Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence

This study included patients with ICC who underwent surgical treatment with curative resection between January 1977 and December 2014 at Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan. A retrospective review of all medical records was performed under the approval of the Institutional Review Board of Chang Gung Memorial Hospital (Approval No.: 201701127B0). The medical records, including clinical characteristics, surgical management, and outcomes were thoroughly reviewed and analyzed. Patients who had no curative resection with macroscopically and/or microscopically positive of carcinoma at the resection margin were not included in the study. Therefore, a total of 225 patients who had pathological confirmation of cholangiocarcinoma were retrieved. After exclusion of 9 patients (4%) with postoperative hospital mortality, 216 patients [99 men (45.8%) and 117 women (54.2%)] were recruited and analyzed for this study.

Transection of hepatic parenchymal was performed using either the surgical clamp-crush technique or a Cavitron Ultrasonic Surgical Aspirator (CUSA; Valleylab, Inc., Integra LifeSciences, Plainsboro, NJ). However, liver resection was mostly performed by CUSA transection after it was introduced into our institute in 2002. After the operation, all patients were followed-up at regular intervals until death or the end of the current study. The clinical assessments included physical examination, blood chemistry tests, measurement of tumor-markers, and abdominal ultrasonography every 3–6 months. A comprehensive assessment was done using computed tomography (CT) and/or magnetic resonance imaging (MRI) on an annual basis or when suspicious of cancer recurrence.

Based on the pathological examination, cancer was staged according to the 7th edition of tumor-node-metastasis (TNM) classification proposed by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) to classify the extent of cholangiocarcinoma. Patients who had cancer staged by former version of classification system were restaged by the 7th edition of UICC/AJCC classification. The administration of postoperative adjuvant chemotherapy was optional and mainly based on tumor characteristics, patient’s physical condition, and availability or affordability of chemotherapeutic regimens. The chemotherapeutic options were mostly fluorouracil plus leucovorin and/or a combination of regimens such as cisplatin, mitomycin, oxaliplatin, gemcitabine, and so on.

Disease recurrence was determined by a tissue sample from either a biopsy or surgical resection confirming cholangiocarcinoma, and/or by serial imaging examinations. Generally, the treatment algorithm of recurrent cholangiocarcinoma after surgical resection was the same as that for the initial management of cholangiocarcinoma. Repeat surgical resection was the preferred treatment whenever the recurrent tumor was considered to be resectable. Palliative chemotherapy was usually recommended for patients who had unresectable recurrent tumor or not received reoperation unless a patient was unsuitable for chemotherapy or unwilling to receive chemotherapy.

The end-point outcome measures included recurrence-free survival (RFS) and overall survival (OS). RFS was defined as the date of liver resection to the date of detected cholangiocarcinoma recurrence or the date of the last follow-up if there was no cancer recurrence. OS was measured from the date of liver resection to the date of death or the date of the last follow-up by the end of this study. Survival curves were constructed using the Kaplan–Meier method and analyzed by means of the log-rank test. The categorical variables were assessed using the χ² or Fisher exact test as appropriate, and the independent samples t-test was used for continuous data. Variables were analyzed using a Cox regression proportional hazards model to identify factors influencing RFS and OS. All significant factors determined by univariate analysis were then entered into a multivariate analysis using the Cox proportional hazards regression model. All statistical analyses were performed using SPSS statistical software version 20.0 (SPSS, Inc., Chicago, IL) for Windows. A P-value of less than 0.05 was considered to be statistically significant.

Table 1 summarizes the clinical features of the 216 patients who underwent curative-intent liver resection for ICC in this study. The median age of patients at the time of initial diagnoses was 60-years-old and ranged from 29 to 90-years-old. The majority of patients (90.3%) were not associated with liver cirrhosis, and 23.2% of patients were noted as having the simultaneous presence of hepatolithiasis in the biliary tree. Of these, major hepatectomy (≥ 3 hepatic segments according to Couinaud’s definition) was performed for 126 patients (58.3%), and the remaining 90 patients (41.7%) underwent minor hepatectomy (< 3 hepatic segments). Meanwhile, 11 patients (5.1%) underwent simultaneous bile duct resection. The majority of patients (50.9%) underwent liver resection during the last decade of the study period.

The median follow-up time for all patients was 26.9 months (range, 1.7 to 268). Overall, 160 patients (74.1%) encountered cancer recurrence after liver resection, and 56 (25.9%) patients had no cancer recurrence by the date of last follow-up or the end of this study. Meanwhile, 168 (77.8%) patients had died during the follow-up period, in which 145 (67.1%) patients died of cholangiocarcinoma, and 23 (10.6%) patients died of diseases other than cholangiocarcinoma. Only 42 (19.4%) patients were still alive by the end of the study, including 28 (13.0%) patients who were cancer free and 14 (6.5%) patients alive with recurrent cholangiocarcinoma. The remaining 6 (2.8%) patients were lost during the follow-up period. The RFS and OS curves are shown in Fig. 1. The 1-, 3-, and 5-year RFS rates were 57.5, 33.0, and 26.1% respectively, and the 1-, 3-, and 5-year OS rates were 84.2, 45.7, and 33.9% respectively.

The prognostic factors affecting cholangiocarcinoma recurrence after curative-intent liver resection were analyzed and summarized in Table 2. Univariate analysis identified nine significant factors including morphology patterns, histologic differentiation, maximum tumor size, pathological T stage, pathological N stage, vascular invasion, perineural invasion, and postoperative adjuvant chemotherapy. Subsequently, multivariate regression analysis of these significant factors showed that morphology patterns, maximum tumor size > 5 cm, pathological lymph node involvement, and vascular invasion were independent risk factors for cholangiocarcinoma recurrence after liver resection.

Of the 160 patients who developed cancer recurrence after curative-intent liver resection, 38 (23.8%) patients occurred only at the intrahepatic area, 57 (35.6%) patients had locoregional recurrence with (n = 22) or without (n = 35) intrahepatic recurrence, and 65 (40.6%) patients had distant metastasis at the detection of cancer recurrence. Table 3 summarizes the location of cholangiocarcinoma recurrence. Only 27 (16.9%) patients were able to receive surgical resection for recurrent lesions. The overall survival based on recurrent patterns showed that patients with intrahepatic recurrence had better survival than those with the other recurrence types. The 5-year survival rates were 14.5, 8.3, and 0% for intrahepatic recurrence, locoregional recurrence, and distant metastasis respectively (Fig. 2). The survival curve of patients who had undergone repeat surgical resection for recurrent cholangiocarcinoma was better than that of patients who were unable to undergo surgical resection, in which the 5-year survival rates after cholangiocarcinoma recurrence were 32.5%. With regard to patients without surgical treatment for recurrent cholangiocarcinoma, the survival curve of patients who had received palliative chemotherapy was better than that of patients without palliative chemotherapy. The 5-year survival rate of patients with palliative chemotherapy was 5.4%, and patients without palliative chemotherapy could not survive more than 5 years reflected by 0% of 5-year survival rate (Fig. 3).