Survival Rate of Extrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand

Cholangiocarcinoma (CCA), both intraand extrahepatic bile duct CCA, is the most common cancer in Thailand, especially in the northeast region. Khon Kaen is one of the provinces in the northeast region of Thailand, which has a very high incidence of CCA with age-standardized annual incidence rates of 36.3 and 87.7 per 100,000 population in females and males, respectively (Khuhaprema et al., 2010). Data from the hospital-based cancer registry of Srinagarind Hospital, a teaching hospital in Khon Kaen Province, show that many CCA patients come to seek treatment every year. For example, in 2009 there were 1,298 CCA patients (944 males, 354 females), who presented at the Srinagarind Hospital (Cancer Unit, Srinagarind Hospital, 2010). The incidence of this disease in Western countries is relatively low with diagnoses ranging 0.5-2 per 100,000 population (Anderson et al., 1992). The high incidence in Northeastern Thailand is probably due to environmental factors, especially the high local rates of infection by Opisthorchis viverrini, which is a strong risk factor for the subsequent development of


Introduction
Cholangiocarcinoma (CCA), both intra-and extrahepatic bile duct CCA, is the most common cancer in Thailand, especially in the northeast region.Khon Kaen is one of the provinces in the northeast region of Thailand, which has a very high incidence of CCA with age-standardized annual incidence rates of 36.3 and 87.7 per 100,000 population in females and males, respectively (Khuhaprema et al., 2010).
Data from the hospital-based cancer registry of Srinagarind Hospital, a teaching hospital in Khon Kaen Province, show that many CCA patients come to seek treatment every year.For example, in 2009 there were 1,298 CCA patients (944 males, 354 females), who presented at the Srinagarind Hospital (Cancer Unit, Srinagarind Hospital, 2010).The incidence of this disease in Western countries is relatively low with diagnoses ranging 0.5-2 per 100,000 population (Anderson et al., 1992).The high incidence in Northeastern Thailand is probably due to environmental factors, especially the high local rates of infection by Opisthorchis viverrini, which is a strong risk factor for the subsequent development of
CCA is a disease of the intrahepatic and extrahepatic bile duct, but does not include the papilla of Vater.Most CCA patients consult the doctor at a late stage of the cancer, and surgery is currently the best method of treatment.Due to the late stage of the CCA, the extent of metastases and an insufficient number of surgeons, surgery has been offered to only one-third of the patients (Uttaravichien et al., 1999;Ohtsuka et al., 2003).
Studies about survival rates or factors affecting the survival of CCA patients after resection, especially those with extrahepatic CCA, are rare, and the results vary from one country to another (Bhudhisawasdi, 1997;Khuntikeo, 2008;American Cancer Society, 2009;Unno et al., 2010).The aim of this study was therefore to evaluate the survival rates and factors affecting survival in extrahepatic CCA patients following surgical treatment at Srinagarind Hospital, Khon Kaen University, Thailand.

Materials and Methods
A retrospective cohort study was conducted with 58 patients, who were diagnosed (histologically confirmed) and treated by surgical excision by the same surgeon during the period 1 January, 2005, to 31 December, 2009, at Srinagarind Hospital, Khon Kaen, Thailand.The patients were followed up until death or the end of the study (31 December, 2011) performed.The dependent variable was the survival time of patients with extrahepatic cholangiocarcinoma.In order to calculate the survival time, the starting point was identified as the date of surgery, and the follow-up period ended when a patient died or on completion of the study.Censored data were used for those, who were still alive at the end of the study or lost to follow-up.The follow-up status of each patient was checked from medical records and by linkage with the death registry of the national statistics database.Descriptive statistics was used for exploratory data analysis.Percentages were used to describe categorical data, and means with standard deviations or medians with ranges were used to describe continuous data.The observed survival rate was calculated by the Kaplan-Meier method.Median survival times with 95% confidence intervals (CIs) and the log-rank test were used for comparisons between groups.The Cox proportional hazard regression model was used to assess associations between the various independent variables (covariates) and survival, and the adjusted hazard ratios were tested for significance with the partial likelihood test.The level of significance was set as p<0.05.All analyses were performed using STATA DOI:http://dx.doi.org/10.7314/APJCP.2013.14.1.321 Survival Rate of Extrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand version 10.0 (StataCorp LP, 2007).
The research was approved by the Khon Kaen University Ethics Committee for Human Research (reference no.HE541333).

Results
The characteristics of the 58 patients with extrahepatic CCA, who were included in the study, are shown in Table 1.Most of patients were male (69%), and the mean age was 56 years.Table 2 summarises the clinical features of the patients, their type of surgery and the outcome.Most patients were at a late stage, and 53.1% had a positive resection margin.By the end of the study, 50 (86.2%)had died.With a total follow-up time of 1,215 person-months, the mortality rate was therefore 50 per 100 person-years.

Discussion
The cumulative survival rates are consistent with the findings of previous studies (Neuhaus et al., 1999;Witzigmann et al., 2006;Li et al., 2011;Murakami et al., 2011).However, our findings are rather different from the from the lower survival rates found in some other studies (Bhudhisawasdi, 1997;Shi QF et al., 2007;Khuntikeo et al., 2008).The median survival in our study is similar to the median survival of 17 months found by Fuller et  Resection margin was found to be the significant factor affecting the survival of extrahepatic CCA patients after surgical resection.Our finding is in line with that of Kosuge et al. (1999), who found that patients with a positive resection margin (R1) had a 2.88 times higher mortality risk.The finding was also similar to those reported in other studies (Jarnagin et al., 2005;Witzigmann et al., 2006;Yubin et al., 2008;Unno et al., 2010;Murakami et al., 2011).
Cholangiocarcinoma is the most common cancer in the northeast area of Thailand, and extrahepatic bile duct cancer is part of this disease.This disease continues to be a major problem for public health in Thailand (Vatanasapt et al., 1993;Sriplung et al., 2005;2006;Khuhaprema et al., 2010).The survival rates of patients who suffer from this disease are rather short compared to those of other diseases (Sriamporn et al., 1995).From the health professional point of view, along with primary prevention, we recommend that improvements in surgical procedures for the treatment of this disease are necessary in order to increase survival times and quality of life.
In conclusion, resection margins are an important prognostic factor affecting survival of extrahepatic CCA patients after surgical treatment.A negative resection margin can reduce the mortality rate following surgery by 56%.An improvement in surgical procedures is a priority.

Figure 1 .
Figure 1.Survival Curve of Extrahepatic Cholangiocarcinoma Patients after Surgical Treatment.A) Gender, B) Stage, C) Resection margin, D) Histological type and E) Treatment

Ta b l e 3 . S u r v i v a l R a t e s o f E x t r a h e p a t i c Cholangiocarcinoma Patients after Surgical Treatment
. The independent variables were age at diagnosis, gender, stage of disease, resection margin, histological type, histological grading and type of surgery

Table 4 . Factors Effecting Survival Rates of Extrahepatic Cholangiocarcinoma Patients after Surgical Treatment (Multivariate Analysis)
*p-value from partial likelihood ratio test; HR=hazard ratio; NA=not applicable Ta b l e 1 .C h a r a c t e r i s t i c s o f E x t r a h e p a t