Clinical Study Received: June 13, 2017 Accepted after revision: August 11, 2017 Published online: October 11, 2017
Oncology DOI: 10.1159/000480703
Prognostic Factors for Survival in Patients with Advanced Intrahepatic Cholangiocarcinoma Treated with Gemcitabine plus Cisplatin as First-Line Treatment Utako Ishimoto Shunsuke Kondo Akihiro Ohba Mitsuhito Sasaki Yasunari Sakamoto Chigusa Morizane Hideki Ueno Takuji Okusaka Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
Keywords Cholangiocarcinoma · Gemcitabine · Biliary tract cancer · Intrahepatic cholangiocarcinoma · Prognostic factors
reliably predicted the prognosis of ICC patients receiving GC therapy. If validated in other studies, these results may provide a useful tool for individual patient-risk evaluation and the design and interpretation of future trials. © 2017 S. Karger AG, Basel
© 2017 S. Karger AG, Basel E-Mail [email protected] www.karger.com/ocl
Introduction
Worldwide, biliary tract cancer (BTC) is a rare type of cancer, though it is more prevalent in East Asian and Latin American countries [1, 2]. Patients with advanced BTC are a heterogeneous group, characterized by both locally advanced and metastatic disease, as well as a variety of primary disease sites (intrahepatic bile ducts, extrahepatic bile ducts, gallbladder, and ampulla). Surgery represents the only curative option, but 3.0, multiple metastatic sites, an intrahepatic primary site the presence of liver metastases, the number of sites of advanced disease, a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and elevated levels of serum alkaline phosphatase (ALP) were reported to be significant poor prognostic factors of overall survival (OS) [7–10]. Intrahepatic cholangiocarcinoma (ICC) is the secondmost common type of primary liver cancer, and its incidence increased by 22% between 1979 and 2004 in the United States [11]. Several studies have reported an increasing global incidence and mortality rate for ICC, in contrast with decreasing rates for extrahepatic cholangiocarcinoma (ECC) [12]. Patients with resectable ICC tend to have a better prognosis than patients with ECC. The median survival time for resected ICC patients has been reported to range from 9 to 30 months [13–15]. With regard to surgery for ICC, lymph node involvement is an important prognostic factor [16]. On the other hand, no useful clinical prognostic factors have been reported in patients with advanced and recurrent ICC treated with GC as first-line chemotherapy. In the present study, we aimed to evaluate the clinical prognostic factors for patients with advanced ICC receiving GC as standard firstline chemotherapy.
tients (40.3%) complained of pain as the first symptom. Forty-one patients (53.2%) had an ECOG PS of 0. UICCTNM stage was stage III in 2 patients (2.6%), stage IVA in 9 patients (11.7%), stage IVB in 48 patients (62.3%), and recurrent in 18 patients (23.4%). Twenty-four patients (31.2%) had prior biliary intervention. The median results of the pretreatment laboratory tests are shown in Table 2. Response Rate and Tumor Control Rate Among the 77 evaluable patients, 1 (1.2%) had a complete response, 7 (9.0%) had partial responses, 45 (58.4%) had stable disease, 18 (23.3%) had progressive disease, and 6 (7.8%) had a nonevaluable response, resulting in a disease control rate of 68.8%. Survival Distribution The median PFS was 4.47 months (95% confidence interval [CI], 2.75–6.19) and the median OS was 13.8 months (95% CI, 8.9–18.6) (Fig. 1a, b). Univariate analysis indicated that pain complaint (p = 0.002), ECOG PS ≥1 (p = 0.038), LDH >220 U/L (p = 0.023), Alb 450 IU/L (p = 0.002), CRP >1.0 mg/dL (p = 0.001), CA 19-9 >1,000 U/mL (p = 0.002), and CEA >5.0 ng/mL (p = 0.001) were statistically associated with a poorer prognosis. Multivariate analysis showed that LDH >220 U/L (HR: 2.53; 95% CI 1.33–4.82, p = 0.005), CRP >1.0 mg/dL (HR: 3.06; 95% CI 1.52–6.15, p = 0.001), and CEA >5.0 ng/mL (HR: 2.37; 95% CI 1.11–5.15, p = 0.03) remained significantly associated with prognosis (Table 3; Fig. 2). Elevations of LDH, CRP, and CEA levels might be prognostic factors in patients with advanced ICC treated with GC.
Table 1. Patient characteristics (n = 77)
Median age (range), years Sex Male Female Pain complaint as first symptom Yes No ECOG PS 0 1 2 Biliary intervention Yes No UICC-TNM stage III IVA IVB Recurrence Median tumor size (range), mm Primary tumor lesion Peripheral Central Macroscopic characteristics of tumor Mass forming Periductal infiltrating Intraductal growth Mass forming + periductal infiltrating Unknown Surgical resection Yes No Length of time from surgical resection to recurrence (range), months
64 (38 – 80) 50 27 31 46 41 35 1 24 53 2 9 48 18 66.6 (13.2 – 169.6) 42 35 57 5 0 13 2 19 58 11.2 (1.4 – 44.0)
ECOG PS, Eastern Cooperative Oncology Group performance status; UICC, Union for International Cancer Control.
Discussion
Prognostic Factors in ICC
Table 2. Median results (range) of the pretreatment laboratory test
White blood cell count, cells/μL 6,200 (3,100 – 14,300) Hemoglobin, g/dL 12.2 (8.1 – 16.6) Neutrophils, cells/μL 4,210 (1,450 – 13,160) Platelets, cells/μL 19.9 (7.9 – 48.7) C-reactive protein, mg/dL 1.18 (0.02 – 17.96) Lactate dehydrogenase level, U/L 205 (107 – 1676) Albumin, g/dL 3.7 (2.1 – 4.8) Total bilirubin, mg/dL 0.7 (0.3 – 3.0) Alkaline phosphatase level, IU/L 450 (157 – 1,649) Aspartate aminotransferase level, IU/L 35 (16 – 152) Alanine aminotransferase level, IU/L 25 (9 – 119) Carbohydrate antigen 19-9 level, U/mL 451 (0 – 172,000) Carcinoembryonic antigen level, ng/dL 2.9 (0.6 – 511)
Oncology DOI: 10.1159/000480703
3
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
GC is widely used for the treatment of advanced ICC patients in clinical practice. The current study identified several reliable prognostic factors in patients with advanced ICC receiving GC as standard chemotherapy. The pretreatment serum levels of LDH, CRP, and CEA were significant prognostic factors. Because these values are readily available and easily measured, they are of potential widespread use in patients who are going to receive first-line chemotherapy. ICC is optimally managed with hepatic resection. However, ICC often presents at an advanced stage, and in some series only 15–20% of the patients have resectable tumors [15]. Patients with advanced BTC have an ex-
1.0 +
1.0 +
Median PFS 4.47 months
0.8
Probability, %
+ + + +
0.6
0.6
0.4
Median OS 13.8 months
+ + + + + + 0.8 +++ + + +
+ ++
+ + + + +
0.4
+
+ ++
+
0.2
0
a
+
0.2
+ +
0
5
10 15 PFS, months
+
20
0
b
+
0
10
20 30 OS, months
40
50
Fig. 1. Kaplan-Meier estimates of progression-free survival (PFS; a) and overall survival (OS; b).
Table 3. Univariate and multivariate analysis for overall survival
Factor
Sex Pain complaint ECOG PS >1 Biliary intervention Tumor size >66.6 mm Primary tumor location White blood cell count >6,200 cells/μL Hemoglobin concentration >12.2 g/dL Platelet count >20.0 cells/μL Lactate dehydrogenase level >220 U/L Albumin concentration 35 IU/L Alanine aminotransferase level >25 IU/L Alkaline phosphatase level >450 IU/L C-reactive protein level >1.0 mg/dL Carbohydrate antigen 19-9 >1,000 U/mL Carcinoembryonic antigen level >5.0 ng/mL
Univariate analysis
Multivariate analysis
HR (95% CI)
p value
1.24 (0.64 – 2.38) 2.08 (1.10 – 3.93) 1.93 (1.04 – 3.60) 1.07 (0.55 – 2.09) 1.20 (0.66 – 2.21) 1.28 (0.81 – 2.03) 1.12 (0.62 – 2.05) 0.78 (0.42 – 1.45) 1.08 (0.58 – 2.02) 2.01 (1.10 – 3.68) 2.00 (1.06 – 3.85) 0.95 (0.51 – 1.75) 1.40 (0.75 – 2.57) 2.41 (1.43 – 5.49) 2.86 (1.50 – 5.46) 2.77 (1.45 – 5.29) 3.39 (1.60 – 7.17)
0.52 0.002 0.038 0.83 0.55 0.28 0.71 0.43 0.81 0.023 0.031 0.87 0.29 0.002 0.001 0.002 0.001
HR (95% CI)
p value
1.73 (0.87 – 3.41) 1.67 (0.88 – 3.20)
0.12 0.12
2.53 (1.33 – 4.82) 1.21 (0.52 – 2.85)
0.005 0.67
1.50 (0.69 – 3.26) 3.06 (1.52 – 6.15) 1.67 (0.69 – 4.03) 2.39 (1.11 – 5.15)
0.30 0.001 0.25 0.03
HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
4
Oncology DOI: 10.1159/000480703
BTC tumors [20]. In the meta-analysis, the OS of patients with ICC and ECC was higher than that of those with carcinomas of the gallbladder and ampulla. In the present study, the median OS of 13.8 months is longer than that previously reported in BTC patients, and the present OS Ishimoto/Kondo/Ohba/Sasaki/Sakamoto/ Morizane/Ueno/Okusaka
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
tremely poor prognosis with a median OS of 7.3–12.0 months [5, 7, 18, 19]. Phase II and III trials were conducted in 2010 in patients with advanced BTC including ICC, and a meta-analysis showed that ICC patients benefited more from GC therapy than did those patients with other
+ 1.0 ++
+ +++ ++++
LDH 200 U/L LDH > 200 U/L
+
0.8
1.0 +
0.8
Probability, %
+ +
0.6
CRP 1.0 mg/dL CRP > 1.0 mg/dL
+ + ++
+ +
0.4
+ + +
0.6
+
+
+
+
+++
++
0.4
+
+
+
0.2
0.2
++ +
0
a
0
15
30 OS, months
1.0 +
+
0
45
b
0
15
30 OS, months
45
CEA 5.0 ng/mL CEA > 5.0 ng/mL
++ +++
0.8
Probability, %
+ +
0.6
+
+ +
0.4
++ +
0.2
0
c
+
0
15
30 OS, months
45
Fig. 2. Kaplan-Meier estimates of overall survival according to LDH (a), CRP (b), and CEA (C). OS, overall sur-
data suggests that patients with ICC might have a better prognosis than those with other BTCs. In the present study, pretreatment CEA levels were associated with the prognosis of patients with advanced ICC. ICC is associated with a different clinical, laboratory, and radiologic presentation than that of perihilar or distal cholangiocarcinomas. CEA levels alone are neither sensitive nor specific for BTC. Moreover, the most widely studied tumor markers are CEA and CA 19-9, and both can be elevated in BTC patients [21–23]. Using the combination of CEA and CA 19-9 levels may be useful. In ad-
dition, there has been recent interest in the use of CA 242 and CA 125 for the diagnosis of BTC. ICC frequently arises under conditions of inflammation, which is believed to contribute to the pathogenesis of this tumor. A variety of cytokines, growth factors, tyrosine kinases, and bile acids can contribute to the alterations in proliferation, apoptosis, senescence, and cell-cycle regulation required for cholangiocarcinogenesis [21]. Inflammatory cytokines activate inducible nitric oxide synthase, leading to excess nitric oxide with resultant single-stranded, double-stranded, and oxidative DNA le-
Prognostic Factors in ICC
Oncology DOI: 10.1159/000480703
5
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
vival; LDH, lactate dehydrogenase; CRP, C-reactive protein; CEA, carcinoembryonic antigen.
6
Oncology DOI: 10.1159/000480703
holds great promise for the next stage of targeted chemotherapies. We are confident that the present study has revealed clinically important prognostic factors, aiding the development of successful therapies for ICC. In conclusion, our model is based on several readily available clinical and laboratory factors, which reliably identify different factors in ICC patients receiving GC therapy. If validated in future studies, these factors may provide a useful tool for individual patient-risk evaluation and aid in the design and interpretation of future trials. Finally, further research on the biological mechanisms leading to the formation of ICC and the development of targeted therapeutic agents is warranted in order to advance the therapeutic armamentarium against this aggressive disease.
Acknowledgements We express our appreciation to Rubi Mukoyama, Keiko Kondo, and Hiroko Hosoi for collecting the clinical data. This work was supported in part by the Japan Society for the Promotion of Science Kakenhi.
Statement of Ethics This study was approved by the Institutional Review Board of the National Cancer Center Hospital, and all patients provided written informed consent.
Disclosure Statement The authors report no potential conflicts of interest.
References
1 Randi G, Malvezzi M, Levi F, et al: Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146–159. 2 Matsuda T, Marugame T: International comparisons of cumulative risk of gallbladder cancer and other biliary tract cancer, from Cancer Incidence in Five Continents Vol. VIII. Jpn J Clin Oncol 2007;37:74–75. 3 de Groen PC, Gores GJ, LaRusso NF, et al: Biliary tract cancers. N Engl J Med 1999;341: 1368–1378. 4 Charbel H, Al-Kawas FH: Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep 2011; 13:182–187. 5 Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–1281.
Ishimoto/Kondo/Ohba/Sasaki/Sakamoto/ Morizane/Ueno/Okusaka
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
sions, as well as the inhibition of DNA repair enzymes [22]. Therefore, inflammatory signaling pathways appear to promote the development of ICC by causing DNA damage and blocking the apoptosis normally induced by the DNA damage response. These cytokines also promote cell proliferation. The combination of DNA damage, inhibition of apoptosis, and promotion of cell proliferation are all components of cell transformation. Interest in inflammation influencing cancer outcome is increasing, in part because of the potential impact of the Glasgow Prognostic Score, based primarily on CRP and Alb levels [23]. In our study, an elevated CRP level was associated with a poor prognosis. Therefore, we suggest that chronic inflammation might be associated with the molecular pathogenesis of ICC. LDH levels were shown to be significant prognostic factors in our study. LDH is a glycolytic enzyme, composed of 4 polypeptide chains, each one encoded by a separate gene (M and H), with a key role in the conversion of pyruvate to lactate under anaerobic conditions. Five isoforms of LDH have been identified as a result of the 5 different combinations of polypeptide subunits. The biological link between hypoxia, LDH levels, and the tumordriven angiogenesis pathway through the abnormal activation of the hypoxia-inducible factor 1α is well established. Since LDH and pro-angiogenesis factors are regulated by the same hypoxia-inducible factor 1α-driven molecular pathway, high LDH levels are usually concomitantly present with the abnormal activation of the vascular endothelial growth factor (VEGF) pathway. It has been in fact demonstrated that high LDH serum levels were associated with tumor overexpression of VEGFA and VEGF receptors in many tumor types. It has been postulated that LDH levels may represent an indirect marker of activated tumor angiogenesis and a worse prognosis [24]. The present study has several limitations, including its retrospective nature and single institution origin, and our findings require further validation. We defined cutoff points as the median value of each variable. LDH and CEA cutoff points were established by the upper limits of normal, and CA19-9 was dichotomized according to values >1,000 U/mL in the multivariate analysis. There have been debates regarding the proper definition and clinical implications of cutoff points. BTC is a rare cancer with heterogeneous characteristics, comprising both locally advanced and metastatic disease, a variety of primary disease sites, and varied histological and genetic findings. The recent genomic analysis of ICC, showing FGFR2 fusion and IDH1/2 mutations,
Prognostic Factors in ICC
13 Pichlmayr R, Lamesch P, Weimann A, et al: Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:83–88. 14 Yamamoto J, Kosuge T, Takayama T, et al: Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111:617–622. 15 Schlinkert RT, Nagorney DM, Van Heerden JA, Adson MA: Intrahepatic cholangiocarcinoma: clinical aspects, pathology and treatment. HPB Surg 1992; 5: 95–101; discussion 101–102. 16 de Jong MC, Nathan H, Sotiropoulos GC, et al: Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140–3145. 17 Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. 18 Furuse J, Okusaka T, Funakoshi A, et al: Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer. Jpn J Clin Oncol 2006;36: 552–556.
Oncology DOI: 10.1159/000480703
19 Grenader T, Waddell T, Peckitt C, et al: Prognostic value of neutrophil-to-lymphocyte ratio in advanced oesophago-gastric cancer: exploratory analysis of the REAL-2 trial. Ann Oncol 2016;27:687–692. 20 Valle JW, Furuse J, Jitlal M, et al: Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014;25:391–398. 21 Blechacz BG, Gores GJ: Tumors of the bile ducts, gallbladder, and ampulla. In: Feldman (ed): Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, vol 1, ed 9. Philadelphia, Saunders, 2010, pp 1171–1176. 22 Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ: Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000;60:184–190. 23 Proctor MJ, Talwar D, Balmar SM, et al: The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow Inflammation Outcome Study. Br J Cancer 2010;103:870–876. 24 Faloppi L, Del Prete M, Casadei Garnidi A, et al: The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy. Sci Rep 2016;6:24136.
7
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
6 Eckel F, Schmid RM: Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896– 902. 7 Park I, Lee JL, Ryu MH, et al: Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy. Cancer 2009;115:4148–4155. 8 Fornaro L, Cereda S, Aprile G, et al: Multivariate prognostic factors analysis for secondline chemotherapy in advanced biliary tract cancer. Br J Cancer 2014;110:2165–2169. 9 McNamara MG, Templeton AJ, Maganti M, et al: Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer. Eur J Cancer 2014;50:1581–1589. 10 Peixoto RD, Renouf D, Lim H: A population based analysis of prognostic factors in advanced biliary tract cancer. J Gastrointest Oncol 2014;5:428–432. 11 Everhart JE, Ruhl CE: Burden of digestive diseases in the United States part II: lower gastrointestinal diseases. Gastroenterology 2009; 136:741–744. 12 Patel T: Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002; 2:10.
Oncology DOI: 10.1159/000480703
Prognostic Factors for Survival in Patients with Advanced Intrahepatic Cholangiocarcinoma Treated with Gemcitabine plus Cisplatin as First-Line Treatment Utako Ishimoto Shunsuke Kondo Akihiro Ohba Mitsuhito Sasaki Yasunari Sakamoto Chigusa Morizane Hideki Ueno Takuji Okusaka Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
Keywords Cholangiocarcinoma · Gemcitabine · Biliary tract cancer · Intrahepatic cholangiocarcinoma · Prognostic factors
reliably predicted the prognosis of ICC patients receiving GC therapy. If validated in other studies, these results may provide a useful tool for individual patient-risk evaluation and the design and interpretation of future trials. © 2017 S. Karger AG, Basel
© 2017 S. Karger AG, Basel E-Mail [email protected] www.karger.com/ocl
Introduction
Worldwide, biliary tract cancer (BTC) is a rare type of cancer, though it is more prevalent in East Asian and Latin American countries [1, 2]. Patients with advanced BTC are a heterogeneous group, characterized by both locally advanced and metastatic disease, as well as a variety of primary disease sites (intrahepatic bile ducts, extrahepatic bile ducts, gallbladder, and ampulla). Surgery represents the only curative option, but 3.0, multiple metastatic sites, an intrahepatic primary site the presence of liver metastases, the number of sites of advanced disease, a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and elevated levels of serum alkaline phosphatase (ALP) were reported to be significant poor prognostic factors of overall survival (OS) [7–10]. Intrahepatic cholangiocarcinoma (ICC) is the secondmost common type of primary liver cancer, and its incidence increased by 22% between 1979 and 2004 in the United States [11]. Several studies have reported an increasing global incidence and mortality rate for ICC, in contrast with decreasing rates for extrahepatic cholangiocarcinoma (ECC) [12]. Patients with resectable ICC tend to have a better prognosis than patients with ECC. The median survival time for resected ICC patients has been reported to range from 9 to 30 months [13–15]. With regard to surgery for ICC, lymph node involvement is an important prognostic factor [16]. On the other hand, no useful clinical prognostic factors have been reported in patients with advanced and recurrent ICC treated with GC as first-line chemotherapy. In the present study, we aimed to evaluate the clinical prognostic factors for patients with advanced ICC receiving GC as standard firstline chemotherapy.
tients (40.3%) complained of pain as the first symptom. Forty-one patients (53.2%) had an ECOG PS of 0. UICCTNM stage was stage III in 2 patients (2.6%), stage IVA in 9 patients (11.7%), stage IVB in 48 patients (62.3%), and recurrent in 18 patients (23.4%). Twenty-four patients (31.2%) had prior biliary intervention. The median results of the pretreatment laboratory tests are shown in Table 2. Response Rate and Tumor Control Rate Among the 77 evaluable patients, 1 (1.2%) had a complete response, 7 (9.0%) had partial responses, 45 (58.4%) had stable disease, 18 (23.3%) had progressive disease, and 6 (7.8%) had a nonevaluable response, resulting in a disease control rate of 68.8%. Survival Distribution The median PFS was 4.47 months (95% confidence interval [CI], 2.75–6.19) and the median OS was 13.8 months (95% CI, 8.9–18.6) (Fig. 1a, b). Univariate analysis indicated that pain complaint (p = 0.002), ECOG PS ≥1 (p = 0.038), LDH >220 U/L (p = 0.023), Alb 450 IU/L (p = 0.002), CRP >1.0 mg/dL (p = 0.001), CA 19-9 >1,000 U/mL (p = 0.002), and CEA >5.0 ng/mL (p = 0.001) were statistically associated with a poorer prognosis. Multivariate analysis showed that LDH >220 U/L (HR: 2.53; 95% CI 1.33–4.82, p = 0.005), CRP >1.0 mg/dL (HR: 3.06; 95% CI 1.52–6.15, p = 0.001), and CEA >5.0 ng/mL (HR: 2.37; 95% CI 1.11–5.15, p = 0.03) remained significantly associated with prognosis (Table 3; Fig. 2). Elevations of LDH, CRP, and CEA levels might be prognostic factors in patients with advanced ICC treated with GC.
Table 1. Patient characteristics (n = 77)
Median age (range), years Sex Male Female Pain complaint as first symptom Yes No ECOG PS 0 1 2 Biliary intervention Yes No UICC-TNM stage III IVA IVB Recurrence Median tumor size (range), mm Primary tumor lesion Peripheral Central Macroscopic characteristics of tumor Mass forming Periductal infiltrating Intraductal growth Mass forming + periductal infiltrating Unknown Surgical resection Yes No Length of time from surgical resection to recurrence (range), months
64 (38 – 80) 50 27 31 46 41 35 1 24 53 2 9 48 18 66.6 (13.2 – 169.6) 42 35 57 5 0 13 2 19 58 11.2 (1.4 – 44.0)
ECOG PS, Eastern Cooperative Oncology Group performance status; UICC, Union for International Cancer Control.
Discussion
Prognostic Factors in ICC
Table 2. Median results (range) of the pretreatment laboratory test
White blood cell count, cells/μL 6,200 (3,100 – 14,300) Hemoglobin, g/dL 12.2 (8.1 – 16.6) Neutrophils, cells/μL 4,210 (1,450 – 13,160) Platelets, cells/μL 19.9 (7.9 – 48.7) C-reactive protein, mg/dL 1.18 (0.02 – 17.96) Lactate dehydrogenase level, U/L 205 (107 – 1676) Albumin, g/dL 3.7 (2.1 – 4.8) Total bilirubin, mg/dL 0.7 (0.3 – 3.0) Alkaline phosphatase level, IU/L 450 (157 – 1,649) Aspartate aminotransferase level, IU/L 35 (16 – 152) Alanine aminotransferase level, IU/L 25 (9 – 119) Carbohydrate antigen 19-9 level, U/mL 451 (0 – 172,000) Carcinoembryonic antigen level, ng/dL 2.9 (0.6 – 511)
Oncology DOI: 10.1159/000480703
3
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
GC is widely used for the treatment of advanced ICC patients in clinical practice. The current study identified several reliable prognostic factors in patients with advanced ICC receiving GC as standard chemotherapy. The pretreatment serum levels of LDH, CRP, and CEA were significant prognostic factors. Because these values are readily available and easily measured, they are of potential widespread use in patients who are going to receive first-line chemotherapy. ICC is optimally managed with hepatic resection. However, ICC often presents at an advanced stage, and in some series only 15–20% of the patients have resectable tumors [15]. Patients with advanced BTC have an ex-
1.0 +
1.0 +
Median PFS 4.47 months
0.8
Probability, %
+ + + +
0.6
0.6
0.4
Median OS 13.8 months
+ + + + + + 0.8 +++ + + +
+ ++
+ + + + +
0.4
+
+ ++
+
0.2
0
a
+
0.2
+ +
0
5
10 15 PFS, months
+
20
0
b
+
0
10
20 30 OS, months
40
50
Fig. 1. Kaplan-Meier estimates of progression-free survival (PFS; a) and overall survival (OS; b).
Table 3. Univariate and multivariate analysis for overall survival
Factor
Sex Pain complaint ECOG PS >1 Biliary intervention Tumor size >66.6 mm Primary tumor location White blood cell count >6,200 cells/μL Hemoglobin concentration >12.2 g/dL Platelet count >20.0 cells/μL Lactate dehydrogenase level >220 U/L Albumin concentration 35 IU/L Alanine aminotransferase level >25 IU/L Alkaline phosphatase level >450 IU/L C-reactive protein level >1.0 mg/dL Carbohydrate antigen 19-9 >1,000 U/mL Carcinoembryonic antigen level >5.0 ng/mL
Univariate analysis
Multivariate analysis
HR (95% CI)
p value
1.24 (0.64 – 2.38) 2.08 (1.10 – 3.93) 1.93 (1.04 – 3.60) 1.07 (0.55 – 2.09) 1.20 (0.66 – 2.21) 1.28 (0.81 – 2.03) 1.12 (0.62 – 2.05) 0.78 (0.42 – 1.45) 1.08 (0.58 – 2.02) 2.01 (1.10 – 3.68) 2.00 (1.06 – 3.85) 0.95 (0.51 – 1.75) 1.40 (0.75 – 2.57) 2.41 (1.43 – 5.49) 2.86 (1.50 – 5.46) 2.77 (1.45 – 5.29) 3.39 (1.60 – 7.17)
0.52 0.002 0.038 0.83 0.55 0.28 0.71 0.43 0.81 0.023 0.031 0.87 0.29 0.002 0.001 0.002 0.001
HR (95% CI)
p value
1.73 (0.87 – 3.41) 1.67 (0.88 – 3.20)
0.12 0.12
2.53 (1.33 – 4.82) 1.21 (0.52 – 2.85)
0.005 0.67
1.50 (0.69 – 3.26) 3.06 (1.52 – 6.15) 1.67 (0.69 – 4.03) 2.39 (1.11 – 5.15)
0.30 0.001 0.25 0.03
HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
4
Oncology DOI: 10.1159/000480703
BTC tumors [20]. In the meta-analysis, the OS of patients with ICC and ECC was higher than that of those with carcinomas of the gallbladder and ampulla. In the present study, the median OS of 13.8 months is longer than that previously reported in BTC patients, and the present OS Ishimoto/Kondo/Ohba/Sasaki/Sakamoto/ Morizane/Ueno/Okusaka
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
tremely poor prognosis with a median OS of 7.3–12.0 months [5, 7, 18, 19]. Phase II and III trials were conducted in 2010 in patients with advanced BTC including ICC, and a meta-analysis showed that ICC patients benefited more from GC therapy than did those patients with other
+ 1.0 ++
+ +++ ++++
LDH 200 U/L LDH > 200 U/L
+
0.8
1.0 +
0.8
Probability, %
+ +
0.6
CRP 1.0 mg/dL CRP > 1.0 mg/dL
+ + ++
+ +
0.4
+ + +
0.6
+
+
+
+
+++
++
0.4
+
+
+
0.2
0.2
++ +
0
a
0
15
30 OS, months
1.0 +
+
0
45
b
0
15
30 OS, months
45
CEA 5.0 ng/mL CEA > 5.0 ng/mL
++ +++
0.8
Probability, %
+ +
0.6
+
+ +
0.4
++ +
0.2
0
c
+
0
15
30 OS, months
45
Fig. 2. Kaplan-Meier estimates of overall survival according to LDH (a), CRP (b), and CEA (C). OS, overall sur-
data suggests that patients with ICC might have a better prognosis than those with other BTCs. In the present study, pretreatment CEA levels were associated with the prognosis of patients with advanced ICC. ICC is associated with a different clinical, laboratory, and radiologic presentation than that of perihilar or distal cholangiocarcinomas. CEA levels alone are neither sensitive nor specific for BTC. Moreover, the most widely studied tumor markers are CEA and CA 19-9, and both can be elevated in BTC patients [21–23]. Using the combination of CEA and CA 19-9 levels may be useful. In ad-
dition, there has been recent interest in the use of CA 242 and CA 125 for the diagnosis of BTC. ICC frequently arises under conditions of inflammation, which is believed to contribute to the pathogenesis of this tumor. A variety of cytokines, growth factors, tyrosine kinases, and bile acids can contribute to the alterations in proliferation, apoptosis, senescence, and cell-cycle regulation required for cholangiocarcinogenesis [21]. Inflammatory cytokines activate inducible nitric oxide synthase, leading to excess nitric oxide with resultant single-stranded, double-stranded, and oxidative DNA le-
Prognostic Factors in ICC
Oncology DOI: 10.1159/000480703
5
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
vival; LDH, lactate dehydrogenase; CRP, C-reactive protein; CEA, carcinoembryonic antigen.
6
Oncology DOI: 10.1159/000480703
holds great promise for the next stage of targeted chemotherapies. We are confident that the present study has revealed clinically important prognostic factors, aiding the development of successful therapies for ICC. In conclusion, our model is based on several readily available clinical and laboratory factors, which reliably identify different factors in ICC patients receiving GC therapy. If validated in future studies, these factors may provide a useful tool for individual patient-risk evaluation and aid in the design and interpretation of future trials. Finally, further research on the biological mechanisms leading to the formation of ICC and the development of targeted therapeutic agents is warranted in order to advance the therapeutic armamentarium against this aggressive disease.
Acknowledgements We express our appreciation to Rubi Mukoyama, Keiko Kondo, and Hiroko Hosoi for collecting the clinical data. This work was supported in part by the Japan Society for the Promotion of Science Kakenhi.
Statement of Ethics This study was approved by the Institutional Review Board of the National Cancer Center Hospital, and all patients provided written informed consent.
Disclosure Statement The authors report no potential conflicts of interest.
References
1 Randi G, Malvezzi M, Levi F, et al: Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146–159. 2 Matsuda T, Marugame T: International comparisons of cumulative risk of gallbladder cancer and other biliary tract cancer, from Cancer Incidence in Five Continents Vol. VIII. Jpn J Clin Oncol 2007;37:74–75. 3 de Groen PC, Gores GJ, LaRusso NF, et al: Biliary tract cancers. N Engl J Med 1999;341: 1368–1378. 4 Charbel H, Al-Kawas FH: Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep 2011; 13:182–187. 5 Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–1281.
Ishimoto/Kondo/Ohba/Sasaki/Sakamoto/ Morizane/Ueno/Okusaka
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
sions, as well as the inhibition of DNA repair enzymes [22]. Therefore, inflammatory signaling pathways appear to promote the development of ICC by causing DNA damage and blocking the apoptosis normally induced by the DNA damage response. These cytokines also promote cell proliferation. The combination of DNA damage, inhibition of apoptosis, and promotion of cell proliferation are all components of cell transformation. Interest in inflammation influencing cancer outcome is increasing, in part because of the potential impact of the Glasgow Prognostic Score, based primarily on CRP and Alb levels [23]. In our study, an elevated CRP level was associated with a poor prognosis. Therefore, we suggest that chronic inflammation might be associated with the molecular pathogenesis of ICC. LDH levels were shown to be significant prognostic factors in our study. LDH is a glycolytic enzyme, composed of 4 polypeptide chains, each one encoded by a separate gene (M and H), with a key role in the conversion of pyruvate to lactate under anaerobic conditions. Five isoforms of LDH have been identified as a result of the 5 different combinations of polypeptide subunits. The biological link between hypoxia, LDH levels, and the tumordriven angiogenesis pathway through the abnormal activation of the hypoxia-inducible factor 1α is well established. Since LDH and pro-angiogenesis factors are regulated by the same hypoxia-inducible factor 1α-driven molecular pathway, high LDH levels are usually concomitantly present with the abnormal activation of the vascular endothelial growth factor (VEGF) pathway. It has been in fact demonstrated that high LDH serum levels were associated with tumor overexpression of VEGFA and VEGF receptors in many tumor types. It has been postulated that LDH levels may represent an indirect marker of activated tumor angiogenesis and a worse prognosis [24]. The present study has several limitations, including its retrospective nature and single institution origin, and our findings require further validation. We defined cutoff points as the median value of each variable. LDH and CEA cutoff points were established by the upper limits of normal, and CA19-9 was dichotomized according to values >1,000 U/mL in the multivariate analysis. There have been debates regarding the proper definition and clinical implications of cutoff points. BTC is a rare cancer with heterogeneous characteristics, comprising both locally advanced and metastatic disease, a variety of primary disease sites, and varied histological and genetic findings. The recent genomic analysis of ICC, showing FGFR2 fusion and IDH1/2 mutations,
Prognostic Factors in ICC
13 Pichlmayr R, Lamesch P, Weimann A, et al: Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:83–88. 14 Yamamoto J, Kosuge T, Takayama T, et al: Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111:617–622. 15 Schlinkert RT, Nagorney DM, Van Heerden JA, Adson MA: Intrahepatic cholangiocarcinoma: clinical aspects, pathology and treatment. HPB Surg 1992; 5: 95–101; discussion 101–102. 16 de Jong MC, Nathan H, Sotiropoulos GC, et al: Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140–3145. 17 Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. 18 Furuse J, Okusaka T, Funakoshi A, et al: Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer. Jpn J Clin Oncol 2006;36: 552–556.
Oncology DOI: 10.1159/000480703
19 Grenader T, Waddell T, Peckitt C, et al: Prognostic value of neutrophil-to-lymphocyte ratio in advanced oesophago-gastric cancer: exploratory analysis of the REAL-2 trial. Ann Oncol 2016;27:687–692. 20 Valle JW, Furuse J, Jitlal M, et al: Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014;25:391–398. 21 Blechacz BG, Gores GJ: Tumors of the bile ducts, gallbladder, and ampulla. In: Feldman (ed): Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, vol 1, ed 9. Philadelphia, Saunders, 2010, pp 1171–1176. 22 Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ: Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000;60:184–190. 23 Proctor MJ, Talwar D, Balmar SM, et al: The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow Inflammation Outcome Study. Br J Cancer 2010;103:870–876. 24 Faloppi L, Del Prete M, Casadei Garnidi A, et al: The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy. Sci Rep 2016;6:24136.
7
Downloaded by: Göteborgs Universitet 130.241.16.16 - 10/15/2017 5:17:54 PM
6 Eckel F, Schmid RM: Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896– 902. 7 Park I, Lee JL, Ryu MH, et al: Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy. Cancer 2009;115:4148–4155. 8 Fornaro L, Cereda S, Aprile G, et al: Multivariate prognostic factors analysis for secondline chemotherapy in advanced biliary tract cancer. Br J Cancer 2014;110:2165–2169. 9 McNamara MG, Templeton AJ, Maganti M, et al: Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer. Eur J Cancer 2014;50:1581–1589. 10 Peixoto RD, Renouf D, Lim H: A population based analysis of prognostic factors in advanced biliary tract cancer. J Gastrointest Oncol 2014;5:428–432. 11 Everhart JE, Ruhl CE: Burden of digestive diseases in the United States part II: lower gastrointestinal diseases. Gastroenterology 2009; 136:741–744. 12 Patel T: Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002; 2:10.
