Survival Rate of Intrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand

Cancer is a major health problem around the world; in 2010, there were 789,620 new cancer cases in males and 739,940 new cancer cases in females. In the same year, the estimated number of deaths from cancer was 299,200 in males and 270,290 in females (American Cancer Society, 2010). Cholangiocarcinoma (CCA), including both the intrahepatic and extrahepatic bile duct forms of the disease, is the most common cancer in Thailand, especially in the northeastern region where the incidence rate has been the highest in the world. In the northeast province of Khon Kaen, where 89% of liver cancers are CCA (Vatanasapt et al., 1995), the age-adjusted incidence rates for liver cancer have been 89.2 and 35.5 per 100,000 in males and in females, respectively (Vatanasapt et al., 1990). Intrahepatic cholangiocarcinoma (ICC) is one of the primary liver cancers. Surgical resection remains the best method of treatment, but patients suffering from ICC usually present at a late stage of the disease. Studies of


Introduction
Cancer is a major health problem around the world; in 2010, there were 789,620 new cancer cases in males and 739,940 new cancer cases in females.In the same year, the estimated number of deaths from cancer was 299,200 in males and 270,290 in females (American Cancer Society, 2010).Cholangiocarcinoma (CCA), including both the intrahepatic and extrahepatic bile duct forms of the disease, is the most common cancer in Thailand, especially in the northeastern region where the incidence rate has been the highest in the world.In the northeast province of Khon Kaen, where 89% of liver cancers are CCA (Vatanasapt et al., 1995), the age-adjusted incidence rates for liver cancer have been 89.2 and 35.5 per 100,000 in males and in females, respectively (Vatanasapt et al., 1990).
Intrahepatic cholangiocarcinoma (ICC) is one of the primary liver cancers.Surgical resection remains the best method of treatment, but patients suffering from ICC usually present at a late stage of the disease.Studies of

Survival Rate of Intrahepatic Cholangiocarcinoma Patients after Surgical Treatment in Thailand
Sudarat Sriputtha 1 , Narong Khuntikeo 2 , Supannee Promthet 1 *, Supot Kamsaard 3   prognostic factors and survival after surgery remain rare, but the survival of patients suffering from this disease is low in both hospital-based and population-based studies (Sriamporn et al., 1995;Khuntikeo et al., 2008;Shen et al., 2009).The particularly high incidence of CCA in northeast Thailand is linked to high levels of infection by the liver fluke, Opisthorchis viverrini, and programmes for the control of infection by this parasite have played a role in the primary prevention of the disease for decades (Saengsawang et al., 2012).However, due to the large number of patients presenting with the disease, tertiary prevention is also important.
A previous study followed up patients with extrahepatic cholangiocarcinoma following surgical treatment at Srinagarind Hospital, Khon Kaen University, Thailand (Pattanathien et al., 2013).The present study aimed to evaluate the survival rates and factors affecting survival in patients with intrahepatic cholangiocarcinoma following surgical treatment at the same hospital.The outcomes are expected to be useful for improving the treatment modality and the quality of life of patients.

Materials and Methods
A retrospective cohort study was conducted with 73 patients, who were diagnosed with intrahepatic bile duct cancer (histologically confirmed) and treated by surgical excision by one 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).
The independent variables were age at diagnosis, gender, stage of disease, resection margin, histological type, histological grade, and macroscopic type.The dependent variable was the survival time of patients with ICC.In order to calculate the survival time, the point was identified as the date of surgery, and the followup period ended when a patient died or on completion of the study.Censored data were used for those 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 were used for exploratory data analysis.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 version 10.0 (StataCorp, 2007).
The research was approved by the Khon Kaen University Ethics Committee for Human Research (reference no.HE541334).

Results
Table 1 shows the characteristics of subjects included in the study.There were 73 patients with ICC (43 males and 30 females), and their mean age was 56 years.Most patients (52%) presented themselves at the hospital at a late stage (stage IV), 58.9% received what was essentially palliative surgery (47.9% R1 plus 11.0% R2), and 80.8% had died by the end of the study.The total follow-up time was 99 person-years, and the total number of deaths was 59.The mortality rate was therefore 59 per 100 personyears (95%CI: 0.45-0.77).

Discussion
There have several reviews of cumulative survival rates after surgery for ICC.Gores (2003) reported that the 3-year survival rates in patients resected for cure were 40-60%, and the 5-year survival rates in patients with tumour-free margins were 20-40%.Khan et al. (2005) found 5-year survival rates of 8-47% with the highest survival in patients with negative resection margins.In a review by Morise et al. (2010), the 1-, 3-, and 5-year survival rates ranged 35%-86%, 20%-52%, and 20%-40%, respectively.The results of the present study are in line with the 1-and 3-year rates in these reviews, but the 5year rates in the previous studies were generally higher.In recent studies (Cho et al., 2010;Ribero et al., 2012) the 1-and 3-year rates were also higher.
The inconsistencies with other studies could be explained in terms of patient and tumour characteristics and differences in the quality of treatment modality or the advanced technology; for example, if a tumour is completely removed, then the survival rates of patients after surgery should be longer.In the present study, although the 1-year survival rates were about the same for those with positive and negative resection margins (57.1% vs. 56.7%,respectively), the 3-and 5-year rates were much lower in those with a positive resection margin (8.0% vs. 40.0%,and 0.0% vs. 25%, respectively).Whereas the studies by Cho et al. (2010) and Ribero et al. (2010) included only 6.4% and 12% (respectively) with a positive resection margin, the majority of patients (58.9%) in the present study had a positive resection margin.
In the univariate analysis, factors found to be associatied with the survival rates after surgery were staging of disease, lymph node metastasis, histological type, histological grade and macroscopic type.These findings are similar to those reported in previous studies (Uenishi et al., 2001;Hirohashi et al., 2002;Suzuki et al., 2002;Khuntikeo et al., 2008).Patients with lymph node metastasis had a 2.68 times (95%CI: 1.33-5.38)higher mortality risk than those with no lymph node metastasis.Similar findings were reported by Hanazaki et al. (2002) and Guglielmi et al. (2009).In the present study, macroscopic type was also found to be associated with survival rates after surgery.When compared with the mass forming type, those with intraductal growth type had a 0.25 times (95% CI: 0.11-0.57)lower risk of death, and those with the periductal infiltrating type had a 0.63 times (95% CI: 0.29-1.34)lower risk of death.These findings are almost the same as those in the study reported by Morimoto et al. (2003).However, Guglielmi et al. (2009) reported a rather different finding; patients with mass forming cancers had longer survival rates.
In the multivariate analysis, macroscopic type was the only factor significantly associated with the survival rates of ICC patients after receiving surgical treatment.When compared with patients with a mass forming type of cancer, patients with intraductal growth had a lower mortality risk, as did those with a periductal infiltrating type of malignancy.When the analysis excluded those subjects whose macroscopic type could not be assessed, the result was no longer significant, but the hazard ratios were in the same direction.
In conclusion, macroscopic classification was the only independent factor found to be significantly associated with survival of intrahepatic cholangiocarcinoma patients following surgical treatment.

Figure 1 .
Figure 1.Survival Curve of Intrahepatic Cholangiocarcinoma Patients after Surgical Treatment.A) Gender, B) Stage, C) Resection Margin and D) Macroscopic Classification