Abstract: Objective:To investigate the longterm outcomes of liver resection in the treatment of 1 370 patients with intrahepatic cholangiocarcinoma (ICC) and the related factors affecting tumor recurrence and patients′ prognosis. Methods:The retrospective cohort study was adopted. The clinicopathological data of 1 370 patients with ICC who underwent liver resection at the Eastern Hepatobiliary Surgery Hospital between January 2005 and December 2012 were collected. Patients received laboratory and imaging examinations, and then surgical plan was determined according to the preoperative results. Observation indicators included (1) preoperative examinations results: liver function, tumor markers and imaging examination, (2) surgical treatment: surgical procedures, operation time, volume of intraoperative blood loss, intraoperative blood transfusion, hepatic inflow occlusion, postoperative complications and duration of hospital stay, (3) postoperative pathological examination: tumor differentiation, vascular invasion, lymph node metastasis, local invasion and TNM stage, (4) results of followup: tumor metastasis and postoperative survival. (5) There were univariate analysis and multivariate analysis affecting postoperative tumor early recurrence. (6) There were univariate analysis and multivariate analysis affecting postoperative patients′ prognosis. (7) Patients′ survival risk was stratified to 3 subgroups, namely, low score group, median score group and high score group, based on tertiles of their nomogram scores. The followup using outpatient examination, telephone interview and letters was performed once every 2-3 months within 2 years postoperatively and once every 3-6 months after 2 years postoperatively up to November 15, 2014. The followup included that data collection of medical history and physical examination, levels of CA19-9, carcinoembryonic antigen (CEA) and alphafetoprotein (AFP), liver function, routine blood test, chest Xray and abdominal ultrasound. The above examinations were applied to patients in advance who were confirmed as suspected recurrence. Diagnosis of recurrence depended on results of imaging examination and clinical manifestations. Continuous variables were represented as M (range). Normality test was done using the ShapiroWilk test, and comparisons among groups with nonnormal distribution and normal distribution were analyzed by the MannWhitney U test and t test, respectively. Ctegorical variables were analyzed using the chisquare test or Fisher′s exact test. Postoperative recurrence rate and overall survival of patients were calculated by the life table method. The survival curve was drawn by the KaplanMeier method, and the survival rate was analyzed using the Logrank test. The univariate analysis and multivariate analysis were done using the COX regression model. The concordance index (cindex) of survival probability was predicted by the nomogram and calibration curve was done by the R version 2.14.1.
Results:(1) Results of preoperative examinations in 1370 patients with ICC: liver function: levels of glutamyltranspeptidase (GGT), total bilirubin (TBil), glutamicpyruvic transaminase (GPT), albumin (Alb) and platelet (PLT) were 71.9 U/L(range, 40.0-162.0 U/L), 12.7 μmol/L(range, 9.7- 17.2 μmol/L), 27.4 U/L(range, 18.0-45.0 U/L), 42.2 g/L(range, 39.5-44.9 g/L) and 191×109/L［range, (145-237)×109/L］, respectively. Tumor markers: levels of AFP, CA19-9 and CEA were respectively 3.8 μg/L (range, 2.3-9.5 μg/L), 44.2 U/mL(range, 16.3 U/mL-257.6 U/mL) and 2.7 μg/L(range, 1.6-5.3 μg/L). Results of imaging examination: tumor diameter was 5.7 cm(range, 4.0-8.0 cm). There were 978 patients with solitary tumors, 392 with multiple tumors, 1 069 without liver cirrhosis and 301 with liver cirrhosis. (2) Surgical treatment: all the 1370 patients with ICC underwent liver resection, including 454 patients with number of hepatic segments resected≥3 and 916 with number of hepatic segments resected<3. Operation time, volume of intraoperative blood loss, number of patients with blood transfusion and complications and duration of hospital stay were 120.0 minutes (range, 60.0-280.0 minutes), 300 mL(range, 50.0-8 000.0 mL), 261, 408 and 16.0 days (range, 13.0-20.0days), respectively. There were 411 patients with hepatic flow occlusion time>20 minutes and 959 patients with hepatic flow occlusion time<20 minutes. (3) Postoperative pathological examination: of 1370 patients with ICC, 32, 1 198 and 140 patients were respectively detected in the high, moderate and lowdifferentiated tumors, 203, 270 and 97 patients had respectively vascular invasion, lymph node metastasis and local invasion, and 706, 327, 57 and 280 patients were detected in stage Ⅰ, Ⅱ, Ⅲ and Ⅳ of TNM stage. (4) Results of followup: 1 359 were followed up for a median time of 23.5 months (range, 1.0-103.3 months). A median tumor recurrence time, 1, 3 and 5 year recurrence rates were 16.2 months (range, 13.9-18.5 months), 42.8%, 67.5% and 75.4%, respectively. There were 555 patients with early recurrence. A median survival time, 1, 3 and 5 year overall survival rates were 26.1 months(range, 23.4-28.7 months), 68.0%, 41.9% and 32.5%, respectively. (5) Results of univariate analysis showed that GGT, AFP, CA19-9, CEA, tumor diameter, number of tumors, method of liver resection, intraoperative blood transfusion, vascular invasion, lymph node metastasis and local invasion were risk factors affecting tumor early recurrence after liver resection of ICC ［HR =1.313, 1.217, 1.352, 1.346, 1.476, 1.928, 1.241, 1.295, 2.180, 2.152, 2.119, 95% confidence interval (CI): 1.133-1.521, 1.013-1.461, 1.167-1.567, 1.109-1.633, 1.271-1.715, 1.656-2.245, 1.067-1.445, 1.084-1.547, 1.815-2.619, 1.826-2.536, 1.655-2.715, P<0.05］. Results of multivariate analysis showed that tumor diameter > 5 cm, multiple tumors, vascular invasion, lymph node metastasis and local invasion were independent risk factors affecting tumor early recurrence after liver resection of ICC (HR=1.830, 1.598, 1.693, 1.773, 1.539, 95%CI: 1.098-1.497, 1.364-1.873, 1.395-2.054, 1.437-2.041, 1.190-1.989, P<0.05). (6) Results of univariate analysis showed that GGT, Alb, CA19-9, CEA, tumor diameter, number of tumors, method of liver resection, intraoperative blood transfusion, vascular invasion, lymph node metastasis and local invasion were risk factors affecting patients′ prognosis after liver resection of ICC (HR=1.401, 1.496, 1.759, 1.759, 1.588, 1.947, 1.284, 1.356, 2.052, 2.513, 2.357, 95% CI: 1.213-1.618, 1.144-1.955, 1.519-2.036, 1.469-2.106, 1.371-1.840, 1.679-2.257, 1.107-1.489, 1.143-1.608, 1.718-2.452, 2.142-2.948, 1.859-2.988, P<0.05). Results of multivariate analysis showed that CA19-9 > 39 U/mL, CEA >10 μg/mL, tumor diameter>5 cm, multiple tumors, vascular invasion, lymph node metastasis and local invasion were independent risk factors affecting patients′ prognosis after liver resection of ICC (HR=1.454, 1.276, 1.344, 1.588, 1.490, 1.949, 1.574, 95% CI: 1.245-1.697, 1.056-1.541, 1.155-1.565, 1.364-1.850, 1.235-1.797, 1.641-2.314, 1.228-2.018, P<0.05). (7) Cindex of 3, 5 year survival probability was 0.74 and 0.71, (95% CI: 0.71-0.77, 0.68-0.73). Calibration curve showed that there was a little difference between predicted probability and actual observation value, with a good curvefitting. There were 456 patients in high score group, 456 in median score group and 458 in low score group based on survival risk of nomogram scores. Levels of CA19-9 and CEA, tumor diameter, number of patients with 1 tumor, 2 tumors and tumors more than 3 or vessel system invasion, vascular invasion, lymph node metastasis and local invasion were 256.7 U/mL (range, 0.7-1 000.0 U/mL), 4.6 μg/L (range, 0.5-849.6 μg/L), 8.0 cm(range, 3.0-18.0 cm), 194, 332, 456, 113, 207, 98 in the high score group and 40.7 U/mL(range, 1.1- 1 000.0 U/mL), 2.5 μg/L(range, 0.7-45.7 μg/L), 6.0 cm(range, 2.0-14.8 cm), 160, 124, 2,67, 50, 19 in the median score groups and 19.5 U/mL(range, 0.6-239.1 U/mL), 2.1 μg/L(range, 0.4-7.5 μg/L), 4.6 cm (range, 1.2-7.4 cm), 102, 0, 0, 0, 0, 50 in the low score group, respectively, showing statistically significant differences in the above indexes among the 3 groups (Z=128.924, 74.923, 131.178, χ2=146.354, 50.298, 135.928, 60.936, P<0.05). The 5year recurrence rate and 5year overall survival rate in the high, median and low score groups were 93.5%, 78.2%, 57.4%; 9.4%, 28.3%, 55.6%, respectively, with statistically significant differences among the 3 groups (χ2=124.478, 161.025, P<0.05).Conclusions:Liver resection produces possible longterm survival in selected patients with ICC. Tumor diameter>5 cm, multiple tumors, vascular invasion, lymph node metastasis and local invasion are independent risk factors affecting tumor early recurrence after liver resection of ICC. CA19-9>39 U/mL, CEA>10 μg/mL, tumor diameter>5 cm, multiple tumors, vascular invasion, lymph node metastasis and local invasion are independent risk factors affecting patients′ prognosis after liver resection of ICC. The nomogram serves as an accurate stage tool to predict longterm outcomes.