1 or 2), TNM stage (III or IV), liver metastasis (Yes or No), primary tumor location (head and neck or body and tail), chemotherapy (gemcitabine monotherapy or other therapies), CAR (≥0.156 or <0.156), Aspartate transaminase (AST) (≥40 IU/L or <40 IU/L), Alanine transaminase (ALT) (≥40 IU/L or <40 IU/L), Carbohydrate antigen 19–9 (CA19-9) (≥1000 U/ml or <1000 U/ml), Carcinoembryonic antigen (CEA) (≥5 ng/ml or <5 ng/ml) and hemo- globin (≥100 g/L or <100 g/L) . Comparison between these groups was conducted using the Pearson Chi-Square test and Continuity Correction. The correlation between CRP and albumin was assessed by Pearson correlation test. OS was defined from the date of chemotherapy initiation to the date of death for any reason or censored to the last follow-up visit censored. Furthermore, survival analysis was performed with the Kaplan-Meier method and the log-rank test. Cox regression analysis was used to investigate prognostic factors for OS. By conducting ROC curve, we evaluated the specificity and sensitivity of CAR, CRP, GPS and mGPS. For each factor, we calcu- lated the HRs and corresponding 95% CIs. Two-sided P < 0.05 was considered statistically significant. Results Patient characteristics. The baseline clinicopathological characteristics of patients with APC were sum- marized in Table 1. 82 patients had a pretreatment CAR of <0.156 while 60 patients had a pretreatment CAR of >0.156. We compared the clinicopathological characteristics between the two groups (Table 2). The percent- ages of patients with TNM stage IV, liver metastasis and AST ≥ 40 IU/L were significantly higher within the CAR ≥ 0.156 group (P < 0.05). However, percentages of patients with other variables were comparable between the two CAR groups. Comparison of OS stratified by pretreatment albumin, CRP and CAR. Pearson correlation test demonstrated that the level of CRP was inversely correlated with the level of albumin (r = −0.387; P < 0.001, Fig. 2). In the the Kaplan-Meier analysis, the median OS of patients with albumin < 35 g/L was 5.4 (95% CI: 4.3–6.5) months which was significantly shorter than 10.0 (95% CI: 8.1–11.9) months of patients with albumin ≥35 g/L (P = 0.008, Fig. 3A). Likewise, patients with CRP ≥ 5 mg/L have a poorer OS compared to those with CRP < 5 mg/L (7.0 months vs. 11.0 months, P = 0.001, Fig. 3B). Moreover, the median OS was 11.2 (95% CI: 8.5–13.9) months in CAR < 0.156 group and 5.9 (95% CI:3.0–8.8) months in CAR ≥ 0.156 group (hazard ratio (HR) 2.004, 95% CI: 1.389–2.891; P < 0.001, Fig. 3C). Prognostic factors for OS. In univariate analysis, five variables of ECOG PS (P = 0.005), TNM stage (P < 0.001), CAR (P < 0.001), AST (P = 0.024) and CA19-9 (P < 0.001) correlated with OS were identified. All these factors were subsequently analyzed in multivariate analysis. Consequently, TNM stage (P = 0.015), CAR (P = 0.016) and CA19- 9 (P = 0.001) were found to be independent prognostic factors (Table 3). Subgroup analysis and discrimination ability of CAR. CAR was significantly correlated with OS in the subgroup identified by CA19-9. However, CAR demonstrated no correlation with OS in the subgroup of patients with ECOG PS 2 or TNM stage III (Fig. 4). Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 3 www.nature.com/scientificreports/ Characteristics CAR < 0.156 n = 82 CAR ≥ 0.156 n = 60 P-value Gender  Male 49 (53.3%) 43 (46.7%) 0.142  Female 33 (66.0%) 17 (34.0%) Age  <60 39 (63.9%) 22 (36.1%) 0.195  ≥60 43 (53.1%) 38 (46.9%) ECOG PS  2 9 (45.0%) 11 (55.0%) 0.213  0–1 73 (59.8%) 49 (40.2%) Primary tumor location  Head and neck 35 (57.4%) 26 (42.6%) 0.938  Body and tail 47 (58.0%) 34 (42.0%) TNM stage  III 33 (80.5%) 8 (19.5%) <0.001  IV 49 (48.5%) 52 (51.5%) Liver metastasis  Yes 35 (49.3%) 36 (50.7%) 0.041  No 47 (66.2%) 24 (33.8%) Chemotherapy  Gemcitabine monotherapy 31 (62.0%) 19 (38.0%) 0.449  Others 51 (55.4%) 41 (44.6%) AST (IU/L)  <40 60 (63.8%) 34 (36.2%) 0.040  ≥40 22 (45.8%) 26 (54.2%) ALT (IU/L)  <40 63(59.4%) 43 (40.6%) 0.485  ≥40 19 (52.8%) 17 (47.2%) CA19-9 (U/ml)  <1000 51 (60.0%) 34 (40.0%) 0.507  ≥1000 31 (54.4%) 26 (45.6%) CEA (ng/ml)  <5 36 (64.3%) 20 (35.7%) 0.203  ≥5 46 (53.5%) 40 (46.5%) Hemoglobin (g/L)  <120 33 (51.6%) 31 (48.4%) 0.177  ≥120 49 (62.8%) 60 (42.3%) Table 2. Baseline clinicopathological characteristics according to CAR. Figure 2. e co Th rrelation between CRP and albumin. Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 4 www.nature.com/scientificreports/ Figure 3. Kaplan-Meier estimates of overall survival according to the level of serum albumin (A), CRP (B) and CAR (C). ROC curves were used to evaluate the discrimination ability of CAR and other inflammation-based factors including CRP, GPS and mGPS (Fig. 5). The discrimination ability of CAR, as assessed by AUC, was 0.648 (P = 0.025), which was the highest among these inflammation-based factors (CRP 0.617, GPS 0.615, and mGPS 0.632). Discussion In the present study, pretreatment CAR was found to be an independent prognostic factor for overall survival in APC patients receiving palliative chemotherapy. Haruki, et.al showed that elevated pretreatment CAR predicted poor clinical outcomes in pancreatic cancer patients with resectable tumors in 2016 . More recently, Mengwan Wu, et.al investigated the prognostic value of CAR in pancreatic cancer patients treated with or without chemo- therapy . However, there was optimal difference in the cutoff values of CAR identified in these two study, which could be explained by the dier ff ent populations of patients enrolled in two studies.To the best of our knowledge, this is the first study to evaluate the prognostic value of CAR in a cohort of APC patients receiving palliative chemotherapy. Systemic inflammation response plays a vital role in the progression of pancreatic cancer. Various prognostics scoring models assessed by peripheral blood cell count or inflammatory factors were developed retrospectively to stratify the optimal pancreatic cancer patients receiving palliative care . However, little has been used predic- atively in clinical practice. CRP, a marker of inflammation, was correlated with survival outcomes in various cancers, including pancre- 6, 7, 33 atic cancer . On the other hand, hypoalbuminemia, an indicator for chronic malnutrition, is also a common complication for advanced cancer patients. Therefore, the CAR, a combined pattern of both CRP and albumin, may reveal the outcome of pancreatic cancer in a better way. Haruki, et.al found that patients in high CAR group happened to be in more advanced TNM stage (p = 0.007). Such finding was consistent with this study as the per - centages of patients with TNM stage IV, liver metastasis and AST ≥ 40 IU/L were significantly higher within the CAR ≥ 0.156 group than CAR < 0.156 group (P < 0.05), which may have reflected the poorer status of patients with this disease. However, aer ad ft justment for TNM stage, AST, ECOG PS and CA19-9 in multivariate analysis, the CAR < 0.156 remained favorable independent of prognostic factor, with a clinically relevant HR value (HR 1.629, 95% CI 1.097–2.419; P = 0.016), which suggested the different prognosis of CAR stratification was not merely attribute to the difference in baseline characteristics between the two groups. Furthermore, the subgroup analysis of CAR in patients with TNM stage IV also demonstrated the prognostic value of CAR regardless of TNM stage (HR: 1.64, 95% CI 1.08–2.51; P = 0.021). Our study also showed there was a reciprocal relationship between CRP and albumin (r = −0.387, P < 0.001, Fig. 2). This is consistent with Hwang JC’s work and can be partly explained by the reason that inflammation reduces albumin concentration by decreasing its synthesis 35 36 rate . In addition, immunonutrition can also suppress the inflammatory response . Previous studies revealed that GPS or mGPS could be independent prognostic factors in pancreatic cancer 37–39 patients . However, in this study, CAR showed superior discrimination ability than other inflammation-based scores including GPS and mGPS in pancreatic cancer patients, which was consistent with the results of sev- 12, 14 eral studies conducted among patients with other cancers types . Furthermore, Haruki, et.al also found CAR (P = 0.035), rather than mGPS (P = 0.091), was independent and significant predictor of the OS. This may be partially explained by the reason that CAR is a simple ratio with a continuous range of values but both GPS and mGPS, consisting of dichotomized variables, have a qualitative nature with discontinuous values. The subgroup analysis (Fig.  4) showed that the prognostic value of CAR in high CA19-9 or low CA19-9 patients were also identified respectively. This means that the CAR with cutoff value of 0.156 may also stratify high or low CA19-9 patients into two groups with prominent difference in OS. er Th e are several strengths of this study. First, this study boasts a cohort with long follow-up period. Second, CAR is a biomarker that can be utilized in clinical practice as the measurement of CAR is non-invasive, easy to acquire and affordable for the patients. Several limitations of this study should also be acknowledged. One potential limitation is that it is a retrospective and single-center study with relatively small sample size which Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 5 www.nature.com/scientificreports/ Univariate analysis Multivariate analysis Characteristics HR 95% CI P-value HR 95% CI P-value Gender  Male 0.988 0.673–1.452 0.952  Female Age  <60 0.876 0.609–1.259 0.475  ≥60 ECOG PS  2 2.011 1.233–3.280 0.005 1.524 0.886–2.261 0.128  0–1 Primary tumor location  Head and neck 1.375 0.948–1.996 0.093  Body and tail TNM stage  IV 2.163 1.415–3.307 <0.001 1.762 1.121–2.771 0.014  III Liver metastasis  Yes 1.999 1.382–2.891 < 0.001  No Chemotherapy  Gemcitabine monotherapy 0.831 0.573–1.207 0.331  Others CRP (mg/L)  ≥5 1.793 1.245–2.580 0.002  <5 Albumin (g/L)  ≥35 0.553 0.354–0.866 0.010  <35 CAR  ≥0.156 2.004 1.389–2.891 <0.001 1.629 1.097–2.419 0.016  <0.156 GPS  2 1.539 1.201–1.971 0.001  1  0 mGPS  2 1.437 1.121–1.844 0.004  1  0 AST (IU/L)  ≥40 1.560 1.059–2.297 0.024 0.937 0.604–1.453 0.771  <40 ALT (IU/L)  ≥40 1.087 0.713–1.658 0.697  <40 CA19–9 (U/ml)  ≥1000 1.989 1.359–2.911 <0.001 1.973 1.332–2.924 0.001  <1000 CEA (ng/ml)  ≥5 1.380 0.948–2.010 0.092  <5 Hemoglobin (g/L)  <120 0.887 0.618–1.274 0.516  ≥120 Table 3. Univariate and multivariate analysis of poor prognostic factors for OS in APC patients. Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 6 www.nature.com/scientificreports/ Figure 4. Hazard ratios (HRs) of CAR in different patient subgroups identified by ECOG PS, TNM stage and CA19-9. HRs >1.0 indicate a worse outcome. Figure 5. e p Th redictive ability of the four inflammation-based prognostic scores was compared by ROC curves. may cause selection bias. Second, this study mainly focused on the pretreatment CAR which may be largely ae ff cted by other factors like infection or cancer complication. Third, heterogeneous treatments in this study may ae ff ct survival outcome although we found chemotherapy was not correlated with OS in this study as some other 10, 40 studies had reported . Both CRP and albumin are produced in liver and various chemotherapy regimens have different effects on patients’ liver function and inflammation status, which may ae ff ct the production of CRP and albumin. Another limitation is the lack of a validation cohort to confirm the cutoff and prognostic value of CAR. Therefore, future study on a larger sample size and same treatment modality should be conducted to verify the findings in this study. Finally, the concrete mechanisms underlying the prognostic value of CAR should be further investigated. In conclusion, this study indicates that the pretreatment CAR could be an independent prognostic biomarker for APC patients. References 1. Torre, L. A. et al. Global cancer statistics, 2012. CA: a cancer journal for clinicians 65, 87–108, doi:10.3322/caac.21262 (2015). 2. Li, D., Xie, K., Wolff, R. & Abbruzzese, J. L. Pancreatic cancer. Lancet (London, England) 363, 1049–1057, doi:10.1016/s0140- 6736(04)15841-8 (2004). 3. 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Annals of surgical oncology 19, 2917–2923, doi:10.1245/s10434-012-2348-9 (2012). 38. Morinaga, S. et al. Glasgow Prognostic Score Predicts Clinical Outcomes in Patients with Pancreatic Cancer Undergoing Adjuvant Gemcitabine Monotherapy Aer C ft urative Surgery. Anticancer research 35, 4865–4870 (2015). 39. Imaoka, H. et al. Evaluation of Modified Glasgow Prognostic Score for Pancreatic Cancer: A Retrospective Cohort Study. Pancreas 45, 211–217, doi:10.1097/mpa.0000000000000446 (2016). 40. Ueno, H. et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 31, 1640–1648, doi:10.1200/jco.2012.43.3680 (2013). Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 8 www.nature.com/scientificreports/ Acknowledgements e N Th ational Science Foundation of China supported this work [Grant Number: 81502017, 81502018, 81572315, 81171887 and 91229117] Author Contributions e s Th tudy was conceived and designed by J.H., P.X. and L.W.. Acquisition and analysis of data was performed by J.H., H.Y., Y.Z., D.C., S.L. and S.R. In addition, P.X. L.Z. and W.H. interpreted the data. J.H., P.X. and L.W. drae ft d the article, and all authors revised the article and approved the final version to be published. Additional Information Competing Interests: The authors declare that they have no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients

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www.nature.com/scientificreports OPEN Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic Received: 29 March 2016 cancer patients Accepted: 25 April 2017 Published: xx xx xxxx 1,2 1,2 2,3 4 1,2 1,2 Junjie Hang , Peng Xue , Haiyan Yang , Shaobo Li , Donghui Chen , Lifei Zhu , Weiyi 1,2 1,2 1,2 1,2,3 Huang , Shujuan Ren , Yue Zhu & Liwei Wang Although previous studies demonstrated that elevated C-reactive protein to albumin ratio (CAR) predicted poor prognosis in various solid tumors, little was known about the prognostic value of CAR in patients with advanced pancreatic cancer (APC). The aim of the present study was to assess CAR as one independent prognostic factor in predicting overall survival (OS) in APC patients who had received palliative chemotherapy. Data of 142 APC patients who received palliative chemotherapy between 2009 and 2014 were retrospectively documented. We classified the patients into two groups based on the optimal cutoff value of CAR identified by generating receiver operating characteristics (ROC) curve. The clinicopathological parameters were compared between two CAR groups. Pearson correlation test showed that the level of C-reactive protein (CRP) was inversely correlated with albumin (r = −0.387; P < 0.001). Kaplan-Meier analysis demonstrated overall survival (OS) was significantly longer in CAR < 0.156 group than CAR ≥ 0.156 group (11.2 vs 5.9 months, P < 0.001). CAR was an independent prognostic factor for OS in the Cox regression model (HR, 1.623; 95% CI, 1.093–2.410; P = 0.016). Furthermore, the discrimination ability of CAR (AUC = 0.648, P = 0.025) was slightly higher than that of other inflammation-based factors. Therefore, pretreatment CAR could be an independent prognostic biomarker for APC patients. Pancreatic cancer is the seventh leading cause of cancer-related mortality among both men and women globally. In more developed regions, the incidence rate of pancreatic cancer is 8.6 per 100,000 in males and 5.9 per 100,000 1 2 in females . Even with curative resection, the 5-year overall survival rate is less than 5% . Most patients with locally advanced or metastatic disease at the first diagnosis can only receive the palliative chemotherapy . The prognosis of advanced pancreatic cancer (APC) remains unsatisfactory. Emerging evidence suggests the cancer-associated inflammation and nutritional status play a critical role in the progress of tumors . Accordingly, previous studies identified several immunologically or nutritionally rele- 5–7 8 vant biomarkers as prognostic factors for survival, such as CRP , Glasgow prognostic score (GPS) , modified 9 10 Glasgow prognostic score (mGPS) , neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) . Among these, both GPS and mGPS are determined based on the serum concentration of CRP and albu- min. As they are qualitative scores in nature, they may have the potential to cause underestimation (a lower CRP level) or overestimation (a lower albumin level) of the prognostic evaluation in cancer patients . Recently, a new prognostic index, CAR, has been reported as an independent prognostic factor in various 12–18 tumors including pancreatic cancer . Although CAR is also calculated based on the serum levels of CRP and albumin, it is a more quantitative parameter when compared with GPS or mGPS. In previous cohort study of the prognostic potential of CAR in pancreatic cancer, a large number of patients with resectable pancreatic Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, New Songjiang Road 650, Shanghai, 201620, China. Shanghai Key laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai, 201620, China. Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pujian Road 160, Shanghai, 200120, China. Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Haining Road 100, Shanghai, 200080, China. Junjie Hang, Peng Xue and Haiyan Yang contributed equally to this work. Correspondence and requests for materials should be addressed to L.W. (email: yzwlw@hotmail.com) Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 1 www.nature.com/scientificreports/ Valuables Category Characteristics Male 92 (64.8%) Gender Female 50 (35.2%) Age Median (Range) 61 (34–86) 0 14 (9.9%) ECOG PS 1 108 (76.1%) 2 20 (14.1%) Head and neck 61 (43.0%) Primary tumor location Body and tail 81 (57.0%) III 41 (28.9%) TNM stage IV 101 (71.1%) Yes 71 (50.0%) Liver metastasis No 71 (50.0%) Gemcitabine monotherapy 50 (35.2%) Chemotherapy Gemcitabine combination therapy 45 (31.7%) Gemcitabine exclusive therapy 47 (33.1%) Albumin (g/L) Median (Range) 39.2 (26.1–48.4) CRP (mg/L) Median (Range) 3.55 (0.2–178.0) CAR Median (Range) 0.099 (0.004–5.266) 0 79 (55.6%) GPS 1 47 (33.1%) 2 16 (11.3%) 0 92 (64.8%) mGPS 1 34 (23.9%) 2 16 (11.3%) AST (IU/L) Median (Range) 25.0 (7.3–1529.0) ALT (IU/L) Median (Range) 20.9 (5.0–1300.0) CA19–9 (U/ml) Median (Range) 430.45 (0.60–2084.00) CEA (ng/ml) Median (Range) 6.57 (0.40–1065.00) Hemoglobin (g/L) Median (Range) 122 (75–168) Table 1. Baseline clinicopathological characteristics of patients with APC. cancer were enrolled . Nevertheless, the prognostic value of CAR in APC patients who can only receive palliative chemotherapy has not been verified. Therefore, this study investigated CAR as an independent prognostic factor for overall survival (OS) in APC patients. Methods Patients. From 2009 to 2014, 142 patients with locally advanced or metastatic pancreatic cancer (ICD, Tenth Revision, codes C25) were enrolled at the Department of Oncology and Pancreatic Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University (Shanghai, China). The following inclusion criteria were applied: (1) without any concurrent cancer at another organ site; (2) with at least two cycles of palliative chemotherapy after the first diagnosis; (3) without any incomplete records of clinicopathological features; (4) pathologically confirmed pancreatic ductal adenocarcinoma. Baseline clinicopathological characteristics were retrieved from electronic medical charts and summarized in Table 1. In 101 patients with metastatic pancreatic cancer, 71 of them had liver metastasis and 30 of them had metastasis in other organs like lung, kidney and spleen. The CAR was calculated by dividing the serum CRP by the albumin obtained at the time of diagnosis. The GPS was deter - mined as follows: the patients with a high CRP level (>10 mg/L) and a low albumin level (<35 g/L) were scored 2, those with either abnormality were given a score of 1 and those without any abnormal values were given a score of 0 . Likewise, the mGPS is almost the same as that of GPS except that the patients with only a low albumin level were scored 0. Palliative chemotherapy regimens included gemcitabine monotherapy (n = 50) , gemcit- abine combination therapy (n = 45, including gemcitabine and oxaliplatin combination therapy , gemcitabine 22 23 and S-1 combination therapy , gemcitabine and erlotinib combination therapy , gemcitabine and nab-paclitexal 24 25 combination therapy ) and gemcitabine exclusive therapy (n = 47, including S-1 monotherapy , nab-paclitexal 26 27 monotherapy and FOLFIRINOX ). The average treatment cycles of first-line chemotherapy were 3.3. Informed consent was obtained from all subjects and all experimental protocols were approved by the Ethics Committees of Shanghai General Hospital. And the methods were carried out in accordance with the relevant guidelines and regulations. 18, 28 Cutoff values for CAR and other factors. There was no consistent cutoff value of CAR , thus it was identified by generating receiver operating characteristics (ROC) curve. The area under the curve (AUC) was calculated as 0.62 (95% CI, 0.51–0.73) for the CAR (Fig. 1). The CAR of 0.156 corresponded to the maximum sum of sensitivity and specificity on the ROC curve, which was equivalent to the maximization of Youden’s J statistics Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 2 www.nature.com/scientificreports/ Figure 1. Cutoff value of CAR assessed by ROC curve. (J = sensitivity + specificity-1) . For other factors, the cutoff values were their upper limit of normal values (AST, ALT and CEA) or those applied in other large trails (CA19–9 and hemoglobin) which were close to the median values of these factors . Statistical analysis. All statistical analyses were performed with SPSS statistical sowa ft re (version 21.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented as median and 95% confidence interval (95% CI). For the assessment of correlation between CAR and other valuables, patients were stratified into two groups according to different factors including gender (male and female), age (≥60 or <60 years), ECOG PS (0, 1 or 2), TNM stage (III or IV), liver metastasis (Yes or No), primary tumor location (head and neck or body and tail), chemotherapy (gemcitabine monotherapy or other therapies), CAR (≥0.156 or <0.156), Aspartate transaminase (AST) (≥40 IU/L or <40 IU/L), Alanine transaminase (ALT) (≥40 IU/L or <40 IU/L), Carbohydrate antigen 19–9 (CA19-9) (≥1000 U/ml or <1000 U/ml), Carcinoembryonic antigen (CEA) (≥5 ng/ml or <5 ng/ml) and hemo- globin (≥100 g/L or <100 g/L) . Comparison between these groups was conducted using the Pearson Chi-Square test and Continuity Correction. The correlation between CRP and albumin was assessed by Pearson correlation test. OS was defined from the date of chemotherapy initiation to the date of death for any reason or censored to the last follow-up visit censored. Furthermore, survival analysis was performed with the Kaplan-Meier method and the log-rank test. Cox regression analysis was used to investigate prognostic factors for OS. By conducting ROC curve, we evaluated the specificity and sensitivity of CAR, CRP, GPS and mGPS. For each factor, we calcu- lated the HRs and corresponding 95% CIs. Two-sided P < 0.05 was considered statistically significant. Results Patient characteristics. The baseline clinicopathological characteristics of patients with APC were sum- marized in Table 1. 82 patients had a pretreatment CAR of <0.156 while 60 patients had a pretreatment CAR of >0.156. We compared the clinicopathological characteristics between the two groups (Table 2). The percent- ages of patients with TNM stage IV, liver metastasis and AST ≥ 40 IU/L were significantly higher within the CAR ≥ 0.156 group (P < 0.05). However, percentages of patients with other variables were comparable between the two CAR groups. Comparison of OS stratified by pretreatment albumin, CRP and CAR. Pearson correlation test demonstrated that the level of CRP was inversely correlated with the level of albumin (r = −0.387; P < 0.001, Fig. 2). In the the Kaplan-Meier analysis, the median OS of patients with albumin < 35 g/L was 5.4 (95% CI: 4.3–6.5) months which was significantly shorter than 10.0 (95% CI: 8.1–11.9) months of patients with albumin ≥35 g/L (P = 0.008, Fig. 3A). Likewise, patients with CRP ≥ 5 mg/L have a poorer OS compared to those with CRP < 5 mg/L (7.0 months vs. 11.0 months, P = 0.001, Fig. 3B). Moreover, the median OS was 11.2 (95% CI: 8.5–13.9) months in CAR < 0.156 group and 5.9 (95% CI:3.0–8.8) months in CAR ≥ 0.156 group (hazard ratio (HR) 2.004, 95% CI: 1.389–2.891; P < 0.001, Fig. 3C). Prognostic factors for OS. In univariate analysis, five variables of ECOG PS (P = 0.005), TNM stage (P < 0.001), CAR (P < 0.001), AST (P = 0.024) and CA19-9 (P < 0.001) correlated with OS were identified. All these factors were subsequently analyzed in multivariate analysis. Consequently, TNM stage (P = 0.015), CAR (P = 0.016) and CA19- 9 (P = 0.001) were found to be independent prognostic factors (Table 3). Subgroup analysis and discrimination ability of CAR. CAR was significantly correlated with OS in the subgroup identified by CA19-9. However, CAR demonstrated no correlation with OS in the subgroup of patients with ECOG PS 2 or TNM stage III (Fig. 4). Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 3 www.nature.com/scientificreports/ Characteristics CAR < 0.156 n = 82 CAR ≥ 0.156 n = 60 P-value Gender  Male 49 (53.3%) 43 (46.7%) 0.142  Female 33 (66.0%) 17 (34.0%) Age  <60 39 (63.9%) 22 (36.1%) 0.195  ≥60 43 (53.1%) 38 (46.9%) ECOG PS  2 9 (45.0%) 11 (55.0%) 0.213  0–1 73 (59.8%) 49 (40.2%) Primary tumor location  Head and neck 35 (57.4%) 26 (42.6%) 0.938  Body and tail 47 (58.0%) 34 (42.0%) TNM stage  III 33 (80.5%) 8 (19.5%) <0.001  IV 49 (48.5%) 52 (51.5%) Liver metastasis  Yes 35 (49.3%) 36 (50.7%) 0.041  No 47 (66.2%) 24 (33.8%) Chemotherapy  Gemcitabine monotherapy 31 (62.0%) 19 (38.0%) 0.449  Others 51 (55.4%) 41 (44.6%) AST (IU/L)  <40 60 (63.8%) 34 (36.2%) 0.040  ≥40 22 (45.8%) 26 (54.2%) ALT (IU/L)  <40 63(59.4%) 43 (40.6%) 0.485  ≥40 19 (52.8%) 17 (47.2%) CA19-9 (U/ml)  <1000 51 (60.0%) 34 (40.0%) 0.507  ≥1000 31 (54.4%) 26 (45.6%) CEA (ng/ml)  <5 36 (64.3%) 20 (35.7%) 0.203  ≥5 46 (53.5%) 40 (46.5%) Hemoglobin (g/L)  <120 33 (51.6%) 31 (48.4%) 0.177  ≥120 49 (62.8%) 60 (42.3%) Table 2. Baseline clinicopathological characteristics according to CAR. Figure 2. e co Th rrelation between CRP and albumin. Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 4 www.nature.com/scientificreports/ Figure 3. Kaplan-Meier estimates of overall survival according to the level of serum albumin (A), CRP (B) and CAR (C). ROC curves were used to evaluate the discrimination ability of CAR and other inflammation-based factors including CRP, GPS and mGPS (Fig. 5). The discrimination ability of CAR, as assessed by AUC, was 0.648 (P = 0.025), which was the highest among these inflammation-based factors (CRP 0.617, GPS 0.615, and mGPS 0.632). Discussion In the present study, pretreatment CAR was found to be an independent prognostic factor for overall survival in APC patients receiving palliative chemotherapy. Haruki, et.al showed that elevated pretreatment CAR predicted poor clinical outcomes in pancreatic cancer patients with resectable tumors in 2016 . More recently, Mengwan Wu, et.al investigated the prognostic value of CAR in pancreatic cancer patients treated with or without chemo- therapy . However, there was optimal difference in the cutoff values of CAR identified in these two study, which could be explained by the dier ff ent populations of patients enrolled in two studies.To the best of our knowledge, this is the first study to evaluate the prognostic value of CAR in a cohort of APC patients receiving palliative chemotherapy. Systemic inflammation response plays a vital role in the progression of pancreatic cancer. Various prognostics scoring models assessed by peripheral blood cell count or inflammatory factors were developed retrospectively to stratify the optimal pancreatic cancer patients receiving palliative care . However, little has been used predic- atively in clinical practice. CRP, a marker of inflammation, was correlated with survival outcomes in various cancers, including pancre- 6, 7, 33 atic cancer . On the other hand, hypoalbuminemia, an indicator for chronic malnutrition, is also a common complication for advanced cancer patients. Therefore, the CAR, a combined pattern of both CRP and albumin, may reveal the outcome of pancreatic cancer in a better way. Haruki, et.al found that patients in high CAR group happened to be in more advanced TNM stage (p = 0.007). Such finding was consistent with this study as the per - centages of patients with TNM stage IV, liver metastasis and AST ≥ 40 IU/L were significantly higher within the CAR ≥ 0.156 group than CAR < 0.156 group (P < 0.05), which may have reflected the poorer status of patients with this disease. However, aer ad ft justment for TNM stage, AST, ECOG PS and CA19-9 in multivariate analysis, the CAR < 0.156 remained favorable independent of prognostic factor, with a clinically relevant HR value (HR 1.629, 95% CI 1.097–2.419; P = 0.016), which suggested the different prognosis of CAR stratification was not merely attribute to the difference in baseline characteristics between the two groups. Furthermore, the subgroup analysis of CAR in patients with TNM stage IV also demonstrated the prognostic value of CAR regardless of TNM stage (HR: 1.64, 95% CI 1.08–2.51; P = 0.021). Our study also showed there was a reciprocal relationship between CRP and albumin (r = −0.387, P < 0.001, Fig. 2). This is consistent with Hwang JC’s work and can be partly explained by the reason that inflammation reduces albumin concentration by decreasing its synthesis 35 36 rate . In addition, immunonutrition can also suppress the inflammatory response . Previous studies revealed that GPS or mGPS could be independent prognostic factors in pancreatic cancer 37–39 patients . However, in this study, CAR showed superior discrimination ability than other inflammation-based scores including GPS and mGPS in pancreatic cancer patients, which was consistent with the results of sev- 12, 14 eral studies conducted among patients with other cancers types . Furthermore, Haruki, et.al also found CAR (P = 0.035), rather than mGPS (P = 0.091), was independent and significant predictor of the OS. This may be partially explained by the reason that CAR is a simple ratio with a continuous range of values but both GPS and mGPS, consisting of dichotomized variables, have a qualitative nature with discontinuous values. The subgroup analysis (Fig.  4) showed that the prognostic value of CAR in high CA19-9 or low CA19-9 patients were also identified respectively. This means that the CAR with cutoff value of 0.156 may also stratify high or low CA19-9 patients into two groups with prominent difference in OS. er Th e are several strengths of this study. First, this study boasts a cohort with long follow-up period. Second, CAR is a biomarker that can be utilized in clinical practice as the measurement of CAR is non-invasive, easy to acquire and affordable for the patients. Several limitations of this study should also be acknowledged. One potential limitation is that it is a retrospective and single-center study with relatively small sample size which Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 5 www.nature.com/scientificreports/ Univariate analysis Multivariate analysis Characteristics HR 95% CI P-value HR 95% CI P-value Gender  Male 0.988 0.673–1.452 0.952  Female Age  <60 0.876 0.609–1.259 0.475  ≥60 ECOG PS  2 2.011 1.233–3.280 0.005 1.524 0.886–2.261 0.128  0–1 Primary tumor location  Head and neck 1.375 0.948–1.996 0.093  Body and tail TNM stage  IV 2.163 1.415–3.307 <0.001 1.762 1.121–2.771 0.014  III Liver metastasis  Yes 1.999 1.382–2.891 < 0.001  No Chemotherapy  Gemcitabine monotherapy 0.831 0.573–1.207 0.331  Others CRP (mg/L)  ≥5 1.793 1.245–2.580 0.002  <5 Albumin (g/L)  ≥35 0.553 0.354–0.866 0.010  <35 CAR  ≥0.156 2.004 1.389–2.891 <0.001 1.629 1.097–2.419 0.016  <0.156 GPS  2 1.539 1.201–1.971 0.001  1  0 mGPS  2 1.437 1.121–1.844 0.004  1  0 AST (IU/L)  ≥40 1.560 1.059–2.297 0.024 0.937 0.604–1.453 0.771  <40 ALT (IU/L)  ≥40 1.087 0.713–1.658 0.697  <40 CA19–9 (U/ml)  ≥1000 1.989 1.359–2.911 <0.001 1.973 1.332–2.924 0.001  <1000 CEA (ng/ml)  ≥5 1.380 0.948–2.010 0.092  <5 Hemoglobin (g/L)  <120 0.887 0.618–1.274 0.516  ≥120 Table 3. Univariate and multivariate analysis of poor prognostic factors for OS in APC patients. Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 6 www.nature.com/scientificreports/ Figure 4. Hazard ratios (HRs) of CAR in different patient subgroups identified by ECOG PS, TNM stage and CA19-9. HRs >1.0 indicate a worse outcome. Figure 5. e p Th redictive ability of the four inflammation-based prognostic scores was compared by ROC curves. may cause selection bias. Second, this study mainly focused on the pretreatment CAR which may be largely ae ff cted by other factors like infection or cancer complication. Third, heterogeneous treatments in this study may ae ff ct survival outcome although we found chemotherapy was not correlated with OS in this study as some other 10, 40 studies had reported . Both CRP and albumin are produced in liver and various chemotherapy regimens have different effects on patients’ liver function and inflammation status, which may ae ff ct the production of CRP and albumin. Another limitation is the lack of a validation cohort to confirm the cutoff and prognostic value of CAR. Therefore, future study on a larger sample size and same treatment modality should be conducted to verify the findings in this study. Finally, the concrete mechanisms underlying the prognostic value of CAR should be further investigated. In conclusion, this study indicates that the pretreatment CAR could be an independent prognostic biomarker for APC patients. References 1. Torre, L. A. et al. Global cancer statistics, 2012. CA: a cancer journal for clinicians 65, 87–108, doi:10.3322/caac.21262 (2015). 2. Li, D., Xie, K., Wolff, R. & Abbruzzese, J. L. Pancreatic cancer. Lancet (London, England) 363, 1049–1057, doi:10.1016/s0140- 6736(04)15841-8 (2004). 3. 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Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 8 www.nature.com/scientificreports/ Acknowledgements e N Th ational Science Foundation of China supported this work [Grant Number: 81502017, 81502018, 81572315, 81171887 and 91229117] Author Contributions e s Th tudy was conceived and designed by J.H., P.X. and L.W.. Acquisition and analysis of data was performed by J.H., H.Y., Y.Z., D.C., S.L. and S.R. In addition, P.X. L.Z. and W.H. interpreted the data. J.H., P.X. and L.W. drae ft d the article, and all authors revised the article and approved the final version to be published. Additional Information Competing Interests: The authors declare that they have no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017 Scientific Repo R ts | 7: 2993 | DOI:10.1038/s41598-017-03153-6 9

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