ORIGINAL ARTICLE
Characterization of Patients With Advanced Pancreatic Cancer and High Serum Interleukin-6 Levels Tomofumi Miura, MD,*†‡ Shuichi Mitsunaga, MD, PhD,*‡ Masafumi Ikeda, MD,* Satoshi Shimizu, MD,* Izumi Ohno, MD, PhD,* Hideaki Takahashi, MD,* Junji Furuse, MD, PhD,§ Masatoshi Inagaki, MD, PhD,|| Sayumi Higashi, PhD,¶ Hiroyuki Kato, PhD,¶ Kimio Terao, PhD,¶ and Atsushi Ochiai, MD, PhD‡ Objectives: High serum level of interleukin 6 (IL-6) is associated with high degree of tumor progression and systemic weakness. Anti–IL-6 therapy possibly improves the deterioration of clinical characteristics in patients with high IL-6 level. However, IL-6–related factors in patients with treatment-naive advanced pancreatic cancer (PC) have not been established. The goal of this study was to identify IL-6–related factors in patients with advanced PC who were scheduled to undergo first-line chemotherapy. Methods: Patients with treatment-naive advanced PC were eligible for inclusion in this study. Patients who did not receive first-line chemotherapy were excluded. Serum IL-6 levels and clinical parameters were prospectively recorded. Analyses were performed to identify risk factors for high IL-6 levels. Results: Eighty patients were analyzed. IL-6–related factors were advanced age (P < 0.01), the presence of liver metastasis (P < 0.01), the large volume of liver metastasis (P < 0.01), severe fatigue (P = 0.02), high carcinoembryonic antigen levels (P = 0.02), anemia (P < 0.01), and high C-reactive protein levels (P = 0.02) in multivariate analyses. Decreased skeletal muscle mass tended to be associated with high IL-6 levels. Conclusions: High serum IL-6 was related to advanced age, the presence of hepatic metastasis, large tumor burden in liver, severe fatigue, high carcinoembryonic antigen, high C-reactive protein, and anemia in patients with treatment-naive advanced PC. Key Words: pancreatic cancer, interleukin 6, anti–IL-6 therapy, cancer cachexia (Pancreas 2015;44: 756–763)
I
nterleukin 6 (IL-6) is produced by various cells, including macrophages, hepatocytes, and pancreatic cancer (PC) cells.1 The biologic actions of IL-6 include an increase in inflammatory proteins as well as anemia, fever, fatigue, lipolysis, catabolism of
From the *Department of Hepatobiliary and Pancreatic Oncology, †Department of Palliative Medicine, and ‡Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa; §Department of Medical Oncology, Kyorin University School of Medicine, Mitaka; ||Center for Suicide Prevention, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira; and ¶Chugai Pharmaceutical Co, Ltd, Tokyo, Japan. Received for publication February 7, 2014; accepted December 5, 2014. Reprints: Shuichi Mitsunaga, MD, PhD, Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan (e‐mail: [email protected]). This study was supported by Grants-in-aid for Cancer Research and for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan; JSPS KAKENHI Grant Number 22790624; the National Cancer Center Research and Development Fund (23-A-2); Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan; and Chugai Pharmacology Co, Ltd. The authors declare no conflict of interest. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.pancreasjournal.com). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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skeletal muscle, and chemoresistance of tumor cells.2–4 High IL-6 serum levels in patients with PC are associated with severe tumor T classification,5,6 large tumor size,7,8 and the presence of liver metastasis.7 Furthermore, patients with advanced PC and a high IL-6 concentration exhibit poor performance status, progressive weight loss, hypoalbuminemia, and poor outcomes.5,6 High IL-6 level is considered as a reflector of the aggressiveness of PC.9 High IL-6 serum levels are also seen in patients with Castleman disease, which is a lymphoproliferative disorder.10 Body weight loss, fatigue, anemia, hypoalbuminemia, and a high C-reactive protein (CRP) concentration are often found in patients with Castleman disease and are alleviated by anti–IL-6 therapy. These findings suggest that IL-6–related symptoms in patients with PC might be alleviated or prevented by anti–IL-6 therapy. Tumors in patients with PC with high serum level of IL-6 are considered to be IL-6–producing tumors.1 IL-6 is a proinflammatory cytokine, and tumor cells responsible for tumor-associated inflammation can acquire core hallmarks of malignancy, including growth, pathologic survival, angiogenesis, invasion, and epithelial-mesenchymal transition.11 Serum IL-6 level can reflect the aggressiveness of cancer in patients as well as the inflammation-related microenvironment of the tumor.9 IL-6– related symptoms might also highlight the crosstalk between disease progression and cancer biology. Previous studies of IL-6–related symptoms were conducted in various populations of resectable, chemotherapyexperienced, and terminally ill patients. IL-6–related symptoms were often found in terminally ill patients, and it is possible that the imbalance of the population with terminal illness could have affected previous results. The development of anti–IL-6 therapy requires knowledge regarding IL-6–related clinical features in patients with treatment-naive advanced PC, which has not been previously studied. The goal of this study was to characterize IL-6–related factors in patients who were scheduled to undergo first-line chemotherapy for treatment-naive advanced PC.
MATERIALS AND METHODS Patients The subjects in this study were included in our previous study.12 Briefly, patients with pathologically proven and chemotherapy-naive advanced PC were eligible. All patients were scheduled to undergo chemotherapy at the National Cancer Center Hospital East. Patients with biliary drainage were excluded from this study, because biliary drainage and cholangitis can result in an elevation of serum IL-6 in patients with biliary and pancreatic malignancy.13 T classification and clinical stage were assessed according to the International Union Against Cancer (UICC) 7th edition. Tumor burden was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.14 We recorded the size of the primary lesion and the sum of the longest diameter of liver lesions according to RECIST version 1.1. This study was Pancreas • Volume 44, Number 5, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 5, July 2015
approved by the National Cancer Center Institutional Review Board. All patients provided written informed consent.
IL-6–Related Characteristics in Pancreatic Cancer
TABLE 1. Patient Characteristics
Body Composition
Variables
Body composition was measured before chemotherapy and 1 month later using a bioimpedance analyzer (InBody S20; BioSpace, Seoul, Korea) according to the manufacturer's instructions. Measurements were taken with the patient in the supine position after body weight and height were input into the analyzer. Eight electrodes were placed at various sites on the patient, including the thumb and middle finger of each hand and on the bilateral sides of each ankle.
Age, median (range), y Sex, n (%) Female Male T classification, n (%) T3 T4 UICC stage, n (%) Stage III Stage IV Primary site, n (%) Head Body or tail Liver metastasis, present, n (%) Ascites, present, n (%) Regimen, n (%) GEM GEM doublets S-1 KPS, n (%) 100–90 80–70 60– Morphine, median (range), mg/d Primary tumor size, median (range), mm The sum of the longest diameter of liver lesions, median (range), mm
Symptoms Fatigue was characterized as an IL-6–related symptom in terminally ill cancer patients in our previous study.15 Therefore, we focused on the relationship between fatigue and IL-6 levels. Fatigue was evaluated at the start of chemotherapy using the Japanese version of the brief fatigue inventory,16 which is a standard, reliable instrument to rapidly assess fatigue in cancer patients. The Japanese version of the brief fatigue inventory consists of 9 numerical scales rated from 0 (“not present”) to 10 (“as bad as you can imagine”), including “fatigue NOW,” “fatigue USUAL,” “fatigue MAX,” and a 6-item interference scale. “Fatigue NOW,” “fatigue USUAL,” and “fatigue MAX” indicate the fatigue level currently present, the usual fatigue level, and the worst level of fatigue during the previous 24 hours, respectively. A global fatigue score, termed as “Global BFI,” is calculated by averaging all 9 items on the BFI. “Global BFI” reflect all BFI data including fatigue severity and interference with function.16
Cytokine Assays and Laboratory Data Sera were collected in the morning before chemotherapy and stored at −70°C until analysis. The IL-6 serum level was measured using multiplex assays (Meso Scale Discovery; Gaithersburg, MD) as described previously.12
Statistical Analysis Patients were assigned to a high IL-6 group (IL-6High) or a low IL-6 group (IL-6Low) on the basis of the median IL-6 value in all patients. To convert the continuous or ranked-variables into categorical data, we determined the cutoff level of each factor without categorical factors using receiver operating characteristic analysis to reflect the IL-6High. The associations between the IL-6 classification and each categorical factor were examined using a χ2 test with significance set at P < 0.05. Each of the significant factors in univariate analyses was classified into patients’ characteristics, body compositions, or laboratory data on the basis of own attribute. The independencies of these factors were tested using multivariate logistic regression analysis in each attribute, because the effects of interaction among different attributes were excluded. All analyses were performed using JMP 9, Windows version (SAS Institute, Cary, NC).
RESULTS Patient Characteristics From 2008 to 2009, 109 patients were enrolled. Reasons for exclusion included obvious infections in 5 patients (cholangitis in 2 patients) and biliary stent placements in 25 patients. Seventy-nine patients were ultimately analyzed in this study. All 79 patients received systemic chemotherapy, including gemcitabine (GEM) © 2015 Wolters Kluwer Health, Inc. All rights reserved.
66 (44–85) 33 (41.8) 46 (58.2) 49 (62.0) 30 (38.0) 28 (35.4) 51 (64.6) 17 (21.5) 62 (78.5) 42 (53.2) 22 (27.8) 47 (59.5) 19 (24.0) 13 (16.5) 59 (74.7) 18 (22.8) 2 (2.5) 0 (0–105) 43.0 (11.6–100.1) 73.4 (10.0–241.8)
BMI indicates body mass index; KPS, Karnofsky Performance Status.
monotherapy (n = 47), S-1 monotherapy (n = 13), GEM plus S-1 (n = 11), GEM plus vaccine (n = 5), and GEM plus axitinib (n = 3). The baseline characteristics are shown in Table 1 and Supplementary Table 1 (Supplemental Digital Content 1, http://links.lww.com/MPA/A364). The median levels of IL-6 were 1.2 pg/mL (range, 0.0–34.3 pg/mL) among all 79 patients, 3.6 pg/mL (range, 1.2–34.3 pg/mL) in the IL-6High group (n = 40), and 0.7 pg/mL (range, 0.0–1.2 pg/mL) in the IL-6Low group (n = 39). IL-6High was associated with age older than 70 years, UICC Stage IV, the presence of liver metastasis, the sum of the longest diameter in the liver lesions of more than 24.7 mm and the primary tumor size greater than 43 mm in univariate analysis (Table 2). Multivariate analysis showed that independent risk factors for IL-6High were advanced age [odds ratio (OR), 6.8; 95% confidence interval (95% CI), 1.9–29.0; P < 0.01], the presence of liver metastasis (OR, 12.3; 95% CI, 1.9–121.9; P < 0.01], large burden of liver metastasis (OR, 14.0; 95% CI, 2.4–129.9; P < 0.01) (Table 2). Median age and the sum of the longest diameter in liver metastasis in the IL-6High group were 66 years and 87 mm, respectively, and were high when compared with those in the IL-6Low group (65 years and 20 mm, respectively) (P < 0.01) (Figs. 1A, B).
Body Composition Body composition was measured in all 79 patients (Supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/MPA/A365). Body weight, body mass index, soft lean mass, and muscle mass at the start of chemotherapy www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreas • Volume 44, Number 5, July 2015
Miura et al
TABLE 2. Relationship Between Serum IL-6 Level and Patient Characteristics Distribution, % Variables Age, y Sex T classification UICC stage Primary site Liver metastasis Ascites KPS Morphine dose, mg/d Primary tumor size, mm The sum of the longest diameter of liver lesions, mm
Cutoff
n
Characterization of Patients With Advanced Pancreatic Cancer and High Serum Interleukin-6 Levels Tomofumi Miura, MD,*†‡ Shuichi Mitsunaga, MD, PhD,*‡ Masafumi Ikeda, MD,* Satoshi Shimizu, MD,* Izumi Ohno, MD, PhD,* Hideaki Takahashi, MD,* Junji Furuse, MD, PhD,§ Masatoshi Inagaki, MD, PhD,|| Sayumi Higashi, PhD,¶ Hiroyuki Kato, PhD,¶ Kimio Terao, PhD,¶ and Atsushi Ochiai, MD, PhD‡ Objectives: High serum level of interleukin 6 (IL-6) is associated with high degree of tumor progression and systemic weakness. Anti–IL-6 therapy possibly improves the deterioration of clinical characteristics in patients with high IL-6 level. However, IL-6–related factors in patients with treatment-naive advanced pancreatic cancer (PC) have not been established. The goal of this study was to identify IL-6–related factors in patients with advanced PC who were scheduled to undergo first-line chemotherapy. Methods: Patients with treatment-naive advanced PC were eligible for inclusion in this study. Patients who did not receive first-line chemotherapy were excluded. Serum IL-6 levels and clinical parameters were prospectively recorded. Analyses were performed to identify risk factors for high IL-6 levels. Results: Eighty patients were analyzed. IL-6–related factors were advanced age (P < 0.01), the presence of liver metastasis (P < 0.01), the large volume of liver metastasis (P < 0.01), severe fatigue (P = 0.02), high carcinoembryonic antigen levels (P = 0.02), anemia (P < 0.01), and high C-reactive protein levels (P = 0.02) in multivariate analyses. Decreased skeletal muscle mass tended to be associated with high IL-6 levels. Conclusions: High serum IL-6 was related to advanced age, the presence of hepatic metastasis, large tumor burden in liver, severe fatigue, high carcinoembryonic antigen, high C-reactive protein, and anemia in patients with treatment-naive advanced PC. Key Words: pancreatic cancer, interleukin 6, anti–IL-6 therapy, cancer cachexia (Pancreas 2015;44: 756–763)
I
nterleukin 6 (IL-6) is produced by various cells, including macrophages, hepatocytes, and pancreatic cancer (PC) cells.1 The biologic actions of IL-6 include an increase in inflammatory proteins as well as anemia, fever, fatigue, lipolysis, catabolism of
From the *Department of Hepatobiliary and Pancreatic Oncology, †Department of Palliative Medicine, and ‡Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa; §Department of Medical Oncology, Kyorin University School of Medicine, Mitaka; ||Center for Suicide Prevention, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira; and ¶Chugai Pharmaceutical Co, Ltd, Tokyo, Japan. Received for publication February 7, 2014; accepted December 5, 2014. Reprints: Shuichi Mitsunaga, MD, PhD, Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan (e‐mail: [email protected]). This study was supported by Grants-in-aid for Cancer Research and for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan; JSPS KAKENHI Grant Number 22790624; the National Cancer Center Research and Development Fund (23-A-2); Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan; and Chugai Pharmacology Co, Ltd. The authors declare no conflict of interest. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.pancreasjournal.com). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
756
www.pancreasjournal.com
skeletal muscle, and chemoresistance of tumor cells.2–4 High IL-6 serum levels in patients with PC are associated with severe tumor T classification,5,6 large tumor size,7,8 and the presence of liver metastasis.7 Furthermore, patients with advanced PC and a high IL-6 concentration exhibit poor performance status, progressive weight loss, hypoalbuminemia, and poor outcomes.5,6 High IL-6 level is considered as a reflector of the aggressiveness of PC.9 High IL-6 serum levels are also seen in patients with Castleman disease, which is a lymphoproliferative disorder.10 Body weight loss, fatigue, anemia, hypoalbuminemia, and a high C-reactive protein (CRP) concentration are often found in patients with Castleman disease and are alleviated by anti–IL-6 therapy. These findings suggest that IL-6–related symptoms in patients with PC might be alleviated or prevented by anti–IL-6 therapy. Tumors in patients with PC with high serum level of IL-6 are considered to be IL-6–producing tumors.1 IL-6 is a proinflammatory cytokine, and tumor cells responsible for tumor-associated inflammation can acquire core hallmarks of malignancy, including growth, pathologic survival, angiogenesis, invasion, and epithelial-mesenchymal transition.11 Serum IL-6 level can reflect the aggressiveness of cancer in patients as well as the inflammation-related microenvironment of the tumor.9 IL-6– related symptoms might also highlight the crosstalk between disease progression and cancer biology. Previous studies of IL-6–related symptoms were conducted in various populations of resectable, chemotherapyexperienced, and terminally ill patients. IL-6–related symptoms were often found in terminally ill patients, and it is possible that the imbalance of the population with terminal illness could have affected previous results. The development of anti–IL-6 therapy requires knowledge regarding IL-6–related clinical features in patients with treatment-naive advanced PC, which has not been previously studied. The goal of this study was to characterize IL-6–related factors in patients who were scheduled to undergo first-line chemotherapy for treatment-naive advanced PC.
MATERIALS AND METHODS Patients The subjects in this study were included in our previous study.12 Briefly, patients with pathologically proven and chemotherapy-naive advanced PC were eligible. All patients were scheduled to undergo chemotherapy at the National Cancer Center Hospital East. Patients with biliary drainage were excluded from this study, because biliary drainage and cholangitis can result in an elevation of serum IL-6 in patients with biliary and pancreatic malignancy.13 T classification and clinical stage were assessed according to the International Union Against Cancer (UICC) 7th edition. Tumor burden was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.14 We recorded the size of the primary lesion and the sum of the longest diameter of liver lesions according to RECIST version 1.1. This study was Pancreas • Volume 44, Number 5, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 5, July 2015
approved by the National Cancer Center Institutional Review Board. All patients provided written informed consent.
IL-6–Related Characteristics in Pancreatic Cancer
TABLE 1. Patient Characteristics
Body Composition
Variables
Body composition was measured before chemotherapy and 1 month later using a bioimpedance analyzer (InBody S20; BioSpace, Seoul, Korea) according to the manufacturer's instructions. Measurements were taken with the patient in the supine position after body weight and height were input into the analyzer. Eight electrodes were placed at various sites on the patient, including the thumb and middle finger of each hand and on the bilateral sides of each ankle.
Age, median (range), y Sex, n (%) Female Male T classification, n (%) T3 T4 UICC stage, n (%) Stage III Stage IV Primary site, n (%) Head Body or tail Liver metastasis, present, n (%) Ascites, present, n (%) Regimen, n (%) GEM GEM doublets S-1 KPS, n (%) 100–90 80–70 60– Morphine, median (range), mg/d Primary tumor size, median (range), mm The sum of the longest diameter of liver lesions, median (range), mm
Symptoms Fatigue was characterized as an IL-6–related symptom in terminally ill cancer patients in our previous study.15 Therefore, we focused on the relationship between fatigue and IL-6 levels. Fatigue was evaluated at the start of chemotherapy using the Japanese version of the brief fatigue inventory,16 which is a standard, reliable instrument to rapidly assess fatigue in cancer patients. The Japanese version of the brief fatigue inventory consists of 9 numerical scales rated from 0 (“not present”) to 10 (“as bad as you can imagine”), including “fatigue NOW,” “fatigue USUAL,” “fatigue MAX,” and a 6-item interference scale. “Fatigue NOW,” “fatigue USUAL,” and “fatigue MAX” indicate the fatigue level currently present, the usual fatigue level, and the worst level of fatigue during the previous 24 hours, respectively. A global fatigue score, termed as “Global BFI,” is calculated by averaging all 9 items on the BFI. “Global BFI” reflect all BFI data including fatigue severity and interference with function.16
Cytokine Assays and Laboratory Data Sera were collected in the morning before chemotherapy and stored at −70°C until analysis. The IL-6 serum level was measured using multiplex assays (Meso Scale Discovery; Gaithersburg, MD) as described previously.12
Statistical Analysis Patients were assigned to a high IL-6 group (IL-6High) or a low IL-6 group (IL-6Low) on the basis of the median IL-6 value in all patients. To convert the continuous or ranked-variables into categorical data, we determined the cutoff level of each factor without categorical factors using receiver operating characteristic analysis to reflect the IL-6High. The associations between the IL-6 classification and each categorical factor were examined using a χ2 test with significance set at P < 0.05. Each of the significant factors in univariate analyses was classified into patients’ characteristics, body compositions, or laboratory data on the basis of own attribute. The independencies of these factors were tested using multivariate logistic regression analysis in each attribute, because the effects of interaction among different attributes were excluded. All analyses were performed using JMP 9, Windows version (SAS Institute, Cary, NC).
RESULTS Patient Characteristics From 2008 to 2009, 109 patients were enrolled. Reasons for exclusion included obvious infections in 5 patients (cholangitis in 2 patients) and biliary stent placements in 25 patients. Seventy-nine patients were ultimately analyzed in this study. All 79 patients received systemic chemotherapy, including gemcitabine (GEM) © 2015 Wolters Kluwer Health, Inc. All rights reserved.
66 (44–85) 33 (41.8) 46 (58.2) 49 (62.0) 30 (38.0) 28 (35.4) 51 (64.6) 17 (21.5) 62 (78.5) 42 (53.2) 22 (27.8) 47 (59.5) 19 (24.0) 13 (16.5) 59 (74.7) 18 (22.8) 2 (2.5) 0 (0–105) 43.0 (11.6–100.1) 73.4 (10.0–241.8)
BMI indicates body mass index; KPS, Karnofsky Performance Status.
monotherapy (n = 47), S-1 monotherapy (n = 13), GEM plus S-1 (n = 11), GEM plus vaccine (n = 5), and GEM plus axitinib (n = 3). The baseline characteristics are shown in Table 1 and Supplementary Table 1 (Supplemental Digital Content 1, http://links.lww.com/MPA/A364). The median levels of IL-6 were 1.2 pg/mL (range, 0.0–34.3 pg/mL) among all 79 patients, 3.6 pg/mL (range, 1.2–34.3 pg/mL) in the IL-6High group (n = 40), and 0.7 pg/mL (range, 0.0–1.2 pg/mL) in the IL-6Low group (n = 39). IL-6High was associated with age older than 70 years, UICC Stage IV, the presence of liver metastasis, the sum of the longest diameter in the liver lesions of more than 24.7 mm and the primary tumor size greater than 43 mm in univariate analysis (Table 2). Multivariate analysis showed that independent risk factors for IL-6High were advanced age [odds ratio (OR), 6.8; 95% confidence interval (95% CI), 1.9–29.0; P < 0.01], the presence of liver metastasis (OR, 12.3; 95% CI, 1.9–121.9; P < 0.01], large burden of liver metastasis (OR, 14.0; 95% CI, 2.4–129.9; P < 0.01) (Table 2). Median age and the sum of the longest diameter in liver metastasis in the IL-6High group were 66 years and 87 mm, respectively, and were high when compared with those in the IL-6Low group (65 years and 20 mm, respectively) (P < 0.01) (Figs. 1A, B).
Body Composition Body composition was measured in all 79 patients (Supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/MPA/A365). Body weight, body mass index, soft lean mass, and muscle mass at the start of chemotherapy www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
757
Pancreas • Volume 44, Number 5, July 2015
Miura et al
TABLE 2. Relationship Between Serum IL-6 Level and Patient Characteristics Distribution, % Variables Age, y Sex T classification UICC stage Primary site Liver metastasis Ascites KPS Morphine dose, mg/d Primary tumor size, mm The sum of the longest diameter of liver lesions, mm
Cutoff
n
