The prognosis of patients with intrahepatic cholangiocarcinoma after liver resection Hsiao-Tien Liu, Chia-Yu Lai, Yi-Ju Chen, Shao-Bin Cheng, Cheng-Chung Wu Division of general surgery, Department of surgery, Taichung Veterans General Hospital

Introduction Intrahepatic cholangiocarcinoma is the most common biliary cancer and the second most common primary liver cancer in the word. (Everhart et. al., 2009, Gastoenterology 136:1134-144; Primary liver cancer in Japan, 1990, Ann Surg 211:277-287.) The prognostic factors vareis in articles, including tumor size, tumor number, vessles invasion, peri-ductal infiltrating, surgical margin, level of serum carcinoembryonic antigen (CEA) or serum carbohdrate antigen 19-9 (CA19-9). (Uenishi et. al., 2014, J Hepatobiliary Pancreat Sci 21:499-508; Cho et. al., 2010, Ann Surg Oncol 17:1823-1830; Hirohashi et. al., Hepatogastroenterology 49:326-329; Spolverato et. al., 2015, Cancer 121:3998-4006; Chang et. al., 2017, J Chin Med Assoc: Epub) We conducted a retrospective study to evaluate the prognostic factors in patients with intrahepatic cholangiocarcinoma after curative liver resection.

Method and material Retrospective data collection between Feb. 1999 and Dec. 2014. Patients with distant metastases and combined hepatocellular/cholangiocellular carcinoma were excluded. Perioperative fectors: age, gender, bilirubin (Bil), alanine aminotransferase (ALT), alkaline phosphatase (Alk-P), CEA, CA19-9, Creatitine (Cr), albumin (Alb), indocyanin green retention rate 15 minutes (ICGR15), hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibody (AntiHCV), alpha-feto protein (AFP), CEA, CA19-9, blood loss, blood transfusion. Pathologic factors: tumor size, tumor number, vessel invasion, perineural invasion, peri-ductal infiltration, surgical margin. Post-operative lomg-term result: overall survives. Statistics: continuous variables showed as mean±standard deviation(SD). Survives revealed by Kaplan-Meier method. Univariate/multivariate comparison performed by log-rank and Cox regession methods. P < 0.05 as significant.

Result - demography Total N = 65 Age (year-old) 62.7±9.6 38 – 81 Gender (female/male) 30/35 46%/54% HBsAg 17 26.1 % Anti-HCV 10 15.3 % ICGR15 (%) 10.4±4.9 3.6 – 24.3 CA19-9 (unit/ml) 1368.5±4358.6 0.0 – 20000.0 CEA (ng/ml) 9.0±25.2 0.0 – 112.0 AFP (ng/ml) 128.4±593.5 1.2 – 4041.0 ALT (U/L) 33.2±22.3 9.0 – 107.0 Alk-P (U/L) 157.2±95.2 50.0 – 527.0 Bil (mg/dl) 0.7±0.4 0.1 – 2.8 Alb (g/dl) 4.0±0.4 2.8 – 5.0 Cr (mg/dl) 0.9±0.4 0.4 – 3.0

Result – surgicopathological features Total N = 65 Blood loss (ml) 658.0±535.5 100 - 3150 Red bood cell transfusion 22 33.8% Tumor size (cm) 5.9±3.4 1.4 – 21.0 Periductal infiltration 19 29.2% Solitary tumor 52 83.8% Vascular inasion 21 32.3% Perineual invasion 17 26.1% R1 resection (positive margin ) 18 27.6% Lymph node metastasis 9 13.8% Cirrhosis 6 9.2 % Poorly differentiation 37 56.9%

Result – complications and long-term survives Dindo-Clavien I II III IV V n 8 5 3 Bile leakage (5) DVT (1) Delirium (1) HBV flare-up (1) Abscess Biloma Liver failure (2) Sepsis (1) Mortality (90d) 4.6% Morbidity 24.6% 1-yr: 73.2% 3-yr: 44.4% 5-yr: 41.9%

Result – univariant analysis Ovrall 5-year survival rate P value Gernder (Male;Female) 34.2%;49.6% 0.195 Age (≧65 year;＜65year) 48.0%;35.1% 0.779 CA19-9 (≧200U/ml; ＜200U/ml) 0%;45.5% 0.000 CEA (≧5ng/ml; ＜5ng/ml) 16.7%;45.0% 0.072 Red blood transfusion (Yes;No) 34.9%;44.6% 0.101 R1 resection (Yes;No) 24.5%;46.7% 0.124 Tumor size (＞5cm; ≦5cm) 26.5%;54.4% 0.004 Tumor number (Multiple;Solitary) 0%;51.7% Periductal invasion (Yes;No) 0%;55.7% Vascular invasion (Yes;No) 25.6%;50.0% 0.043 Perineual invasion (Yes;No) 0%;52.5% 0.002 Lymph node mets (Yes;No) 0%;49.1% Cirrhosis (Yes;No) 66.7%;39.0% 0.986 Poorly differentiation (Yes;No) 30.3%;67.2% 0.119

Result – multivariant analysis Hazard ratio P value CA19-9 (≧200U/ml; ＜200U/ml) 3.904 0.104 CEA (≧5ng/ml; ＜5ng/ml) 0.848 0.822 Tumor size (＞5cm; ≦5cm) 3.354 0.004 Tumor number (Multiple;Solitary) 2.725 0.058 Periductal invasion (Yes;No) 3.559 0.019 Vascular invasion (Yes;No) 1.520 0.338 Perineual invasion (Yes;No) 0.876 0.809 Lymph node mets (Yes;No) 1.799 0.264 Poorly differentiation (Yes;No) 1.236 0.625

Discussion Tumor size and number are the well documented prognostic factors and also are included in staging of American Joint Committee on Cancer 8th edition. Periductal infiltration is controversial in certain articles especially while associated with major biliary invasion, lymph node invasion, and limited resection margin. (Sakamoto et. al., 2016, Cancer 122:61-70; Hirohashi et. al., 2002, Hepatogastroenterology 49:326-329) The cut-off value of serum CA19-9 and CEA varies in articles and still directly influences prognosis. (Yeh et. al., 2016, Anticancer Res 36:4249-4258; Chang et. al., 2017, J Chin Med Assoc: Epub; Cho et. al., 2010, Ann Surg Oncol 17:1823-1830. Wang et. al., 2013, J Clin Oncol 31:1188-1195; Ohtsuka et. al., 2002, BJS 89:1525-1531)

Discussion Although there is no statistic significance of surgical margin for prognosis in our study, attempting to R0 surgery is still important. (Hirohashi et. al., 2002, Hepatogastroenterology 49:326-329; Yeh et. al., 2016, Anticancer Res 36:4249-4258; Cho et. al., 2010, Ann Surg Oncol 17:1823-1830; Ohtsuka et. al., 2002, BJS 89:1525-1531) Limitation: only patients with liver resection were included, lymph node status depended on range of lymphadenectomy, no routine post-operative adjuvant chemotherapy.

Conclusion Primary tumor behaviors (size, number, periductal infiltration) are the most important prognostic factor in patients with intrahepatic cholangiocarcinoma. Overall 5-year survival rate is below 50% in all articles, adjuvant chemotherapy might be considered in patients with poor prognostic features in the future.

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