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Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer – Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort
European Journal of Surgical Oncology xxx (xxxx) xxx
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Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort € rkstro € m b, Christian Sturesson a, Hannes Jansson a, *, Martin Cornillet b, Niklas K. Bjo a Ernesto Sparrelid a b
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 July 2019 Received in revised form 4 December 2019 Accepted 10 December 2019 Available online xxx
Introduction: Established preoperative prognostic factors for risk stratification of patients with biliary tract cancer (BTC) are lacking. A prognostic value of the inflammation-based Glasgow Prognostic Score (GPS) and Modified Glasgow Prognostic Score (mGPS) in BTC has been indicated in several Eastern cohorts. We sought to validate and compare the prognostic value of the GPS and the mGPS for overall survival (OS), in a large Western cohort of patients with BTC. Material and methods: We performed a retrospective single-center study for the period 2009 until 2017. 216 consecutive patients that underwent surgical exploration with a diagnosis of perihilar cholangiocarcinoma (PHCC), intrahepatic cholangiocarcinoma (IHCC), or gallbladder cancer (GBC) were assessed. GPS and mGPS were calculated where both CRP and albumin were measured pre-operatively (n ¼ 168/216). Survival was analyzed by Kaplan-Meier estimate and uni-/multivariate Cox regression. Results: GPS and mGPS were negatively associated with survival (p < 0.001/p < 0.001), and the association was significant in all three subgroups. GPS, but not the mGPS, identified an intermediate risk group: with GPS ¼ 1 having better OS than GPS ¼ 2 (p ¼ 0.003), but worse OS than GPS ¼ 0 (p ¼ 0.008). In multivariate analyses of resected patients, GPS (p ¼ 0.001) and mGPS (p ¼ 0.03) remained significant predictors of survival, independent of postoperatively available risk factors. Conclusions: Preoperative GPS and mGPS are independent prognostic factors in BTC. The association to OS was shown in all patients undergoing exploration, in resected patients only, and in both cholangiocarcinoma and gallbladder cancer. Furthermore, GPS e which weights hypoalbuminemia higher e could identify an intermediate risk group. © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Keywords: Biliary tract cancer Preoperative Prognostic factor Risk stratification Glasgow prognostic score Systemic inflammatory response
Introduction
Abbreviations: BTC, biliary tract cancer; CI, confidence interval; CRP, C-reactive protein; ERC, endoscopic retrograde cholangiography; GBC, gallbladder cancer; GPS, Glasgow Prognostic Score; HR, hazard ratio; IHCC, intrahepatic cholangiocarcinoma; IQR, interquartile range; mGPS, modified Glasgow Prognostic Score; OS, overall survival; PHCC, perihilar cholangiocarcinoma; PHLF, posthepatectomy liver failure; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; PVE, portal vein embolization. * Corresponding author. Karolinska Institutet, Dept. of Clinical Science, Intervention and Technology Division of surgery, C1 77, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden. E-mail address: [email protected] (H. Jansson).
Important prognostic factors in biliary tract cancer (BTC) are determined only after surgical resection, as is the case with lymph node metastasis [1e4]. Preoperative prognostic markers in BTC could allow better risk-benefit assessments before surgery and permit stratification of patients for a more individualized treatment [3]. The Glasgow Prognostic Score (GPS) and Modified Glasgow Prognostic Score (mGPS), are preoperative inflammation-based scores that have shown prognostic value in several malignancies [5e7]. Recent studies have indicated a prognostic value of the GPS/ mGPS in BTC in Eastern cohorts [8e11]. It is known that significant
https://doi.org/10.1016/j.ejso.2019.12.008 0748-7983/© 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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H. Jansson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
differences in BTC prevalence, risk factors, and prognosis exist between Western and Eastern countries [4,12]. The aim of this study was to evaluate and compare the prognostic value of the GPS and the mGPS for overall survival (OS), in a large Western cohort of patients with BTC. Material and methods Study design Consecutive patients that underwent surgical exploration with a diagnosis of perihilar cholangiocarcinoma (PHCC), intrahepatic cholangiocarcinoma (IHCC) or gallbladder cancer (GBC), confirmed postoperatively by pathology, at Karolinska University Hospital (Stockholm, Sweden), a tertiary referral center, from January 2009 until January 2017 were assessed for inclusion. Data was retrospectively collected from the electronic health record. The study was approved by the Regional Ethical Review Board. Outcome variables and demographic-/clinicopathological data The primary outcome variable of this study was overall survival (OS), calculated from date of surgery. Secondary outcome variables were postoperative complications graded by the Clavien-Dindo classification [13], posthepatectomy liver failure (PHLF) as defined by the applied Balzan 50:50 criteria [14,15] (bilirubin >50 mmol/L and prothrombin-International Normalized Ratio >1.5 on postoperative day 5), and in-hospital mortality (not limited to 90 days after surgery). Demographic and clinicopathological variables were: age, sex, American Society of Anesthesiologists (ASA) physical status classification, preoperative portal vein embolization (PVE), preoperative endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography (ERC/PTC), preoperative C-reactive protein (CRP), preoperative albumin, preoperative bilirubin, postoperative bilirubin, postoperative prothrombinInternational Normalized Ratio, resectability at surgical exploration, tumor extension (T), lymph node status (N), resection margin (R), perineural- (Pn) and lymphovascular invasion (LV), and histologic tumor grade according to the College of American Pathologists. Preoperative samples were routinely taken the day before surgery, or at latest preoperative outpatient visit (regularly within two weeks before surgery). Tumor stage was recorded according to the seventh edition of the TNM Classification of Malignant Tumors (TNM-7) [16]. Prognostic scores GPS and mGPS were calculated as previously described, from preoperative plasma CRP- and albumin concentrations [5]. The GPS is defined as: GPS ¼ 0, albumin 35 g/L and CRP 10 mg/L; GPS ¼ 1, albumin <35 g/L or CRP >10 mg/L; GPS ¼ 2, albumin <35 g/L and CRP >10 mg/L. The mGPS is defined as: mGPS ¼ 0, any albumin concentration and CRP 10 mg/L; mGPS ¼ 1, albumin 35 g/L and CRP >10 mg/L; mGPS ¼ 2, albumin <35 g/L and CRP >10 mg/L.
time dependent covariates. Median follow-up time was calculated according to the reverse Kaplan-Meier method. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors for OS. All variables with a p-value < 0.10 in initial univariate analysis were included in multivariate Cox models and backward elimination applied at p 0.10 to reach the final models. All significance tests were two-sided, and p-values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS Statistics v25 (IBM, New York, USA). Results Cohort characteristics Out of a total of 216 consecutive patients, preoperative CRP- and albumin values for calculation of GPS/mGPS were available for 168 patients, which were included for analysis (see study flow diagram in Fig. 1). Baseline characteristics are presented in Table 1. There were no significant differences in baseline characteristics or OS between the analysis cohort and patients excluded due to missing data on preoperative CRP and albumin. In the analysis cohort 57 patients (34%) had PHCC, 43 patients (26%) IHCC, and 68 patients (40%) GBC. Twenty-nine patients (17%) were found unresectable at exploration (locally advanced disease n ¼ 11, non-regional lymph node metastasis n ¼ 5, distant liver-/peritoneal metastasis n ¼ 13). Of resected patients, 65% underwent major hepatectomy (3 segments). Median OS was 18 months (IQR 43 months) for the entire cohort, 21 months (IQR 52 months) for resected patients and 7 months (IQR 9 months) for unresected patients. Median follow-up time calculated by the reverse Kaplan-Meier method was 48 months (IQR 35 months). Overall survival stratified by GPS/mGPS Fifty-three patients (32%) had either CRP > 10 mg/L (n ¼ 15, 9%) or albumin <35 g/L (n ¼ 38, 23%), whereas 61 patients (36%) had both CRP > 10 mg/L and albumin <35 g/L. Calculated prognostic scores and survival curves stratified by GPS and mGPS are shown in Fig. 2: in 2a and b for the whole cohort, and in 2c and d for resected patients only. Both the GPS and the mGPS were significantly negatively associated with survival, but only the GPS could identify an intermediate risk group, with GPS ¼ 1 having better OS than GPS ¼ 2 (p ¼ 0.003), but worse OS than GPS ¼ 0 (p ¼ 0.008). Also in analysis of resected patients alone, only the GPS identified an intermediate risk group (GPS ¼ 1 compared to GPS ¼ 2 p ¼ 0.015, GPS ¼ 1 compared to GPS ¼ 0 p ¼ 0.039). The proportional hazards assumption for GPS and mGPS was tested using time dependent covariates, with no significant time-dependent hazard (GPS
Statistical analysis Continuous variables were reported with median and interquartile range (IQR). Categorical variables were reported with whole numbers and proportions. Proportions were compared using the chisquare test or the Fisher Exact test. Distributions of continuous variables were compared using the Mann-Whitney U test. Survival was estimated with the Kaplan-Meier method, and differences in OS compared using the log-rank test. The proportional hazards assumption for the prognostic scores was significance tested using
Fig. 1. Study flow diagram.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
H. Jansson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
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Table 1 Baseline characteristics and OS for patients assessed and patients included. Variable
All consecutive patients (n ¼ 216)
GPS/mGPS data available (n ¼ 168)
p-value*
Age, md years (IQR) Sex, n (%) Female Male Diagnosis, n (%) PHCC IHCC GBC ASA, n (%) 1-2 3-4 PSC, n (%) Y N ERC/PTC, n (%) Y N PVE, n (%) Y N Bilirubin, md mmol/L (IQR) Resection, n (%) Y N Major resection, n (%)** Y N OS, md months (IQR)
66 (14)
66 (14)
0.75
121 (56) 95 (44)
93 (55) 75 (45)
0.71
67 (31) 54 (25) 95 (44)
57 (34) 43 (26) 68 (40)
0.12
149 (69) 67 (31)
113 (67) 55 (33)
0.31
20 (9) 196 (91)
18 (11) 150 (89)
100 (46) 116 (54)
82 (49) 86 (51)
0.17
29 (13) 187 (87) 8 (9)
26 (15) 142 (85) 9 (10)
0.10 0.48
177 (82) 39 (18)
139 (83) 29 (17)
0.57
109 (62) 68 (38) 19 (40)
90 (65) 49 (35) 18 (43)
0.10 xx 0.93
x
0.26
ASA: American Society of Antesthesiologists class; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GBC: gallbladder cancer; GPS: Glasgow prognostic score; IHCC: intrahepatic cholangiocarcinoma; IQR: interquartile range; md: median; mGPS: modified Glasgow prognostic score; OS: overall survival; PHCC: perihilar cholangiocarcinoma; PSC: primary sclerosing cholangitis; PVE: portal vein embolization; mmol/L: micromole per litre. Continuous variables presented with median and IQR, significance by Mann-Whitney U test or log rank test. Categorical variables presented with whole numbers and proportions, significance by chi-square test or Fisher Exact test. * Patients included compared to patients excluded; x Fisher Exact test; xx Log rank test; ** Resected patients.
p ¼ 0.27, mGPS p ¼ 0.42). Outcomes after resection by GPS In Table 2, outcomes for resected patients are presented. Sixtyseven patients (48%) suffered a complication Clavien-Dindo grade 3a or higher. Thirteen patients (9%) suffered PHLF. In-hospital mortality was 10% (14 patients). Median OS was 21 months (IQR 52 months). There were no significant differences in postoperative complications or mortality between GPS groups, but a significant difference in OS (p < 0.001).
(p ¼ 0.15) were not significantly associated with survival in univariate analysis, but were included in additional multivariate Cox regression analyses for both the whole cohort and resected patients, to control for any interference with inflammatory status (Supplemental Tables A and B). Resectability was also included in multivariate analysis for the whole cohort (Supplemental Table A). In all the adjusted models, GPS and mGPS remained significant independent prognostic factors. Moreover, no significant association was found between increased bilirubin and increased GPS in the perihilar subgroup (p ¼ 0.67 Fisher Exact test), the group where increased bilirubin was most frequent (18% compared to 12% overall).
Univariate analyses of prognostic factors Discussion In univariate Cox regression analyses, GPS, mGPS, resection, preoperative ERC/PTC, T-stage, lymph node metastasis, perineural invasion, resection margin, and histologic grade were statistically significant at p < 0.05 for OS (Table 3). The GPS and the mGPS were found to be significant for OS in all three subgroups of BTC. Sex and lymphovascular invasion were not statistically significant, but at p < 0.10 they were included in multivariate Cox regression analyses. Multivariate analyses of prognostic factors On multivariate analysis of resected patients, including postoperatively available risk factors, both increased GPS (p ¼ 0.001) and mGPS (p ¼ 0.03) were independent prognostic factors for OS (Table 4). Other factors found significant for OS in multivariate analysis were advanced T-stage and presence of lymph node metastasis. Preoperative PVE (p ¼ 0.12) and increased preoperative bilirubin
Established preoperative prognostic factors for risk stratification of patients with BTC are lacking. A systemic inflammatory response in malignancy has been shown to carry a prognostic value. In several Asian cohorts, a prognostic value of the inflammationbased GPS and the updated mGPS has been indicated [8e11]. In this analysis of 168 BTC patients undergoing surgical exploration in a Western tertiary referral center, we could show that the GPS and mGPS were significantly negatively associated with OS. The association was found in all patients undergoing exploration, in resected patients only, and in all three BTC subgroups. In multivariate analysis the GPS, mGPS, advanced T-stage, and N1-disease were independent prognostic factors. However, GPS was a stronger prognostic factor compared to mGPS, and the only one to identify an intermediate risk group. The association between GPS/ mGPS and survival remained significant after adjusting for preoperative factors such as PVE, ERC/PTC and increased bilirubin, both in
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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H. Jansson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
Fig. 2. Overall survival stratified by GPS (top panels) and mGPS (bottom panels). (a) and (b): Whole cohort (n ¼ 168); (c) and (d): Resected patients (n ¼ 139).
Table 2 Outcomes after resection stratified for GPS. All resected patients (n ¼ 139)
GPS ¼ 0 (n ¼ 51)
GPS ¼ 1 (n ¼ 41)
GPS ¼ 2 (n ¼ 47)
p-value
CD 3a (%)
67 (48)
21 (41)
19 (46)
27 (57)
0.27
Posthepatectomy liver failurea (%)
13 (9)
2 (4)
3 (7)
8 (17)
0.09
Mortality in-hospital (%)
14 (10)
3 (6)
3 (7)
8 (17)
0.19
OS months, md (IQR)
21 (52)
50 (57)
21 (77)
13 (23)
<0.001
CD 3a: any complication Clavien-Dindo classification grade 3a or higher; GPS: Glasgow prognostic score; md: median; IQR: interquartile range; OS: overall survival. Categorical variables presented with whole numbers and proportions, significance by Fisher Exact test. Overall survival presented with median and IQR, significance by log rank test. a Posthepatectomy liver failure according to the applied Balzan 50:50 criteria.
the whole cohort, and in resected patients. Of the postoperative outcomes for resected patients (complication Clavien-Dindo grade 3 or higher, PHLF, in-hospital mortality, median OS) only OS was significantly associated with GPS, suggesting that an increased rate of severe complications after surgery is not the main cause of shorter survival in patients with increased preoperative GPS. Outcomes for patients resected with a preoperative GPS ¼ 2 were poor, with a median OS of 13 months (IQR 23 months), which can be compared to a median OS of 50 months (IQR 57 months) for
patients resected with GPS ¼ 0 and a median OS of 7 months (IQR 9 months) for unresected patients in this cohort. The mGPS differs from the original GPS in that it weights hypoalbuminemia lower, by awarding a score of 0 to albumin <35 g/L in the absence of CRP >10 mg/L [5]. The mGPS was presented by McMillan et al., in 2007, as it was shown that in patients with colorectal cancer, hypoalbuminemia alone was a weaker prognostic factor than CRP [5]. The proportion of patients with preoperative isolated hypoalbuminemia in our cohort of BTC was
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
H. Jansson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
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Table 3 Univariate Cox regression analyses for OS. Variable
All BTC N (%)
Age
HR
95% CI
p-value
1.01
0.99e1.02
0.28
Sex (Female)
Y ¼ 93 (55), N ¼ 75 (45)
0.74x
0.52e1.04
0.09
ASA3
Y ¼ 55 (33), N ¼ 113 (67)
1.23
0.86e1.77
0.26
Resection
Y ¼ 139 (83), N ¼ 29 (17)
0.38**
0.24e0.58
<0.001
GPS1
Y ¼ 114 (68), N ¼ 54 (32)
2.43**
1.61e3.67
<0.001
mGPS1
Y ¼ 76 (45), N ¼ 92 (55)
2.09**
1.48e2.97
<0.001
ERC/PTC
Y ¼ 82 (49), N ¼ 86 (51)
1.51*
1.07e2.15
0.02
PVE
Y ¼ 26 (15), N ¼ 142 (85)
1.43
0.91e2.23
0.12
Bilirubin (>25 mmol/L)
Y ¼ 20 (12), N ¼ 146 (88)
1.45
0.88e2.39
0.15
T3
Y ¼ 96 (57), N ¼ 72 (43)
2.71**
1.87e3.93
<0.001
N1
Y ¼ 72 (57), N ¼ 55 (43)
1.71*
1.13e2.59
0.01
LV1
Y ¼ 103 (77), N ¼ 31 (23)
1.55x
0.94e2.57
0.09
Pn1
Y ¼ 101 (75), N ¼ 33 (25)
1.91*
1.14e3.19
0.01
R1
Y ¼ 89 (65), N ¼ 48 (35)
1.78*
1.16e2.74
0.01
Grade (2 or 3)xx
Y ¼ 126 (88), N ¼ 17 (12)
1.98*
1.03e3.80
0.04
PHCC HR (95% CI) p-value
IHCC HR (95% CI) p-value
GBC HR (95% CI) p-value
1.01 (0.99e1.04) 0.31 0.76 (0.42e1.37) 0.36 1.42 (0.78e2.58) 0.25 0.26** (0.13e0.54) <0.001 2.55* (1.13e5.77) 0.02 2.08* (1.16e3.75) 0.02 1.47 (0.53e4.12) 0.46 1.31 (0.70e2.44) 0.40 1.13 (0.53e2.44) 0.75 2.04* (1.13e3.67) 0.02 1.77 (0.89e3.49) 0.10 1.04 (0.43e2.52) 0.93 2.78 (0.38e20.49) 0.32 1.21 (0.49e2.98) 0.68 1.35 (0.48e3.82) 0.57
1.00 (0.97e1.04) 0.97 0.60 (0.28e1.28) 0.19 0.71 (0.30e1.68) 0.44 0.47 (0.16e1.39) 0.17 2.75* (1.23e6.14) 0.01 2.44* (1.14e5.20) 0.02 3.86* (1.27e11.78) 0.02 (no PVE)
1.02 (0.99e1.05) 0.24 0.84 (0.49e1.44) 0.52 1.35 (0.78e2.36) 0.29 0.47* (0.24e0.90) 0.02 1.88* (1.02e3.47) 0.04 1.80* (1.05e3.10) 0.03 1.33 (0.78e2.27) 0.30 1.27 (0.62e2.60) 0.52 1.45 (0.68e3.07) 0.34 3.51** (1.75e7.04) <0.001 1.28 (0.69e2.37) 0.43 2.08x (0.92e4.71) 0.08 2.93* (1.29e6.67) 0.01 3.67** (1.90e7.11) <0.001 2.93* (1.05e8.20) 0.04
2.85 (0.66e12.24) 0.16 2.66* (1.24e5.70) 0.01 2.67x (0.92e7.73) 0.07 1.34 (0.52e3.43) 0.54 1.06 (0.46e2.46) 0.89 1.41 (0.61e3.24) 0.42 1.78 (0.41e7.72) 0.44
ASA: American Society of Anesthesiologists; BTC: biliary tract cancer; CI: confidence interval; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GBC: gallbladder cancer; GPS: Glasgow prognostic score; HR: hazard ratio; IHCC: intrahepatic cholangiocarcinoma; LV1: lymphovascular invasion; mGPS: modified Glasgow prognostic score; N1: lymph node metastasis; OS: overall survival; PHCC: perihilar cholangiocarcinoma; Pn1: perineural invasion; PVE: portal vein embolization; R1: resection margin positive; T: primary tumor extension; mmol/L: micromole per litre. xx Tumor grade according to the College of American Pathologists. x P-value < 0.10; * P-value < 0.05; ** P-value < 0.001.
Table 4 Multivariate Cox regression models for overall survival. Multivariate model with GPS
GPS1 Sex (Female) ERC/PTC T3 N1 LV1 Pn1 R1 Grade (2 or 3)xx
Multivariate model with mGPS HR (95% CI)
p-value
2.44* (1.44e4.13) e e 2.03* (1.27e3.24) 1.68* (1.05e2.67) e e e e
0.001 0.33 0.24 0.003 0.03 0.41 0.70 0.42 0.15
mGPS1 Sex (Female) ERC/PTC T3 N1 LV1 Pn1 R1 Grade (2 or 3)xx
HR (95% CI)
p-value
1.67* (1.06e2.62) e e 2.00* (1.25e3.19) 1.54 (0.97e2.44) e e e e
0.03 0.15 0.12 0.004 0.07 0.66 0.78 0.21 0.28
CI: confidence interval; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GPS: Glasgow prognostic score; HR: hazard ratio; LV1: lymphovascular invasion; mGPS: modified Glasgow prognostic score; N1: lymph node metastasis; Pn1: perineural invasion; R1: resection margin positive; T: primary tumor extension. xx Tumor grade according to the College of American Pathologists. * P-value < 0.05. Variables with hazard ratios retained in final models.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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23%, which can be compared to 5% in the cohort of colorectal cancer used by McMillan et al. to develop the mGPS [5]. That hypoalbuminemia is more common in BTC than in colorectal cancer could mirror both a stronger systemic inflammatory response and that BTCs are primary hepatic malignancies. The role of albumin as a negative acute phase reactant and marker of inflammation rather than a marker of nutritional status has been underscored by recent research in both benign chronic disease and malignancy [17e19]. Regarding OS stratified by GPS and mGPS, we could confirm the previous findings from Asian reports by Oshiro et al. [8] (GPS in perihilar- and distal cholangiocarcinoma, n ¼ 62), Okuno et al. [9] (mGPS in PHCC, n ¼ 534), Wu et al. [11] (GPS in GBC, n ¼ 85), and Shiba et al. [10] (GPS in GBC, n ¼ 51). In contrast to the previous studies by Oshiro et al. [8] and Wu et al. [11], analysis of GPS in our cohort could stratify patients in three separate risks groups. Notably, in addition to differences in study populations, these previous cohorts were smaller and could be underpowered to separate the GPS ¼ 1 group. We could also confirm GPS/mGPS as independent prognostic factors for OS in multivariate analyses, together with N1-disease and advanced T-stage. Previous authors have integrated various factors in multivariate models, but all with the exception of Oshiro (p ¼ 0.07) reported independent significance for N1 [8e11]. Okuno et al., in the largest of the studies, did not include T-stage in their survival analysis [9]. Wu et al. found independent significance of T-stage, while Shiba et al. (p ¼ 0.07) and Oshiro et al. (p ¼ 0.10) did not [8,10,11]. To exclude that inflammatory markers were just surrogates for other preoperative factors, such as cholestasis or biliary-/vascular interventions, we performed uni- and multivariate analysis with preoperative bilirubin, ERC/PTC and PVE. Controlling for these variables, GPS and mGPS remained independent prognostic factors. Sex was included in our multivariate regression analysis as univariate regression gave HR ¼ 0.74 at p < 0.10 for OS in female compared to male patients. However, sex was not significant at p < 0.05 in the univariate analysis, and was not a prognostic factor in the multivariate analyses. The literature suggests possible differences between BTC subgroups regarding sex as a prognostic factor for survival after resection. Sex has not been indicated to affect prognosis in meta-analyses on resectable PHCC [4,20], but has been shown to be a prognostic factor in nation-wide studies both of resectable and non-resectable IHCC, with male patients having worse survival [21e23]. While incidence of GBC is higher among women, a nation-wide study on resectable GBC did not show sex to have prognostic value [24]. The present retrospective single-center study has several limitations. Data for calculation of preoperative scores was missing in 22% of all patients assessed; a possible confounder even if no differences in baseline characteristics or OS were noted between patients analyzed and patients excluded. As BTC is relatively rare, and most often inoperable at diagnosis, the size of our single-center cohort also limits the statistical power for more extensive multivariate- and subgroup analyses. Moreover, complete postoperative pathological risk factor data was not available for all patients, further restricting analysis and statistical power. The cohort was also heterogenous regarding diagnoses and type of resection. Overall a majority of resected patients underwent major resection, but in GBC less extensive resections such as bisegmentectomy or wedge resection were commonly performed. Liver resection for BTC carries a significant risk of morbidity and mortality. Even after curative intent resection, a majority of patients will suffer recurrence within 5 years [2,21]. Multimodal treatment for BTC, to improve prognosis after surgery, is still under development [25]. Criteria and protocols for adjuvant chemotherapy as standard of care are being established [26], while neoadjuvant therapy is under investigation [27]. Preoperative identification of
patients with poor prognosis could permit selection for multimodal therapy [27e29]. Inflammation-based prognostic scores have been suggested as a way to assess the host response both to tumor disease and oncological treatment, and a prognostic value of the GPS/ mGPS has been validated in randomized control trials of chemotherapy in colorectal and prostate cancer [30]. In this retrospective study, we have confirmed preoperative GPS and mGPS as prognostic factors for OS after resection in a Western cohort of BTC; independent of postoperatively available tumor characteristics. Prospective validation of the scores in randomized controlled trials in BTC, and further examination of our findings in multi-center studies, could be future steps toward a preoperative risk stratification of BTC-patients. Moreover, the prognostic value of inflammation-based scores in BTC motivates efforts to decipher host immunological responses in this group of malignancies. Conclusions Preoperative GPS and mGPS are independent prognostic factors for OS in BTC. The association with OS was shown in all patients undergoing exploration, in resected patients only, and in both cholangiocarcinoma and gallbladder cancer. Furthermore, GPS e which weights hypoalbuminemia higher e could identify an intermediate risk group. Declaration of competing interest The authors declare no conflict of interest. Acknowledgements This study was supported by grants from the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Bengt Ihre Foundation, the Center for Innovative Medicine at Karolinska Institutet, and Region Stockholm. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejso.2019.12.008. References [1] Giuliante F, Ardito F, Guglielmi A, et al. Association of lymph node status with survival in patients after liver resection for hilar cholangiocarcinoma in an Italian multicenter analysis. JAMA Surg 2016;151:916e22. [2] Groot Koerkamp B, Wiggers JK, Allen PJ, et al. Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg 2015;221:1041e9. [3] Saito H, Noji T, Okamura K, Tsuchikawa T, Shichinohe T, Hirano S. A new prognostic scoring system using factors available preoperatively to predict survival after operative resection of perihilar cholangiocarcinoma. Surgery 2016;159:842e51. [4] Tang Z, Yang Y, Zhao Z, Wei K, Meng W, Li X. The clinicopathological factors associated with prognosis of patients with resectable perihilar cholangiocarcinoma: a systematic review and meta-analysis. Medicine (Baltim) 2018;97:e11999. [5] McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 2007;22:881e6. [6] Hefler-Frischmuth K, Seebacher V, Polterauer S, Tempfer C, Reinthaller A, Hefler L. The inflammation-based modified Glasgow Prognostic Score in patients with vulvar cancer. Eur J Obstet Gynecol Reprod Biol 2010;149:102e5. [7] Li MX, Bi XY, Li ZY, et al. Prognostic role of Glasgow prognostic score in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Medicine (Baltim) 2015;94:e2133. [8] Oshiro Y, Sasaki R, Fukunaga K, et al. Inflammation-based prognostic score is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma. Int J Hepatobiliary Pancreat Dis 2013;20:389e95. [9] Okuno M, Ebata T, Yokoyama Y, et al. Evaluation of inflammation-based prognostic scores in patients undergoing hepatobiliary resection for
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Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort € rkstro € m b, Christian Sturesson a, Hannes Jansson a, *, Martin Cornillet b, Niklas K. Bjo a Ernesto Sparrelid a b
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 July 2019 Received in revised form 4 December 2019 Accepted 10 December 2019 Available online xxx
Introduction: Established preoperative prognostic factors for risk stratification of patients with biliary tract cancer (BTC) are lacking. A prognostic value of the inflammation-based Glasgow Prognostic Score (GPS) and Modified Glasgow Prognostic Score (mGPS) in BTC has been indicated in several Eastern cohorts. We sought to validate and compare the prognostic value of the GPS and the mGPS for overall survival (OS), in a large Western cohort of patients with BTC. Material and methods: We performed a retrospective single-center study for the period 2009 until 2017. 216 consecutive patients that underwent surgical exploration with a diagnosis of perihilar cholangiocarcinoma (PHCC), intrahepatic cholangiocarcinoma (IHCC), or gallbladder cancer (GBC) were assessed. GPS and mGPS were calculated where both CRP and albumin were measured pre-operatively (n ¼ 168/216). Survival was analyzed by Kaplan-Meier estimate and uni-/multivariate Cox regression. Results: GPS and mGPS were negatively associated with survival (p < 0.001/p < 0.001), and the association was significant in all three subgroups. GPS, but not the mGPS, identified an intermediate risk group: with GPS ¼ 1 having better OS than GPS ¼ 2 (p ¼ 0.003), but worse OS than GPS ¼ 0 (p ¼ 0.008). In multivariate analyses of resected patients, GPS (p ¼ 0.001) and mGPS (p ¼ 0.03) remained significant predictors of survival, independent of postoperatively available risk factors. Conclusions: Preoperative GPS and mGPS are independent prognostic factors in BTC. The association to OS was shown in all patients undergoing exploration, in resected patients only, and in both cholangiocarcinoma and gallbladder cancer. Furthermore, GPS e which weights hypoalbuminemia higher e could identify an intermediate risk group. © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Keywords: Biliary tract cancer Preoperative Prognostic factor Risk stratification Glasgow prognostic score Systemic inflammatory response
Introduction
Abbreviations: BTC, biliary tract cancer; CI, confidence interval; CRP, C-reactive protein; ERC, endoscopic retrograde cholangiography; GBC, gallbladder cancer; GPS, Glasgow Prognostic Score; HR, hazard ratio; IHCC, intrahepatic cholangiocarcinoma; IQR, interquartile range; mGPS, modified Glasgow Prognostic Score; OS, overall survival; PHCC, perihilar cholangiocarcinoma; PHLF, posthepatectomy liver failure; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; PVE, portal vein embolization. * Corresponding author. Karolinska Institutet, Dept. of Clinical Science, Intervention and Technology Division of surgery, C1 77, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden. E-mail address: [email protected] (H. Jansson).
Important prognostic factors in biliary tract cancer (BTC) are determined only after surgical resection, as is the case with lymph node metastasis [1e4]. Preoperative prognostic markers in BTC could allow better risk-benefit assessments before surgery and permit stratification of patients for a more individualized treatment [3]. The Glasgow Prognostic Score (GPS) and Modified Glasgow Prognostic Score (mGPS), are preoperative inflammation-based scores that have shown prognostic value in several malignancies [5e7]. Recent studies have indicated a prognostic value of the GPS/ mGPS in BTC in Eastern cohorts [8e11]. It is known that significant
https://doi.org/10.1016/j.ejso.2019.12.008 0748-7983/© 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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differences in BTC prevalence, risk factors, and prognosis exist between Western and Eastern countries [4,12]. The aim of this study was to evaluate and compare the prognostic value of the GPS and the mGPS for overall survival (OS), in a large Western cohort of patients with BTC. Material and methods Study design Consecutive patients that underwent surgical exploration with a diagnosis of perihilar cholangiocarcinoma (PHCC), intrahepatic cholangiocarcinoma (IHCC) or gallbladder cancer (GBC), confirmed postoperatively by pathology, at Karolinska University Hospital (Stockholm, Sweden), a tertiary referral center, from January 2009 until January 2017 were assessed for inclusion. Data was retrospectively collected from the electronic health record. The study was approved by the Regional Ethical Review Board. Outcome variables and demographic-/clinicopathological data The primary outcome variable of this study was overall survival (OS), calculated from date of surgery. Secondary outcome variables were postoperative complications graded by the Clavien-Dindo classification [13], posthepatectomy liver failure (PHLF) as defined by the applied Balzan 50:50 criteria [14,15] (bilirubin >50 mmol/L and prothrombin-International Normalized Ratio >1.5 on postoperative day 5), and in-hospital mortality (not limited to 90 days after surgery). Demographic and clinicopathological variables were: age, sex, American Society of Anesthesiologists (ASA) physical status classification, preoperative portal vein embolization (PVE), preoperative endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography (ERC/PTC), preoperative C-reactive protein (CRP), preoperative albumin, preoperative bilirubin, postoperative bilirubin, postoperative prothrombinInternational Normalized Ratio, resectability at surgical exploration, tumor extension (T), lymph node status (N), resection margin (R), perineural- (Pn) and lymphovascular invasion (LV), and histologic tumor grade according to the College of American Pathologists. Preoperative samples were routinely taken the day before surgery, or at latest preoperative outpatient visit (regularly within two weeks before surgery). Tumor stage was recorded according to the seventh edition of the TNM Classification of Malignant Tumors (TNM-7) [16]. Prognostic scores GPS and mGPS were calculated as previously described, from preoperative plasma CRP- and albumin concentrations [5]. The GPS is defined as: GPS ¼ 0, albumin 35 g/L and CRP 10 mg/L; GPS ¼ 1, albumin <35 g/L or CRP >10 mg/L; GPS ¼ 2, albumin <35 g/L and CRP >10 mg/L. The mGPS is defined as: mGPS ¼ 0, any albumin concentration and CRP 10 mg/L; mGPS ¼ 1, albumin 35 g/L and CRP >10 mg/L; mGPS ¼ 2, albumin <35 g/L and CRP >10 mg/L.
time dependent covariates. Median follow-up time was calculated according to the reverse Kaplan-Meier method. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors for OS. All variables with a p-value < 0.10 in initial univariate analysis were included in multivariate Cox models and backward elimination applied at p 0.10 to reach the final models. All significance tests were two-sided, and p-values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS Statistics v25 (IBM, New York, USA). Results Cohort characteristics Out of a total of 216 consecutive patients, preoperative CRP- and albumin values for calculation of GPS/mGPS were available for 168 patients, which were included for analysis (see study flow diagram in Fig. 1). Baseline characteristics are presented in Table 1. There were no significant differences in baseline characteristics or OS between the analysis cohort and patients excluded due to missing data on preoperative CRP and albumin. In the analysis cohort 57 patients (34%) had PHCC, 43 patients (26%) IHCC, and 68 patients (40%) GBC. Twenty-nine patients (17%) were found unresectable at exploration (locally advanced disease n ¼ 11, non-regional lymph node metastasis n ¼ 5, distant liver-/peritoneal metastasis n ¼ 13). Of resected patients, 65% underwent major hepatectomy (3 segments). Median OS was 18 months (IQR 43 months) for the entire cohort, 21 months (IQR 52 months) for resected patients and 7 months (IQR 9 months) for unresected patients. Median follow-up time calculated by the reverse Kaplan-Meier method was 48 months (IQR 35 months). Overall survival stratified by GPS/mGPS Fifty-three patients (32%) had either CRP > 10 mg/L (n ¼ 15, 9%) or albumin <35 g/L (n ¼ 38, 23%), whereas 61 patients (36%) had both CRP > 10 mg/L and albumin <35 g/L. Calculated prognostic scores and survival curves stratified by GPS and mGPS are shown in Fig. 2: in 2a and b for the whole cohort, and in 2c and d for resected patients only. Both the GPS and the mGPS were significantly negatively associated with survival, but only the GPS could identify an intermediate risk group, with GPS ¼ 1 having better OS than GPS ¼ 2 (p ¼ 0.003), but worse OS than GPS ¼ 0 (p ¼ 0.008). Also in analysis of resected patients alone, only the GPS identified an intermediate risk group (GPS ¼ 1 compared to GPS ¼ 2 p ¼ 0.015, GPS ¼ 1 compared to GPS ¼ 0 p ¼ 0.039). The proportional hazards assumption for GPS and mGPS was tested using time dependent covariates, with no significant time-dependent hazard (GPS
Statistical analysis Continuous variables were reported with median and interquartile range (IQR). Categorical variables were reported with whole numbers and proportions. Proportions were compared using the chisquare test or the Fisher Exact test. Distributions of continuous variables were compared using the Mann-Whitney U test. Survival was estimated with the Kaplan-Meier method, and differences in OS compared using the log-rank test. The proportional hazards assumption for the prognostic scores was significance tested using
Fig. 1. Study flow diagram.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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Table 1 Baseline characteristics and OS for patients assessed and patients included. Variable
All consecutive patients (n ¼ 216)
GPS/mGPS data available (n ¼ 168)
p-value*
Age, md years (IQR) Sex, n (%) Female Male Diagnosis, n (%) PHCC IHCC GBC ASA, n (%) 1-2 3-4 PSC, n (%) Y N ERC/PTC, n (%) Y N PVE, n (%) Y N Bilirubin, md mmol/L (IQR) Resection, n (%) Y N Major resection, n (%)** Y N OS, md months (IQR)
66 (14)
66 (14)
0.75
121 (56) 95 (44)
93 (55) 75 (45)
0.71
67 (31) 54 (25) 95 (44)
57 (34) 43 (26) 68 (40)
0.12
149 (69) 67 (31)
113 (67) 55 (33)
0.31
20 (9) 196 (91)
18 (11) 150 (89)
100 (46) 116 (54)
82 (49) 86 (51)
0.17
29 (13) 187 (87) 8 (9)
26 (15) 142 (85) 9 (10)
0.10 0.48
177 (82) 39 (18)
139 (83) 29 (17)
0.57
109 (62) 68 (38) 19 (40)
90 (65) 49 (35) 18 (43)
0.10 xx 0.93
x
0.26
ASA: American Society of Antesthesiologists class; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GBC: gallbladder cancer; GPS: Glasgow prognostic score; IHCC: intrahepatic cholangiocarcinoma; IQR: interquartile range; md: median; mGPS: modified Glasgow prognostic score; OS: overall survival; PHCC: perihilar cholangiocarcinoma; PSC: primary sclerosing cholangitis; PVE: portal vein embolization; mmol/L: micromole per litre. Continuous variables presented with median and IQR, significance by Mann-Whitney U test or log rank test. Categorical variables presented with whole numbers and proportions, significance by chi-square test or Fisher Exact test. * Patients included compared to patients excluded; x Fisher Exact test; xx Log rank test; ** Resected patients.
p ¼ 0.27, mGPS p ¼ 0.42). Outcomes after resection by GPS In Table 2, outcomes for resected patients are presented. Sixtyseven patients (48%) suffered a complication Clavien-Dindo grade 3a or higher. Thirteen patients (9%) suffered PHLF. In-hospital mortality was 10% (14 patients). Median OS was 21 months (IQR 52 months). There were no significant differences in postoperative complications or mortality between GPS groups, but a significant difference in OS (p < 0.001).
(p ¼ 0.15) were not significantly associated with survival in univariate analysis, but were included in additional multivariate Cox regression analyses for both the whole cohort and resected patients, to control for any interference with inflammatory status (Supplemental Tables A and B). Resectability was also included in multivariate analysis for the whole cohort (Supplemental Table A). In all the adjusted models, GPS and mGPS remained significant independent prognostic factors. Moreover, no significant association was found between increased bilirubin and increased GPS in the perihilar subgroup (p ¼ 0.67 Fisher Exact test), the group where increased bilirubin was most frequent (18% compared to 12% overall).
Univariate analyses of prognostic factors Discussion In univariate Cox regression analyses, GPS, mGPS, resection, preoperative ERC/PTC, T-stage, lymph node metastasis, perineural invasion, resection margin, and histologic grade were statistically significant at p < 0.05 for OS (Table 3). The GPS and the mGPS were found to be significant for OS in all three subgroups of BTC. Sex and lymphovascular invasion were not statistically significant, but at p < 0.10 they were included in multivariate Cox regression analyses. Multivariate analyses of prognostic factors On multivariate analysis of resected patients, including postoperatively available risk factors, both increased GPS (p ¼ 0.001) and mGPS (p ¼ 0.03) were independent prognostic factors for OS (Table 4). Other factors found significant for OS in multivariate analysis were advanced T-stage and presence of lymph node metastasis. Preoperative PVE (p ¼ 0.12) and increased preoperative bilirubin
Established preoperative prognostic factors for risk stratification of patients with BTC are lacking. A systemic inflammatory response in malignancy has been shown to carry a prognostic value. In several Asian cohorts, a prognostic value of the inflammationbased GPS and the updated mGPS has been indicated [8e11]. In this analysis of 168 BTC patients undergoing surgical exploration in a Western tertiary referral center, we could show that the GPS and mGPS were significantly negatively associated with OS. The association was found in all patients undergoing exploration, in resected patients only, and in all three BTC subgroups. In multivariate analysis the GPS, mGPS, advanced T-stage, and N1-disease were independent prognostic factors. However, GPS was a stronger prognostic factor compared to mGPS, and the only one to identify an intermediate risk group. The association between GPS/ mGPS and survival remained significant after adjusting for preoperative factors such as PVE, ERC/PTC and increased bilirubin, both in
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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Fig. 2. Overall survival stratified by GPS (top panels) and mGPS (bottom panels). (a) and (b): Whole cohort (n ¼ 168); (c) and (d): Resected patients (n ¼ 139).
Table 2 Outcomes after resection stratified for GPS. All resected patients (n ¼ 139)
GPS ¼ 0 (n ¼ 51)
GPS ¼ 1 (n ¼ 41)
GPS ¼ 2 (n ¼ 47)
p-value
CD 3a (%)
67 (48)
21 (41)
19 (46)
27 (57)
0.27
Posthepatectomy liver failurea (%)
13 (9)
2 (4)
3 (7)
8 (17)
0.09
Mortality in-hospital (%)
14 (10)
3 (6)
3 (7)
8 (17)
0.19
OS months, md (IQR)
21 (52)
50 (57)
21 (77)
13 (23)
<0.001
CD 3a: any complication Clavien-Dindo classification grade 3a or higher; GPS: Glasgow prognostic score; md: median; IQR: interquartile range; OS: overall survival. Categorical variables presented with whole numbers and proportions, significance by Fisher Exact test. Overall survival presented with median and IQR, significance by log rank test. a Posthepatectomy liver failure according to the applied Balzan 50:50 criteria.
the whole cohort, and in resected patients. Of the postoperative outcomes for resected patients (complication Clavien-Dindo grade 3 or higher, PHLF, in-hospital mortality, median OS) only OS was significantly associated with GPS, suggesting that an increased rate of severe complications after surgery is not the main cause of shorter survival in patients with increased preoperative GPS. Outcomes for patients resected with a preoperative GPS ¼ 2 were poor, with a median OS of 13 months (IQR 23 months), which can be compared to a median OS of 50 months (IQR 57 months) for
patients resected with GPS ¼ 0 and a median OS of 7 months (IQR 9 months) for unresected patients in this cohort. The mGPS differs from the original GPS in that it weights hypoalbuminemia lower, by awarding a score of 0 to albumin <35 g/L in the absence of CRP >10 mg/L [5]. The mGPS was presented by McMillan et al., in 2007, as it was shown that in patients with colorectal cancer, hypoalbuminemia alone was a weaker prognostic factor than CRP [5]. The proportion of patients with preoperative isolated hypoalbuminemia in our cohort of BTC was
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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Table 3 Univariate Cox regression analyses for OS. Variable
All BTC N (%)
Age
HR
95% CI
p-value
1.01
0.99e1.02
0.28
Sex (Female)
Y ¼ 93 (55), N ¼ 75 (45)
0.74x
0.52e1.04
0.09
ASA3
Y ¼ 55 (33), N ¼ 113 (67)
1.23
0.86e1.77
0.26
Resection
Y ¼ 139 (83), N ¼ 29 (17)
0.38**
0.24e0.58
<0.001
GPS1
Y ¼ 114 (68), N ¼ 54 (32)
2.43**
1.61e3.67
<0.001
mGPS1
Y ¼ 76 (45), N ¼ 92 (55)
2.09**
1.48e2.97
<0.001
ERC/PTC
Y ¼ 82 (49), N ¼ 86 (51)
1.51*
1.07e2.15
0.02
PVE
Y ¼ 26 (15), N ¼ 142 (85)
1.43
0.91e2.23
0.12
Bilirubin (>25 mmol/L)
Y ¼ 20 (12), N ¼ 146 (88)
1.45
0.88e2.39
0.15
T3
Y ¼ 96 (57), N ¼ 72 (43)
2.71**
1.87e3.93
<0.001
N1
Y ¼ 72 (57), N ¼ 55 (43)
1.71*
1.13e2.59
0.01
LV1
Y ¼ 103 (77), N ¼ 31 (23)
1.55x
0.94e2.57
0.09
Pn1
Y ¼ 101 (75), N ¼ 33 (25)
1.91*
1.14e3.19
0.01
R1
Y ¼ 89 (65), N ¼ 48 (35)
1.78*
1.16e2.74
0.01
Grade (2 or 3)xx
Y ¼ 126 (88), N ¼ 17 (12)
1.98*
1.03e3.80
0.04
PHCC HR (95% CI) p-value
IHCC HR (95% CI) p-value
GBC HR (95% CI) p-value
1.01 (0.99e1.04) 0.31 0.76 (0.42e1.37) 0.36 1.42 (0.78e2.58) 0.25 0.26** (0.13e0.54) <0.001 2.55* (1.13e5.77) 0.02 2.08* (1.16e3.75) 0.02 1.47 (0.53e4.12) 0.46 1.31 (0.70e2.44) 0.40 1.13 (0.53e2.44) 0.75 2.04* (1.13e3.67) 0.02 1.77 (0.89e3.49) 0.10 1.04 (0.43e2.52) 0.93 2.78 (0.38e20.49) 0.32 1.21 (0.49e2.98) 0.68 1.35 (0.48e3.82) 0.57
1.00 (0.97e1.04) 0.97 0.60 (0.28e1.28) 0.19 0.71 (0.30e1.68) 0.44 0.47 (0.16e1.39) 0.17 2.75* (1.23e6.14) 0.01 2.44* (1.14e5.20) 0.02 3.86* (1.27e11.78) 0.02 (no PVE)
1.02 (0.99e1.05) 0.24 0.84 (0.49e1.44) 0.52 1.35 (0.78e2.36) 0.29 0.47* (0.24e0.90) 0.02 1.88* (1.02e3.47) 0.04 1.80* (1.05e3.10) 0.03 1.33 (0.78e2.27) 0.30 1.27 (0.62e2.60) 0.52 1.45 (0.68e3.07) 0.34 3.51** (1.75e7.04) <0.001 1.28 (0.69e2.37) 0.43 2.08x (0.92e4.71) 0.08 2.93* (1.29e6.67) 0.01 3.67** (1.90e7.11) <0.001 2.93* (1.05e8.20) 0.04
2.85 (0.66e12.24) 0.16 2.66* (1.24e5.70) 0.01 2.67x (0.92e7.73) 0.07 1.34 (0.52e3.43) 0.54 1.06 (0.46e2.46) 0.89 1.41 (0.61e3.24) 0.42 1.78 (0.41e7.72) 0.44
ASA: American Society of Anesthesiologists; BTC: biliary tract cancer; CI: confidence interval; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GBC: gallbladder cancer; GPS: Glasgow prognostic score; HR: hazard ratio; IHCC: intrahepatic cholangiocarcinoma; LV1: lymphovascular invasion; mGPS: modified Glasgow prognostic score; N1: lymph node metastasis; OS: overall survival; PHCC: perihilar cholangiocarcinoma; Pn1: perineural invasion; PVE: portal vein embolization; R1: resection margin positive; T: primary tumor extension; mmol/L: micromole per litre. xx Tumor grade according to the College of American Pathologists. x P-value < 0.10; * P-value < 0.05; ** P-value < 0.001.
Table 4 Multivariate Cox regression models for overall survival. Multivariate model with GPS
GPS1 Sex (Female) ERC/PTC T3 N1 LV1 Pn1 R1 Grade (2 or 3)xx
Multivariate model with mGPS HR (95% CI)
p-value
2.44* (1.44e4.13) e e 2.03* (1.27e3.24) 1.68* (1.05e2.67) e e e e
0.001 0.33 0.24 0.003 0.03 0.41 0.70 0.42 0.15
mGPS1 Sex (Female) ERC/PTC T3 N1 LV1 Pn1 R1 Grade (2 or 3)xx
HR (95% CI)
p-value
1.67* (1.06e2.62) e e 2.00* (1.25e3.19) 1.54 (0.97e2.44) e e e e
0.03 0.15 0.12 0.004 0.07 0.66 0.78 0.21 0.28
CI: confidence interval; ERC/PTC: endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography; GPS: Glasgow prognostic score; HR: hazard ratio; LV1: lymphovascular invasion; mGPS: modified Glasgow prognostic score; N1: lymph node metastasis; Pn1: perineural invasion; R1: resection margin positive; T: primary tumor extension. xx Tumor grade according to the College of American Pathologists. * P-value < 0.05. Variables with hazard ratios retained in final models.
Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008
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H. Jansson et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
23%, which can be compared to 5% in the cohort of colorectal cancer used by McMillan et al. to develop the mGPS [5]. That hypoalbuminemia is more common in BTC than in colorectal cancer could mirror both a stronger systemic inflammatory response and that BTCs are primary hepatic malignancies. The role of albumin as a negative acute phase reactant and marker of inflammation rather than a marker of nutritional status has been underscored by recent research in both benign chronic disease and malignancy [17e19]. Regarding OS stratified by GPS and mGPS, we could confirm the previous findings from Asian reports by Oshiro et al. [8] (GPS in perihilar- and distal cholangiocarcinoma, n ¼ 62), Okuno et al. [9] (mGPS in PHCC, n ¼ 534), Wu et al. [11] (GPS in GBC, n ¼ 85), and Shiba et al. [10] (GPS in GBC, n ¼ 51). In contrast to the previous studies by Oshiro et al. [8] and Wu et al. [11], analysis of GPS in our cohort could stratify patients in three separate risks groups. Notably, in addition to differences in study populations, these previous cohorts were smaller and could be underpowered to separate the GPS ¼ 1 group. We could also confirm GPS/mGPS as independent prognostic factors for OS in multivariate analyses, together with N1-disease and advanced T-stage. Previous authors have integrated various factors in multivariate models, but all with the exception of Oshiro (p ¼ 0.07) reported independent significance for N1 [8e11]. Okuno et al., in the largest of the studies, did not include T-stage in their survival analysis [9]. Wu et al. found independent significance of T-stage, while Shiba et al. (p ¼ 0.07) and Oshiro et al. (p ¼ 0.10) did not [8,10,11]. To exclude that inflammatory markers were just surrogates for other preoperative factors, such as cholestasis or biliary-/vascular interventions, we performed uni- and multivariate analysis with preoperative bilirubin, ERC/PTC and PVE. Controlling for these variables, GPS and mGPS remained independent prognostic factors. Sex was included in our multivariate regression analysis as univariate regression gave HR ¼ 0.74 at p < 0.10 for OS in female compared to male patients. However, sex was not significant at p < 0.05 in the univariate analysis, and was not a prognostic factor in the multivariate analyses. The literature suggests possible differences between BTC subgroups regarding sex as a prognostic factor for survival after resection. Sex has not been indicated to affect prognosis in meta-analyses on resectable PHCC [4,20], but has been shown to be a prognostic factor in nation-wide studies both of resectable and non-resectable IHCC, with male patients having worse survival [21e23]. While incidence of GBC is higher among women, a nation-wide study on resectable GBC did not show sex to have prognostic value [24]. The present retrospective single-center study has several limitations. Data for calculation of preoperative scores was missing in 22% of all patients assessed; a possible confounder even if no differences in baseline characteristics or OS were noted between patients analyzed and patients excluded. As BTC is relatively rare, and most often inoperable at diagnosis, the size of our single-center cohort also limits the statistical power for more extensive multivariate- and subgroup analyses. Moreover, complete postoperative pathological risk factor data was not available for all patients, further restricting analysis and statistical power. The cohort was also heterogenous regarding diagnoses and type of resection. Overall a majority of resected patients underwent major resection, but in GBC less extensive resections such as bisegmentectomy or wedge resection were commonly performed. Liver resection for BTC carries a significant risk of morbidity and mortality. Even after curative intent resection, a majority of patients will suffer recurrence within 5 years [2,21]. Multimodal treatment for BTC, to improve prognosis after surgery, is still under development [25]. Criteria and protocols for adjuvant chemotherapy as standard of care are being established [26], while neoadjuvant therapy is under investigation [27]. Preoperative identification of
patients with poor prognosis could permit selection for multimodal therapy [27e29]. Inflammation-based prognostic scores have been suggested as a way to assess the host response both to tumor disease and oncological treatment, and a prognostic value of the GPS/ mGPS has been validated in randomized control trials of chemotherapy in colorectal and prostate cancer [30]. In this retrospective study, we have confirmed preoperative GPS and mGPS as prognostic factors for OS after resection in a Western cohort of BTC; independent of postoperatively available tumor characteristics. Prospective validation of the scores in randomized controlled trials in BTC, and further examination of our findings in multi-center studies, could be future steps toward a preoperative risk stratification of BTC-patients. Moreover, the prognostic value of inflammation-based scores in BTC motivates efforts to decipher host immunological responses in this group of malignancies. Conclusions Preoperative GPS and mGPS are independent prognostic factors for OS in BTC. The association with OS was shown in all patients undergoing exploration, in resected patients only, and in both cholangiocarcinoma and gallbladder cancer. Furthermore, GPS e which weights hypoalbuminemia higher e could identify an intermediate risk group. Declaration of competing interest The authors declare no conflict of interest. Acknowledgements This study was supported by grants from the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Bengt Ihre Foundation, the Center for Innovative Medicine at Karolinska Institutet, and Region Stockholm. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejso.2019.12.008. References [1] Giuliante F, Ardito F, Guglielmi A, et al. Association of lymph node status with survival in patients after liver resection for hilar cholangiocarcinoma in an Italian multicenter analysis. JAMA Surg 2016;151:916e22. [2] Groot Koerkamp B, Wiggers JK, Allen PJ, et al. Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg 2015;221:1041e9. [3] Saito H, Noji T, Okamura K, Tsuchikawa T, Shichinohe T, Hirano S. A new prognostic scoring system using factors available preoperatively to predict survival after operative resection of perihilar cholangiocarcinoma. Surgery 2016;159:842e51. [4] Tang Z, Yang Y, Zhao Z, Wei K, Meng W, Li X. The clinicopathological factors associated with prognosis of patients with resectable perihilar cholangiocarcinoma: a systematic review and meta-analysis. Medicine (Baltim) 2018;97:e11999. [5] McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 2007;22:881e6. [6] Hefler-Frischmuth K, Seebacher V, Polterauer S, Tempfer C, Reinthaller A, Hefler L. The inflammation-based modified Glasgow Prognostic Score in patients with vulvar cancer. Eur J Obstet Gynecol Reprod Biol 2010;149:102e5. [7] Li MX, Bi XY, Li ZY, et al. Prognostic role of Glasgow prognostic score in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Medicine (Baltim) 2015;94:e2133. [8] Oshiro Y, Sasaki R, Fukunaga K, et al. Inflammation-based prognostic score is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma. Int J Hepatobiliary Pancreat Dis 2013;20:389e95. [9] Okuno M, Ebata T, Yokoyama Y, et al. Evaluation of inflammation-based prognostic scores in patients undergoing hepatobiliary resection for
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Please cite this article as: Jansson H et al., Prognostic value of preoperative inflammatory markers in resectable biliary tract cancer e Validation and comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western cohort, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.12.008