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Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy
Pancreatology xxx (2015) 1e6
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Original article
Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy Hiroshi Kurahara a, *, Kosei Maemura a, Yuko Mataki a, Masahiko Sakoda a, Satoshi Iino a, Kiyokazu Hiwatashi a, Yota Kawasaki a, Takaaki Arigami a, Sumiya Ishigami a, Yuko Kijima a, Hiroyuki Shinchi b, Sonshin Takao c, Shoji Natsugoe a a b c
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan Health Sciences, Kagoshima University, Kagoshima, Japan Frontier Science Research Center, Kagoshima University, Kagoshima, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Background: An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). Methods: Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. Results: The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen 400 mg/dL, and GPS 2 and fibrinogen 400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. Conclusions: GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Inflammation Chemoradiotherapy Pancreatic cancer Prognostic score Concomitant chemotherapy Cox regression analysis
Introduction In 2010, pancreatic cancer was the fourth leading cause of cancer-related mortalities in the United States [1]. Pancreatic cancer is generally detected at an advanced stage at the time of diagnosis (metastatic, 50.5%; regional spread, 25.9%; localized, 8%; and unstaged, 15.5%) [2]. Despite developments in the detection and management of pancreatic cancer, the 5-year survival rate is only 4% [3]. Even after potentially curative resection, over 50% of
* Corresponding author. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan. Tel.: þ81 99 275 5361; fax: þ81 99 265 7426. E-mail address: [email protected] (H. Kurahara).
patients experience local or distant recurrence [4], underscoring the need to develop a more effective therapy. The therapeutic efficacy of chemoradiotherapy (CRT) in combination with various anticancer drugs such as gemcitabine, cisplatin, and 5-fluorouracil (5-FU) for locally advanced pancreatic cancer has been reported in clinical trials [5e7]. We have reported the efficacy of CRT using S-1, an oral form of 5-FU with improved antitumor activity that inhibits dihydropyrimidine dehydrogenase (a key enzyme in 5-FU catabolism), followed by systemic chemotherapy for unresectable pancreatic cancer without metastasis [8]. Furthermore, neoadjuvant CRT has been recently adopted to achieve local control of primary tumors, sterilization of lymphadenopathy and surgical margins, and evaluation of tumor biology prior to surgery [9,10]. Several factors have been investigated as potential prognostic predictors in cancer patients. In particular, an association between
http://dx.doi.org/10.1016/j.pan.2015.09.015 1424-3903/Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
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inflammatory and immunonutritional status has been demonstrated with postoperative complications and the long-term outcomes of patients with various malignant tumors. The Glasgow Prognostic Score (GPS) considers the albumin and CRP levels [11,12]; Onodera's prognostic nutritional index (PNI) incorporates albumin levels and lymphocyte counts [13,14]; plasma fibrinogen, an essential hemostatic factor that is converted to fibrin by activated thrombin [15,16]; and the neutrophilelymphocyte ratio (NLR) [17,18]. These factors have been reported as clinical predictors of outcome in patients with various types of cancer [11e18]. The predictive value of inflammatory-based scores for therapeutic effect and prognosis in patients with pancreatic cancer treated by CRT is unclear. The primary aim of this study was to evaluate the usefulness of the inflammatory-based scores as predictors of high reduction rate of the primary tumor, progression-free survival (PFS), and overall survival (OS) in patients with locally advanced pancreatic cancer who underwent CRT.
Materials and methods Patient enrollment Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT at Kagoshima University Hospital between October 2005 and May 2014 were enrolled in this study. This was a retrospective study of a prospectively maintained dataset. This study was approved by the institutional ethics review board of Kagoshima University Hospital, and written informed consent to data analysis for identification of the therapeutic and prognostic predictors was obtained. The present study had strict exclusion criteria. To enroll patients with locally advanced pancreatic cancer, patients without pretreatment histological diagnosis and those with distant metastasis were excluded. To uniform the treatment process, patients who received other treatment including chemotherapy before CRT were excluded. The criteria for locally advanced pancreatic cancer were as follows: unreconstructible portal vein/superior mesenteric vein (PV/SMV) involvement demonstrating venous occlusion and/or tumor abutment 180 with the superior mesenteric artery (SMA), hepatic artery (HA), or celiac artery (CA).
Clinical examination Before treatment, all patients underwent a clinical evaluation, routine laboratory tests and imaging studies, including multidetector row computed tomography (MDCT), gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), and endoscopic ultrasonography. GPS was calculated as previously described [11,12,19]. In brief, patients with both an elevated CRP (10 mg/L) and hypoalbuminemia (35 g/L) were allocated a score of 2 (GPS 2); patients with neither were allocated a score of 0 (GPS 0); and patients with only one of these abnormalities were allocated a score of 1 (GPS 1). Onodera's PNI was calculated as 10 albumin (g/dL) þ 0.005 total lymphocyte count (per mm3) [13,14,20]. The PNI cut-off value was set at 45 as previously described. NLR was calculated as neutrophil count divided by lymphocyte count [17,18,21]. The NLR cut-off value was set at 3.0, as previously described. According to the reference range of clinical criterion in our hospital, plasma fibrinogen levels 400 mg/dL were defined as hyperfibrinogenemia. All analyzed factors were measured a few days before CRT initiation.
Treatment and evaluation Patients initially received 4 weeks of CRT. S-1 (Taiho Pharmaceutical Co., Ltd. Tokyo, Japan) was administrated orally twice daily at a dose of 80 mg/m2/day from days 1e21. We have adopted hyperfractionated accelerated radiotherapy as radiotherapy [22]. In brief, conformal radiotherapy was administered twice daily, 5 days a week for 4 weeks. A total dose of 50e58 Gy was delivered in 40 fractions over the 4 weeks. The radiotherapy field covered the primary tumor and adjacent lymph nodes as defined by CT-assisted treatment planning before CRT. One month after CRT completion, S1 was administrated for 2 weeks followed by a 2-week rest period. This cycle was repeated until disease progression or unacceptable toxicity [8]. Tumors were evaluated by using MDCT, 1 month after CRT and every 3 months thereafter. OS and PFS were calculated from the date of CRT initiation to the date of death or the last follow-up (censoring). Disease progression was confirmed by MDCT/EOB-MRI or the last follow-up (censoring), respectively. Statistical analysis OS and PFS curves of the patients were plotted using the KaplaneMeyer method and analyzed using the log-rank test. Continuous variables were compared using the ManneWhitney U test, paired Student's t-test, or ANOVA test. Multivariate analyses for OS and PFS were performed by Cox regression analysis presented as Hazard Ratio (HR) with 95% confidence interval (95% CI). P values < 0.05 were considered statistically significant. Statistical evaluation of the data was performed using SigmaPlot version 12.5 for Windows (HULINKS Inc., Tokyo, Japan). Results Patient characteristics and post-chemoradiotherapy course The mean contractionary rate of the primary tumor was 25.4% (range, 56.0% to 76.0%). Twenty-six patients (27.1%) achieved a partial response, 56 (58.3%) had stable disease, and 14 (14.6%) had progressive disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Ten (10.4%) of the 96 patients underwent surgical resection after CRT followed by S-1 administration. The median PFS and OS was 10 and 18 months, respectively. Fifty-seven patients (59.4%) had metastatic disease after CRT. The sites of the first metastasis after CRT were the liver (n ¼ 30), peritoneum (n ¼ 17), lungs (n ¼ 7), and lymph nodes (n ¼ 3). Thirty (31.3%) of the 96 patients had metastasis within 6 months after CRT. Followup periods after CRT ranged from 4 to 92 months. At the time of this analysis 79/96 patients (82.3%) had died. Predictors of prognosis after chemoradiotherapy In univariate analysis, GPS 2, PNI < 45, and plasma fibrinogen 400 mg/dL were significant predictors of poor PFS and OS (Table 1). In multivariate analysis, GPS 2 and plasma fibrinogen 400 mg/dL were independent predictors of poor PFS and OS (Table 2). The median PFS of patients with GPS 0/1 and fibrinogen <400 mg/dL was 10 and 11 months, respectively. In contrast, the median PFS of patients with GPS 2 and plasma fibrinogen 400 mg/dL was 4 and 5 months, respectively. The median OS of patients with GPS 0/1 and serum plasma fibrinogen <400 mg/dL was 19 and 21 months, respectively. In contrast, the median OS of patients with GPS 2 and plasma fibrinogen 400 mg/ dL was 7 and 12 months, respectively.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
H. Kurahara et al. / Pancreatology xxx (2015) 1e6
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Table 1 Progression free survival (PFS) and overall survival (OS) after CRT. PFS (95% CI) (months)
P value
OS (95% CI) (months)
P value
Gender
Factor Male Female
n 51 45
9.0 (7.2e10.9) 11.0 (6.7e15.3)
NS
17.0 (14.2e19.8) 19.0 (13.2e24.8)
NS
Age (years)
<75 75
78 18
8.0 (5.6e10.4) 11.0 (6.3e15.7)
NS
17.0 (13.0e21.0) 19.0 (17.2e20.8)
NS
BMI
<20 20
33 63
7.0 (5.1e8.9) 10.0 (8.4e11.6)
NS
13.0 (11.7e14.3) 19.0 (16.6e21.4)
NS
DM
Yes No
41 55
10.0 (7.9e12.1) 9.0 (6.2e11.8)
NS
18.0 (14.1e21.9) 17.0 (12.7e21.3)
NS
Tumor position
Head Body-tail
64 32
9.0 (6.5e11.5) 11.0 (8.3e13.7)
NS
16.0 (13.0e19.0) 20.0 (17.3e22.7)
NS
GPS
0/1 2
89 7
10.0 (8.5e11.5) 4.0 (2.4e5.6)
<0.001
19.0 (16.2e21.8) 7.0 (4.4e9.6)
<0.001
PNI
<45 45
<32 64
5.0 (1.8e8.2) 11.0 (9.3e12.7)
0.019
12.0 (8.5e15.5) 20.0 (17.0e23.0)
0.007
NLR
<3 3
72 24
10.0 (7.3e12.7) 8.0 (3.7e12.3)
NS
19.0 (15.2e22.8) 13.0 (5.6e20.4)
NS
Fibrinogen (mg/dL)
<400 400
68 28
11.0 (9.2e12.8) 5.0 (1.3e8.7)
<0.001
21.0 (18.4e23.7) 12.0 (8.3e15.7)
<0.001
CA 19-9 (U/mL)
<37 37
18 78
11.0 (8.2e13.8) 9.0 (6.7e11.3)
NS
20.0 (13.8e26.2) 17.0 (13.9e20.1)
NS
NS: not significant, BMI: body mass index, DM: diabetes mellitus, GPS: Glasgow prognostic score, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, CA 19-9: carbohydrate antigen 19-9.
Predictor of high reduction rate of the primary tumor after chemoradiotherapy Only PNI was a predictor of high reduction rate of the primary tumor after CRT (Table 3). Patients with a PNI 45 showed a tumor reduction rate of 32.1%; in contrast, this rate was only 12.1% in patients with PNI < 45. The median time of maximum reduction rate was 4 months after CRT. Patients who underwent surgical resection after CRT showed a dramatic reduction rate (mean, 57.3%); the reduction rate was 21.7% in patients who did not undergo surgery. Eight of the 10 patients who underwent surgical resection had a PNI 45.
Combination analysis of inflammatory-based score for prognostification of patients with locally advanced pancreatic cancer treated with chemoradiotherapy To effectively distinguish prognosis in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, we performed combination analysis using GPS and plasma fibrinogen that were independent predictors of PFS and OS (Fig. 1). We divided all patients into 3 groups: group 1 (n ¼ 66) with GPS 0/1 and plasma fibrinogen < 400 mg/dL; group 2 (n ¼ 25) with GPS 2 or plasma fibrinogen 400 mg/dL; and group 3 (n ¼ 5) with GPS 2 and plasma fibrinogen 400 mg/dL. The median PFS of patients of groups 1, 2, 3 was 11, 7, 4 months, respectively. The difference was significant
(P < 0.001) (Fig. 1A). The median OS of patients of groups 1, 2, 3 was 21, 12, 8.5 months, respectively. The difference was significant (P < 0.001). Furthermore, significant differences were observed between each group (Fig. 1B). Predictors of metastasis within 6 months after chemoradiotherapy We analyzed the association between clinicopathological factors and metastasis within 6 months after CRT to identify the predictor of early metastasis (Table 4). Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of the early metastasis. Discussion Concomitant chemotherapy and radiotherapy are used for the treatment of locally advanced pancreatic cancer [5e8]. We used S-1 as an anticancer agent in CRT and subsequent systemic chemotherapy. S-1 has been demonstrated to be non-inferior to gemcitabine in OS in patients with metastatic or locally advanced pancreatic cancer [23] and superior to adjuvant chemotherapy with gemcitabine in OS in patients with resected pancreatic cancer [24]. In this study, the PFS and OS were 10 and 18 months, respectively. CRT with subsequent systemic chemotherapy was a useful strategy for locally advanced pancreatic cancer; however, the therapeutic effect on the primary tumor varied considerably by individual, and
Table 2 Cox regression analysis of progression free survival (PFS) and overall survival (OS) after CRT. Factor
GPS 2 PNI 45 Fibrinogen 400
PFS
OS
HR
95% CI
P value
HR
95% CI
P value
3.421 1.121 1.899
1.353e8.651 0.646e1.944 1.110e3.249
0.009 NS 0.019
4.673 1.256 2.000
1.802e12.11 0.729e2.169 1.136e3.521
0.002 NS 0.016
HR: Hazard ratio, NS: not significant, GPS: Glasgow prognostic score, PNI: prognostic nutritional index.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
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H. Kurahara et al. / Pancreatology xxx (2015) 1e6
Table 3 Association between clinical factors and reduction rate of the primary tumor after CRT. Factor
n
Maximum reduction ratea (%)
P value
Gender
Male Female
51 45
25.2 (±4.0) 23.8 (±3.7)
NS
Age
<75 75
78 18
24.3 (±3.1) 30.6 (±5.5)
NS
BMI
<20 20
33 63
20.1 (±4.5) 28.3 (±3.4)
NS
DM
Yes No
41 55
25.8 (±4.4) 25.2 (±3.5)
NS
Tumor position
Head Body-tail
64 32
24.0 (±3.2) 22.0 (±3.9)
NS
GPS
0/1 2
89 7
26.5 (±2.8) 12.0 (±8.7)
NS
PNI
<45 45
<32 ±64
12.1 (±4.6) 32.1 (±3.1)
<0.001
NLR
<3 3
72 24
26.7 (±3.0) 21.6 (±5.9)
NS
Fibrinogen
<400 400
86 10
26.7 (±2.9) 14.9 (±5.9)
NS
CA 19-9 (U/mL)
<37 37
18 78
27.7 (±6.9) 24.9 (±3.0)
NS
NS: not significant, BMI: body mass index, DM: diabetes mellitus, GPS: Glasgow prognostic score, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, CA 19-9: carbohydrate antigen 19-9. a Mean value (±SE).
30 patients (31.3%) experienced metastasis within 6 months after CRT. In our study, PNI 45 was a significant predictor of high reduction rate of the primary tumor in patients with locally advanced pancreatic cancer who underwent CRT followed by systemic chemotherapy. GPS 2 and plasma fibrinogen 400 mg/dL were revealed as independent prognostic factors of poor PSF and OS. Furthermore, there were significant differences between the prognoses of patients with GPS 0/1 and plasma fibrinogen <400 mg/dL, GPS 2 or plasma fibrinogen 400 mg/dL, and GPS 2 and plasma fibrinogen 400 mg/dL. Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. The early metastasis may
be one of the causes of poor PFS and OS of patients with GPS 2 and/ or plasma fibrinogen 400 mg/dL. Plasma fibrinogen 400 mg/dL and GPS 2 may indicate the need for more intensive systemic chemotherapy rather than CRT to improve PFS and OS. Inflammation plays a pivotal role in the development and progression of pancreatic cancer [25], and a dense, desmoplastic stroma rich in inflammatory cells, fibroblasts, and extracellular matrix (ECM) proteins is a trait of pancreatic cancer [26]. Malnutrition at diagnosis caused by tumor progression and decreased oral intake due to gastrointestinal obstruction, pancreatitis, and cancerous pain has been reported as another trait [13]. Therefore, an association between inflammatory/immunonutritional factors
Fig. 1. KaplaneMeier survival curves of patients treated with chemoradiotherapy divided into 3 groups: group 1 (n ¼ 66) with GPS 0/1 and plasma fibrinogen < 400 mg/dL; groups 2 (n ¼ 25) with GPS 2 or plasma fibrinogen 400 mg/dL; and group 3 (n ¼ 5) with GPS 2 and plasma fibrinogen 400 mg/dL. (A) The median progression free survival of patients of groups 1, 2, 3 was 11, 7, 4 months, respectively. The difference was significant (P < 0.001). (B) The median overall survival of patients of groups 1, 2, 3 was 21, 12, 8.5 months, respectively. The difference was significant (P < 0.001). Furthermore, significant differences were observed between each group.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
H. Kurahara et al. / Pancreatology xxx (2015) 1e6
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Table 4 Association between clinical factors and distant metastasis within 6 months after CRT. n
Metastasis (n ¼ 30)
No metastasis (n ¼ 66)
P value
Gender
Male Female
51 45
19 11
32 34
NS
Age (year)
<75 75
78 18
27 3
51 15
NS
BMI
<20 20
33 63
14 16
19 47
NS
DM
Yes No
41 55
12 18
29 37
NS
Tumor position
Head Body-tail
64 32
21 9
43 23
NS
PNI
<45 45
72 24
14 16
18 48
NS
NLR
<3 3
72 24
20 10
52 14
NS
GPS 2 and/or Fibrinogen 400
Yes No
30 66
15 15
15 51
0.015
CA 19-9 (U/mL)
<37 37
18 78
2 28
16 50
NS
Factor
NS: not significant, BMI: body mass index, DM: diabetes mellitus, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, GPS: Glasgow prognostic score, CA 19-9: carbohydrate antigen 19-9.
and prognosis has been investigated. However, few studies have compared inflammatory/immunonutritional factors to each other. High GPS was reported as a predictor of poor prognosis [11] and of worse treatment outcome with gemcitabine-based chemotherapy [19] in unresectable pancreatic cancer. Hypoalbuminemia and elevated CRP levels suggest the presence of systemic inflammation in cancer patients [12]. A correlation between increased plasma fibrinogen levels has been reported as a useful predictor of distant metastasis in pancreatic cancer [15]. Fibrinogen deposits in the ECM serve as a scaffold to support binding of growth factors and to promote adhesion, proliferation, and migration during angiogenesis and tumor growth [15]. Fibrinogen is also an acute phase reactant; its plasma level increases under inflammatory conditions [27]. An association of PNI with OS and postoperative complications in patients with pancreatic cancer has been reported [13]. Although the mechanism responsible for the enhanced anti-tumor effect has not been elucidated, immunonutritional status may affect the pharmacokinetics of many anticancer agents through altered protein binding and P450 activity [20]. Recently, outcomes of neoadjuvant CRT in pancreatic cancer have been reported [9,10,28,29]. Although patients who underwent neoadjuvant CRT had higher rates of negative margins and lower rates of positive lymph nodes, the survival benefit from neoadjuvant CRT is controversial. Normal CA 19-9 levels before treatment and normalization of CA 19-9 levels after neoadjuvant CRT are associated with better prognosis after surgery [10,28]. In the neoadjuvant setting, prediction of high reduction ratio of the primary tumor and early metastasis are crucial for treatment strategy. Patients with PNI 45, GPS 0/1, and plasma fibrinogen <400 mg/dL may benefit from neoadjuvant CRT for locally advanced pancreatic cancer. Utility of PNI, GPS, and plasma fibrinogen in neoadjuvant therapy for locally advanced pancreatic cancer should be confirmed in a prospective study. The mechanism of contribution of these inflammatory/immunonutritional factors to the therapeutic effect of CRT should be elucidated. Identification of predictors of the therapeutic effect of CRT has strategic significance for locally advanced pancreatic cancer. In conclusion, we suggest that GPS and plasma fibrinogen are useful metastatic and prognostic predictors, and PNI may be a
predictor of high reduction rate of the primary tumor in patients with locally advanced pancreatic cancer treated by CRT. By using combination of GPS and plasma fibrinogen level, the patients could be divided into 3 groups with significantly different PFS and OS.
Disclosures and funding sources The authors state that they have no conflicts of interest and that they received no financial or material support. Acknowledgments Supported in part by Grants-in-Aid for Scientific Research (26462067) from the Japan Society for the Promotion of Science, Ministry of Health, Labour, and Welfare, Japan.
References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a Cancer J Clin 2010;60:277e300. [2] Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol 2012;18:736e45. [3] Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378:607e20. [4] Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006;244:10e5. [5] Okusaka T, Ito Y, Ueno H, Ikeda M, Takezako Y, Morizane C, et al. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 2004;91:673e7. [6] Small Jr W, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol Off J Am Soc Clin Oncol 2008;26:942e7. [7] Wilkowski R, Boeck S, Ostermaier S, Sauer R, Herbst M, Fietkau R, et al. Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer e a multi-centre randomised phase II study. Br J Cancer 2009;101: 1853e9. [8] Shinchi H, Maemura K, Mataki Y, Kurahara H, Sakoda M, Ueno S, et al. A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer. J Hepatobiliary Pancreat Sci 2012;19:152e8.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
6
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[9] Estrella JS, Rashid A, Fleming JB, Katz MH, Lee JE, Wolf RA, et al. Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation. Cancer 2012;118:268e77. [10] Tzeng CW, Balachandran A, Ahmad M, Lee JE, Krishnan S, Wang H, et al. Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer. HPB Off J Int Hepato Pancreato Biliary Assoc 2014;16:430e8. [11] Glen P, Jamieson NB, McMillan DC, Carter R, Imrie CW, McKay CJ. Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology 2006;6:450e3. [12] Vashist YK, Loos J, Dedow J, Tachezy M, Uzunoglu G, Kutup A, et al. Glasgow prognostic score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer. Ann Surg Oncol 2011;18:1130e8. [13] Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A. Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg 2011;98:268e74. [14] Mohri Y, Inoue Y, Tanaka K, Hiro J, Uchida K, Kusunoki M. Prognostic nutritional index predicts postoperative outcome in colorectal cancer. World J Surg 2013;37:2688e92. [15] Guo Q, Zhang B, Dong X, Xie Q, Guo E, Huang H, et al. Elevated levels of plasma fibrinogen in patients with pancreatic cancer: possible role of a distant metastasis predictor. Pancreas 2009;38:e75e9. [16] Shu YJ, Weng H, Bao RF, Wu XS, Ding Q, Cao Y, et al. Clinical and prognostic significance of preoperative plasma hyperfibrinogenemia in gallbladder cancer patients following surgical resection: a retrospective and in vitro study. BMC Cancer 2014;14:566. [17] Stotz M, Gerger A, Eisner F, Szkandera J, Loibner H, Ress AL, et al. Increased neutrophilelymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer 2013;109: 416e21. [18] Luo G, Guo M, Liu Z, Xiao Z, Jin K, Long J, et al. Blood neutrophilelymphocyte ratio predicts survival in patients with advanced pancreatic cancer treated with chemotherapy. Ann Surg Oncol 2015;22:670e6. [19] Shimoda M, Katoh M, Kita J, Sawada T, Kubota K. The glasgow prognostic score is a good predictor of treatment outcome in patients with unresectable pancreatic cancer. Chemotherapy 2010;56:501e6.
[20] Pinato DJ, North BV, Sharma R. A novel, externally validated inflammationbased prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI). Br J Cancer 2012;106:1439e45. [21] Huang J, Xu L, Luo Y, He F, Zhang Y, Chen M. The inflammation-based scores to predict prognosis of patients with hepatocellular carcinoma after hepatectomy. Med Oncol 2014;31:883. [22] Maemura K, Shinchi H, Noma H, Mataki Y, Kurahara H, Maeda S, et al. Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer. Anticancer Res 2008;28:2369e72. [23] Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, 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. J Clin Oncol Off J Am Soc Clin Oncol 2013;31:1640e8. [24] Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, et al. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan adjuvant study group of pancreatic cancer (JASPAC-01). Jpn J Clin Oncol 2008;38:227e9. [25] Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004;239:763e9 [Discussion 769e771]. [26] Kurahara H, Takao S, Kuwahata T, Nagai T, Ding Q, Maeda K, et al. Clinical significance of folate receptor beta-expressing tumor-associated macrophages in pancreatic cancer. Ann Surg Oncol 2012;19:2264e71. [27] Son HJ, Park JW, Chang HJ, Kim DY, Kim BC, Kim SY, et al. Preoperative plasma hyperfibrinogenemia is predictive of poor prognosis in patients with nonmetastatic colon cancer. Ann Surg Oncol 2013;20:2908e13. [28] Katz MH, Varadhachary GR, Fleming JB, Wolff RA, Lee JE, Pisters PW, et al. Serum ca 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. Ann Surg Oncol 2010;17:1794e801. [29] Colbert LE, Hall WA, Nickleach D, Switchenko J, Kooby DA, Liu Y, et al. Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the national cancer data base. Cancer 2014;120:499e506.
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Original article
Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy Hiroshi Kurahara a, *, Kosei Maemura a, Yuko Mataki a, Masahiko Sakoda a, Satoshi Iino a, Kiyokazu Hiwatashi a, Yota Kawasaki a, Takaaki Arigami a, Sumiya Ishigami a, Yuko Kijima a, Hiroyuki Shinchi b, Sonshin Takao c, Shoji Natsugoe a a b c
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan Health Sciences, Kagoshima University, Kagoshima, Japan Frontier Science Research Center, Kagoshima University, Kagoshima, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Background: An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). Methods: Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. Results: The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen 400 mg/dL, and GPS 2 and fibrinogen 400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. Conclusions: GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Inflammation Chemoradiotherapy Pancreatic cancer Prognostic score Concomitant chemotherapy Cox regression analysis
Introduction In 2010, pancreatic cancer was the fourth leading cause of cancer-related mortalities in the United States [1]. Pancreatic cancer is generally detected at an advanced stage at the time of diagnosis (metastatic, 50.5%; regional spread, 25.9%; localized, 8%; and unstaged, 15.5%) [2]. Despite developments in the detection and management of pancreatic cancer, the 5-year survival rate is only 4% [3]. Even after potentially curative resection, over 50% of
* Corresponding author. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan. Tel.: þ81 99 275 5361; fax: þ81 99 265 7426. E-mail address: [email protected] (H. Kurahara).
patients experience local or distant recurrence [4], underscoring the need to develop a more effective therapy. The therapeutic efficacy of chemoradiotherapy (CRT) in combination with various anticancer drugs such as gemcitabine, cisplatin, and 5-fluorouracil (5-FU) for locally advanced pancreatic cancer has been reported in clinical trials [5e7]. We have reported the efficacy of CRT using S-1, an oral form of 5-FU with improved antitumor activity that inhibits dihydropyrimidine dehydrogenase (a key enzyme in 5-FU catabolism), followed by systemic chemotherapy for unresectable pancreatic cancer without metastasis [8]. Furthermore, neoadjuvant CRT has been recently adopted to achieve local control of primary tumors, sterilization of lymphadenopathy and surgical margins, and evaluation of tumor biology prior to surgery [9,10]. Several factors have been investigated as potential prognostic predictors in cancer patients. In particular, an association between
http://dx.doi.org/10.1016/j.pan.2015.09.015 1424-3903/Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
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H. Kurahara et al. / Pancreatology xxx (2015) 1e6
inflammatory and immunonutritional status has been demonstrated with postoperative complications and the long-term outcomes of patients with various malignant tumors. The Glasgow Prognostic Score (GPS) considers the albumin and CRP levels [11,12]; Onodera's prognostic nutritional index (PNI) incorporates albumin levels and lymphocyte counts [13,14]; plasma fibrinogen, an essential hemostatic factor that is converted to fibrin by activated thrombin [15,16]; and the neutrophilelymphocyte ratio (NLR) [17,18]. These factors have been reported as clinical predictors of outcome in patients with various types of cancer [11e18]. The predictive value of inflammatory-based scores for therapeutic effect and prognosis in patients with pancreatic cancer treated by CRT is unclear. The primary aim of this study was to evaluate the usefulness of the inflammatory-based scores as predictors of high reduction rate of the primary tumor, progression-free survival (PFS), and overall survival (OS) in patients with locally advanced pancreatic cancer who underwent CRT.
Materials and methods Patient enrollment Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT at Kagoshima University Hospital between October 2005 and May 2014 were enrolled in this study. This was a retrospective study of a prospectively maintained dataset. This study was approved by the institutional ethics review board of Kagoshima University Hospital, and written informed consent to data analysis for identification of the therapeutic and prognostic predictors was obtained. The present study had strict exclusion criteria. To enroll patients with locally advanced pancreatic cancer, patients without pretreatment histological diagnosis and those with distant metastasis were excluded. To uniform the treatment process, patients who received other treatment including chemotherapy before CRT were excluded. The criteria for locally advanced pancreatic cancer were as follows: unreconstructible portal vein/superior mesenteric vein (PV/SMV) involvement demonstrating venous occlusion and/or tumor abutment 180 with the superior mesenteric artery (SMA), hepatic artery (HA), or celiac artery (CA).
Clinical examination Before treatment, all patients underwent a clinical evaluation, routine laboratory tests and imaging studies, including multidetector row computed tomography (MDCT), gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), and endoscopic ultrasonography. GPS was calculated as previously described [11,12,19]. In brief, patients with both an elevated CRP (10 mg/L) and hypoalbuminemia (35 g/L) were allocated a score of 2 (GPS 2); patients with neither were allocated a score of 0 (GPS 0); and patients with only one of these abnormalities were allocated a score of 1 (GPS 1). Onodera's PNI was calculated as 10 albumin (g/dL) þ 0.005 total lymphocyte count (per mm3) [13,14,20]. The PNI cut-off value was set at 45 as previously described. NLR was calculated as neutrophil count divided by lymphocyte count [17,18,21]. The NLR cut-off value was set at 3.0, as previously described. According to the reference range of clinical criterion in our hospital, plasma fibrinogen levels 400 mg/dL were defined as hyperfibrinogenemia. All analyzed factors were measured a few days before CRT initiation.
Treatment and evaluation Patients initially received 4 weeks of CRT. S-1 (Taiho Pharmaceutical Co., Ltd. Tokyo, Japan) was administrated orally twice daily at a dose of 80 mg/m2/day from days 1e21. We have adopted hyperfractionated accelerated radiotherapy as radiotherapy [22]. In brief, conformal radiotherapy was administered twice daily, 5 days a week for 4 weeks. A total dose of 50e58 Gy was delivered in 40 fractions over the 4 weeks. The radiotherapy field covered the primary tumor and adjacent lymph nodes as defined by CT-assisted treatment planning before CRT. One month after CRT completion, S1 was administrated for 2 weeks followed by a 2-week rest period. This cycle was repeated until disease progression or unacceptable toxicity [8]. Tumors were evaluated by using MDCT, 1 month after CRT and every 3 months thereafter. OS and PFS were calculated from the date of CRT initiation to the date of death or the last follow-up (censoring). Disease progression was confirmed by MDCT/EOB-MRI or the last follow-up (censoring), respectively. Statistical analysis OS and PFS curves of the patients were plotted using the KaplaneMeyer method and analyzed using the log-rank test. Continuous variables were compared using the ManneWhitney U test, paired Student's t-test, or ANOVA test. Multivariate analyses for OS and PFS were performed by Cox regression analysis presented as Hazard Ratio (HR) with 95% confidence interval (95% CI). P values < 0.05 were considered statistically significant. Statistical evaluation of the data was performed using SigmaPlot version 12.5 for Windows (HULINKS Inc., Tokyo, Japan). Results Patient characteristics and post-chemoradiotherapy course The mean contractionary rate of the primary tumor was 25.4% (range, 56.0% to 76.0%). Twenty-six patients (27.1%) achieved a partial response, 56 (58.3%) had stable disease, and 14 (14.6%) had progressive disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Ten (10.4%) of the 96 patients underwent surgical resection after CRT followed by S-1 administration. The median PFS and OS was 10 and 18 months, respectively. Fifty-seven patients (59.4%) had metastatic disease after CRT. The sites of the first metastasis after CRT were the liver (n ¼ 30), peritoneum (n ¼ 17), lungs (n ¼ 7), and lymph nodes (n ¼ 3). Thirty (31.3%) of the 96 patients had metastasis within 6 months after CRT. Followup periods after CRT ranged from 4 to 92 months. At the time of this analysis 79/96 patients (82.3%) had died. Predictors of prognosis after chemoradiotherapy In univariate analysis, GPS 2, PNI < 45, and plasma fibrinogen 400 mg/dL were significant predictors of poor PFS and OS (Table 1). In multivariate analysis, GPS 2 and plasma fibrinogen 400 mg/dL were independent predictors of poor PFS and OS (Table 2). The median PFS of patients with GPS 0/1 and fibrinogen <400 mg/dL was 10 and 11 months, respectively. In contrast, the median PFS of patients with GPS 2 and plasma fibrinogen 400 mg/dL was 4 and 5 months, respectively. The median OS of patients with GPS 0/1 and serum plasma fibrinogen <400 mg/dL was 19 and 21 months, respectively. In contrast, the median OS of patients with GPS 2 and plasma fibrinogen 400 mg/ dL was 7 and 12 months, respectively.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
H. Kurahara et al. / Pancreatology xxx (2015) 1e6
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Table 1 Progression free survival (PFS) and overall survival (OS) after CRT. PFS (95% CI) (months)
P value
OS (95% CI) (months)
P value
Gender
Factor Male Female
n 51 45
9.0 (7.2e10.9) 11.0 (6.7e15.3)
NS
17.0 (14.2e19.8) 19.0 (13.2e24.8)
NS
Age (years)
<75 75
78 18
8.0 (5.6e10.4) 11.0 (6.3e15.7)
NS
17.0 (13.0e21.0) 19.0 (17.2e20.8)
NS
BMI
<20 20
33 63
7.0 (5.1e8.9) 10.0 (8.4e11.6)
NS
13.0 (11.7e14.3) 19.0 (16.6e21.4)
NS
DM
Yes No
41 55
10.0 (7.9e12.1) 9.0 (6.2e11.8)
NS
18.0 (14.1e21.9) 17.0 (12.7e21.3)
NS
Tumor position
Head Body-tail
64 32
9.0 (6.5e11.5) 11.0 (8.3e13.7)
NS
16.0 (13.0e19.0) 20.0 (17.3e22.7)
NS
GPS
0/1 2
89 7
10.0 (8.5e11.5) 4.0 (2.4e5.6)
<0.001
19.0 (16.2e21.8) 7.0 (4.4e9.6)
<0.001
PNI
<45 45
<32 64
5.0 (1.8e8.2) 11.0 (9.3e12.7)
0.019
12.0 (8.5e15.5) 20.0 (17.0e23.0)
0.007
NLR
<3 3
72 24
10.0 (7.3e12.7) 8.0 (3.7e12.3)
NS
19.0 (15.2e22.8) 13.0 (5.6e20.4)
NS
Fibrinogen (mg/dL)
<400 400
68 28
11.0 (9.2e12.8) 5.0 (1.3e8.7)
<0.001
21.0 (18.4e23.7) 12.0 (8.3e15.7)
<0.001
CA 19-9 (U/mL)
<37 37
18 78
11.0 (8.2e13.8) 9.0 (6.7e11.3)
NS
20.0 (13.8e26.2) 17.0 (13.9e20.1)
NS
NS: not significant, BMI: body mass index, DM: diabetes mellitus, GPS: Glasgow prognostic score, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, CA 19-9: carbohydrate antigen 19-9.
Predictor of high reduction rate of the primary tumor after chemoradiotherapy Only PNI was a predictor of high reduction rate of the primary tumor after CRT (Table 3). Patients with a PNI 45 showed a tumor reduction rate of 32.1%; in contrast, this rate was only 12.1% in patients with PNI < 45. The median time of maximum reduction rate was 4 months after CRT. Patients who underwent surgical resection after CRT showed a dramatic reduction rate (mean, 57.3%); the reduction rate was 21.7% in patients who did not undergo surgery. Eight of the 10 patients who underwent surgical resection had a PNI 45.
Combination analysis of inflammatory-based score for prognostification of patients with locally advanced pancreatic cancer treated with chemoradiotherapy To effectively distinguish prognosis in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, we performed combination analysis using GPS and plasma fibrinogen that were independent predictors of PFS and OS (Fig. 1). We divided all patients into 3 groups: group 1 (n ¼ 66) with GPS 0/1 and plasma fibrinogen < 400 mg/dL; group 2 (n ¼ 25) with GPS 2 or plasma fibrinogen 400 mg/dL; and group 3 (n ¼ 5) with GPS 2 and plasma fibrinogen 400 mg/dL. The median PFS of patients of groups 1, 2, 3 was 11, 7, 4 months, respectively. The difference was significant
(P < 0.001) (Fig. 1A). The median OS of patients of groups 1, 2, 3 was 21, 12, 8.5 months, respectively. The difference was significant (P < 0.001). Furthermore, significant differences were observed between each group (Fig. 1B). Predictors of metastasis within 6 months after chemoradiotherapy We analyzed the association between clinicopathological factors and metastasis within 6 months after CRT to identify the predictor of early metastasis (Table 4). Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of the early metastasis. Discussion Concomitant chemotherapy and radiotherapy are used for the treatment of locally advanced pancreatic cancer [5e8]. We used S-1 as an anticancer agent in CRT and subsequent systemic chemotherapy. S-1 has been demonstrated to be non-inferior to gemcitabine in OS in patients with metastatic or locally advanced pancreatic cancer [23] and superior to adjuvant chemotherapy with gemcitabine in OS in patients with resected pancreatic cancer [24]. In this study, the PFS and OS were 10 and 18 months, respectively. CRT with subsequent systemic chemotherapy was a useful strategy for locally advanced pancreatic cancer; however, the therapeutic effect on the primary tumor varied considerably by individual, and
Table 2 Cox regression analysis of progression free survival (PFS) and overall survival (OS) after CRT. Factor
GPS 2 PNI 45 Fibrinogen 400
PFS
OS
HR
95% CI
P value
HR
95% CI
P value
3.421 1.121 1.899
1.353e8.651 0.646e1.944 1.110e3.249
0.009 NS 0.019
4.673 1.256 2.000
1.802e12.11 0.729e2.169 1.136e3.521
0.002 NS 0.016
HR: Hazard ratio, NS: not significant, GPS: Glasgow prognostic score, PNI: prognostic nutritional index.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
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H. Kurahara et al. / Pancreatology xxx (2015) 1e6
Table 3 Association between clinical factors and reduction rate of the primary tumor after CRT. Factor
n
Maximum reduction ratea (%)
P value
Gender
Male Female
51 45
25.2 (±4.0) 23.8 (±3.7)
NS
Age
<75 75
78 18
24.3 (±3.1) 30.6 (±5.5)
NS
BMI
<20 20
33 63
20.1 (±4.5) 28.3 (±3.4)
NS
DM
Yes No
41 55
25.8 (±4.4) 25.2 (±3.5)
NS
Tumor position
Head Body-tail
64 32
24.0 (±3.2) 22.0 (±3.9)
NS
GPS
0/1 2
89 7
26.5 (±2.8) 12.0 (±8.7)
NS
PNI
<45 45
<32 ±64
12.1 (±4.6) 32.1 (±3.1)
<0.001
NLR
<3 3
72 24
26.7 (±3.0) 21.6 (±5.9)
NS
Fibrinogen
<400 400
86 10
26.7 (±2.9) 14.9 (±5.9)
NS
CA 19-9 (U/mL)
<37 37
18 78
27.7 (±6.9) 24.9 (±3.0)
NS
NS: not significant, BMI: body mass index, DM: diabetes mellitus, GPS: Glasgow prognostic score, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, CA 19-9: carbohydrate antigen 19-9. a Mean value (±SE).
30 patients (31.3%) experienced metastasis within 6 months after CRT. In our study, PNI 45 was a significant predictor of high reduction rate of the primary tumor in patients with locally advanced pancreatic cancer who underwent CRT followed by systemic chemotherapy. GPS 2 and plasma fibrinogen 400 mg/dL were revealed as independent prognostic factors of poor PSF and OS. Furthermore, there were significant differences between the prognoses of patients with GPS 0/1 and plasma fibrinogen <400 mg/dL, GPS 2 or plasma fibrinogen 400 mg/dL, and GPS 2 and plasma fibrinogen 400 mg/dL. Patients with GPS 2 and/or plasma fibrinogen 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. The early metastasis may
be one of the causes of poor PFS and OS of patients with GPS 2 and/ or plasma fibrinogen 400 mg/dL. Plasma fibrinogen 400 mg/dL and GPS 2 may indicate the need for more intensive systemic chemotherapy rather than CRT to improve PFS and OS. Inflammation plays a pivotal role in the development and progression of pancreatic cancer [25], and a dense, desmoplastic stroma rich in inflammatory cells, fibroblasts, and extracellular matrix (ECM) proteins is a trait of pancreatic cancer [26]. Malnutrition at diagnosis caused by tumor progression and decreased oral intake due to gastrointestinal obstruction, pancreatitis, and cancerous pain has been reported as another trait [13]. Therefore, an association between inflammatory/immunonutritional factors
Fig. 1. KaplaneMeier survival curves of patients treated with chemoradiotherapy divided into 3 groups: group 1 (n ¼ 66) with GPS 0/1 and plasma fibrinogen < 400 mg/dL; groups 2 (n ¼ 25) with GPS 2 or plasma fibrinogen 400 mg/dL; and group 3 (n ¼ 5) with GPS 2 and plasma fibrinogen 400 mg/dL. (A) The median progression free survival of patients of groups 1, 2, 3 was 11, 7, 4 months, respectively. The difference was significant (P < 0.001). (B) The median overall survival of patients of groups 1, 2, 3 was 21, 12, 8.5 months, respectively. The difference was significant (P < 0.001). Furthermore, significant differences were observed between each group.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
H. Kurahara et al. / Pancreatology xxx (2015) 1e6
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Table 4 Association between clinical factors and distant metastasis within 6 months after CRT. n
Metastasis (n ¼ 30)
No metastasis (n ¼ 66)
P value
Gender
Male Female
51 45
19 11
32 34
NS
Age (year)
<75 75
78 18
27 3
51 15
NS
BMI
<20 20
33 63
14 16
19 47
NS
DM
Yes No
41 55
12 18
29 37
NS
Tumor position
Head Body-tail
64 32
21 9
43 23
NS
PNI
<45 45
72 24
14 16
18 48
NS
NLR
<3 3
72 24
20 10
52 14
NS
GPS 2 and/or Fibrinogen 400
Yes No
30 66
15 15
15 51
0.015
CA 19-9 (U/mL)
<37 37
18 78
2 28
16 50
NS
Factor
NS: not significant, BMI: body mass index, DM: diabetes mellitus, PNI: prognostic nutritional index, NLR: neutrophil lymphocyte ratio, GPS: Glasgow prognostic score, CA 19-9: carbohydrate antigen 19-9.
and prognosis has been investigated. However, few studies have compared inflammatory/immunonutritional factors to each other. High GPS was reported as a predictor of poor prognosis [11] and of worse treatment outcome with gemcitabine-based chemotherapy [19] in unresectable pancreatic cancer. Hypoalbuminemia and elevated CRP levels suggest the presence of systemic inflammation in cancer patients [12]. A correlation between increased plasma fibrinogen levels has been reported as a useful predictor of distant metastasis in pancreatic cancer [15]. Fibrinogen deposits in the ECM serve as a scaffold to support binding of growth factors and to promote adhesion, proliferation, and migration during angiogenesis and tumor growth [15]. Fibrinogen is also an acute phase reactant; its plasma level increases under inflammatory conditions [27]. An association of PNI with OS and postoperative complications in patients with pancreatic cancer has been reported [13]. Although the mechanism responsible for the enhanced anti-tumor effect has not been elucidated, immunonutritional status may affect the pharmacokinetics of many anticancer agents through altered protein binding and P450 activity [20]. Recently, outcomes of neoadjuvant CRT in pancreatic cancer have been reported [9,10,28,29]. Although patients who underwent neoadjuvant CRT had higher rates of negative margins and lower rates of positive lymph nodes, the survival benefit from neoadjuvant CRT is controversial. Normal CA 19-9 levels before treatment and normalization of CA 19-9 levels after neoadjuvant CRT are associated with better prognosis after surgery [10,28]. In the neoadjuvant setting, prediction of high reduction ratio of the primary tumor and early metastasis are crucial for treatment strategy. Patients with PNI 45, GPS 0/1, and plasma fibrinogen <400 mg/dL may benefit from neoadjuvant CRT for locally advanced pancreatic cancer. Utility of PNI, GPS, and plasma fibrinogen in neoadjuvant therapy for locally advanced pancreatic cancer should be confirmed in a prospective study. The mechanism of contribution of these inflammatory/immunonutritional factors to the therapeutic effect of CRT should be elucidated. Identification of predictors of the therapeutic effect of CRT has strategic significance for locally advanced pancreatic cancer. In conclusion, we suggest that GPS and plasma fibrinogen are useful metastatic and prognostic predictors, and PNI may be a
predictor of high reduction rate of the primary tumor in patients with locally advanced pancreatic cancer treated by CRT. By using combination of GPS and plasma fibrinogen level, the patients could be divided into 3 groups with significantly different PFS and OS.
Disclosures and funding sources The authors state that they have no conflicts of interest and that they received no financial or material support. Acknowledgments Supported in part by Grants-in-Aid for Scientific Research (26462067) from the Japan Society for the Promotion of Science, Ministry of Health, Labour, and Welfare, Japan.
References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a Cancer J Clin 2010;60:277e300. [2] Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol 2012;18:736e45. [3] Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378:607e20. [4] Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006;244:10e5. [5] Okusaka T, Ito Y, Ueno H, Ikeda M, Takezako Y, Morizane C, et al. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 2004;91:673e7. [6] Small Jr W, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol Off J Am Soc Clin Oncol 2008;26:942e7. [7] Wilkowski R, Boeck S, Ostermaier S, Sauer R, Herbst M, Fietkau R, et al. Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer e a multi-centre randomised phase II study. Br J Cancer 2009;101: 1853e9. [8] Shinchi H, Maemura K, Mataki Y, Kurahara H, Sakoda M, Ueno S, et al. A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer. J Hepatobiliary Pancreat Sci 2012;19:152e8.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015
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H. Kurahara et al. / Pancreatology xxx (2015) 1e6
[9] Estrella JS, Rashid A, Fleming JB, Katz MH, Lee JE, Wolf RA, et al. Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation. Cancer 2012;118:268e77. [10] Tzeng CW, Balachandran A, Ahmad M, Lee JE, Krishnan S, Wang H, et al. Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer. HPB Off J Int Hepato Pancreato Biliary Assoc 2014;16:430e8. [11] Glen P, Jamieson NB, McMillan DC, Carter R, Imrie CW, McKay CJ. Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology 2006;6:450e3. [12] Vashist YK, Loos J, Dedow J, Tachezy M, Uzunoglu G, Kutup A, et al. Glasgow prognostic score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer. Ann Surg Oncol 2011;18:1130e8. [13] Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A. Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg 2011;98:268e74. [14] Mohri Y, Inoue Y, Tanaka K, Hiro J, Uchida K, Kusunoki M. Prognostic nutritional index predicts postoperative outcome in colorectal cancer. World J Surg 2013;37:2688e92. [15] Guo Q, Zhang B, Dong X, Xie Q, Guo E, Huang H, et al. Elevated levels of plasma fibrinogen in patients with pancreatic cancer: possible role of a distant metastasis predictor. Pancreas 2009;38:e75e9. [16] Shu YJ, Weng H, Bao RF, Wu XS, Ding Q, Cao Y, et al. Clinical and prognostic significance of preoperative plasma hyperfibrinogenemia in gallbladder cancer patients following surgical resection: a retrospective and in vitro study. BMC Cancer 2014;14:566. [17] Stotz M, Gerger A, Eisner F, Szkandera J, Loibner H, Ress AL, et al. Increased neutrophilelymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer 2013;109: 416e21. [18] Luo G, Guo M, Liu Z, Xiao Z, Jin K, Long J, et al. Blood neutrophilelymphocyte ratio predicts survival in patients with advanced pancreatic cancer treated with chemotherapy. Ann Surg Oncol 2015;22:670e6. [19] Shimoda M, Katoh M, Kita J, Sawada T, Kubota K. The glasgow prognostic score is a good predictor of treatment outcome in patients with unresectable pancreatic cancer. Chemotherapy 2010;56:501e6.
[20] Pinato DJ, North BV, Sharma R. A novel, externally validated inflammationbased prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI). Br J Cancer 2012;106:1439e45. [21] Huang J, Xu L, Luo Y, He F, Zhang Y, Chen M. The inflammation-based scores to predict prognosis of patients with hepatocellular carcinoma after hepatectomy. Med Oncol 2014;31:883. [22] Maemura K, Shinchi H, Noma H, Mataki Y, Kurahara H, Maeda S, et al. Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer. Anticancer Res 2008;28:2369e72. [23] Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, 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. J Clin Oncol Off J Am Soc Clin Oncol 2013;31:1640e8. [24] Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, et al. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan adjuvant study group of pancreatic cancer (JASPAC-01). Jpn J Clin Oncol 2008;38:227e9. [25] Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004;239:763e9 [Discussion 769e771]. [26] Kurahara H, Takao S, Kuwahata T, Nagai T, Ding Q, Maeda K, et al. Clinical significance of folate receptor beta-expressing tumor-associated macrophages in pancreatic cancer. Ann Surg Oncol 2012;19:2264e71. [27] Son HJ, Park JW, Chang HJ, Kim DY, Kim BC, Kim SY, et al. Preoperative plasma hyperfibrinogenemia is predictive of poor prognosis in patients with nonmetastatic colon cancer. Ann Surg Oncol 2013;20:2908e13. [28] Katz MH, Varadhachary GR, Fleming JB, Wolff RA, Lee JE, Pisters PW, et al. Serum ca 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. Ann Surg Oncol 2010;17:1794e801. [29] Colbert LE, Hall WA, Nickleach D, Switchenko J, Kooby DA, Liu Y, et al. Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the national cancer data base. Cancer 2014;120:499e506.
Please cite this article in press as: Kurahara H, et al., Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.09.015