Treatment Outcome of Palliative Chemotherapy in Inoperable Cholangiocarcinoma in Thailand

Cholangiocarcinoma arises from epithelial cells of the intrahepatic and extrahepatic bile ducts (de Groen et al., 1999; Murad et al., 2009). It is a rare cancer in United States and Europe (de Groen et al., 1999; Jemal et al., 2011), but common in Thailand. The reported incidence is one to two cases per 100,000 patients in United States (Murad et al., 2009; Siegel et al., 2012). In Thailand, it is a common cancer. Interestingly, it is the most common cancer in male and third common cancer in female. The reported incidence of primary liver cancer is 38.6 cases per 100,000 patients and remarkable, is highest in north and northeast of Thailand. More than 80% of primary liver cancer in Thailand is cholangiocarcinoma (Khuntikao, 2005; Khuhaprema et al., 2010; Sararat, 2010). Although surgical resection is the only potential curative treatment, less than 25% of patients are successfully resectable at presentation and among these patients, relapse rate is obviously high (Khan et al., 2002; Thongprasert, 2005; Chaiwerawattana et al., 2011). Patients with unresectable and metastatic cholangiocarcinoma have a poor prognosis, with a median overall survival less than 1 year (Anderson et al., 2004; Yonemoto et al., 2007; Jongha et al., 2009). Systemic chemotherapy has been used in an attempt to improve disease control, quality of life and prolong survival. Previous studies reported the results in limited


Introduction
Cholangiocarcinoma arises from epithelial cells of the intrahepatic and extrahepatic bile ducts (de Groen et al., 1999;Murad et al., 2009). It is a rare cancer in United States and Europe (de Groen et al., 1999;Jemal et al., 2011), but common in Thailand. The reported incidence is one to two cases per 100,000 patients in United States (Murad et al., 2009;Siegel et al., 2012). In Thailand, it is a common cancer. Interestingly, it is the most common cancer in male and third common cancer in female. The reported incidence of primary liver cancer is 38.6 cases per 100,000 patients and remarkable, is highest in north and northeast of Thailand. More than 80% of primary liver cancer in Thailand is cholangiocarcinoma (Khuntikao, 2005;Khuhaprema et al., 2010;Sararat, 2010).
Although surgical resection is the only potential curative treatment, less than 25% of patients are successfully resectable at presentation and among these patients, relapse rate is obviously high (Khan et al., 2002;Thongprasert, 2005;Chaiwerawattana et al., 2011). Patients with unresectable and metastatic cholangiocarcinoma have a poor prognosis, with a median overall survival less than 1 year (Anderson et al., 2004;Yonemoto et al., 2007;Jongha et al., 2009).
Systemic chemotherapy has been used in an attempt to improve disease control, quality of life and prolong survival. Previous studies reported the results in limited subjects consisting of a mixed bile duct cancers, gall bladder cancer, ampullary cancer and pancreatic cancer with elicited variable outcomes (Thongprasert, 2005;Hezel et al., 2008). Glimelius, et al demonstrated an improvement in quality of life and overall survival for patients treated with palliative chemotherapy compared with best supportive care. Overall survival was significantly longer in the chemotherapy group (median survival 6 vs. 2.5 month) (Glimelius et al., 1996).
5FU-based regimens have overall response rate ranging from 0-40% and a median survival ranging from 2-12 months. The combination of cisplatin with 5FU resulted in a response rate of 10-40% and median overall survival time somewhat better than 5FU alone (Thongprasert, 2005;Hezel et al., 2008).
To our knowledge, there is no rarandomized controlled trial demonsttrated the efficacy of gemcitabine based over 5FU-based regimens in unresectable and metastatic cholangiocarcinoma.
In Udonthani Cancer Hospital, unresectable and metastatic cholangiocarcinoma patients were treated by systemic chemotherapy. Both gemcitabine based and 5FU-based regimens have been used. This study is the retrospective analysis of the treatment outcome of palliative chemotherapy in unresectable and inoperable changiocarcinoma at medical oncology unit, Udonthani Cancer Hospital during 2007-2010.

Materials and Methods
After approval by the institutional review board, the medical records of all patients, who were diagnosed unresectable and metastatic cholangiocarcinoma and treated by systemic chemotherapy at Udonthani Cancer Hospital from January 2007 through December 2010, were reviewed for patient characteristics, tumor response, time to disease progression, survival and toxicity of treatment. The data from total 105 patients were collected in this retrospective cohort study. The statistical analysis was performed using statistical software. Frequency and percentage were used for general data. The survival rate and time to progression were analyzed according to Kaplan-Meier methodology.

Treatment and dose modifications
In clinical practice at Udonthani Cancer Hospital from January 2007 through December 2010, all patients suspected of having cholangiocarcinoma with good performance status and organ functions, were undergone biopsy in order to verify the diagnosis. In addition, working up for staging was done. If the disease was surgical unresectable or metastatic, the patients would received systemic chemotherapy. Gemcitabine-based or 5FU-based regimens have been used depending on the drug cost affordability of patients. Gemcitabine-based regimens included gemcitabine single agent, gemcitabine plus cisplatin, gemcitabine plus carboplatin, gemcitabine plus capecitabine. 5FU-based regimens included 5FU plus cisplatin, 5FU plus carboplatin and 5FU plus leucovorin. During the course of chemotherapy, if patients developed renal impairment or electrolyte imbalance, cisplatin was switched to carboplatin. The dose of chemotherapy was reduced about 10-20% in subsequence cycles in the cases developed grade ≥3 neutropenia and thrombocytopenia in association with bleeding or febrile neutropenia. No further chemotherapy was given in patients with complete course (6 cycles) or progressive disease or unacceptable toxicity whichever came first. WHO criteria was applied to define the degree of treatment response.

Patient characteristics
Demographic characteristics are listed in Table  1. Twenty one patients received gemcitabine-based regimens. 5FU-based regimen shave been used in the rest eighty-four patients. The mean age of patients receiving gemcitabine-based and 5FU-based regimens were 55 years

Treatment and response to treatment
Treatment and responses are listed in Table 2. In gemcitabine-based use, eighteen patients received gemcitabine plus ciplatin (85.71%). In 5FU-based use, 5FU plus cisplatin and 5FU plus carboplatin were used in sixty eight patients (80.78%). More than 80% of patients in both group received chemotherapy without dose or drug modification. Median number of chemotherapy was three cycles. Four patients (19.05%) in gemcitabine-based group achieved controlled disease (partial response and stable disease). Twenty patients (23.81%) in 5FU-based group achieved controlled disease (partial response and stable disease). None of the patient in both groups achieved clinically complete response.

Survival and time to progression
Of all 105 patients, 103 patients died. Notably, one patient who received 5FU-based chemotherapy was alive with disease progression. Unfortunately, there was no vital status of another one patient receiving gemcitabine-based chemotherapy. The one-year overall survival was 24.42% (95%-CI 16.66 to 33.00) with the median overall survival of 7.77 months (95%CI 6.46 to 9.08) as shown in Figure  1.
Median time to progression was 4.97 months (95%-CI 3.51 to 6.41) in all patients. In patients with gemcitabinebased chemotherapy, the median time to progression was 7 months (95%CI 4.81 to 9.18) while it was 4.1 months (95%CI 2.86 to 5.34) in patients receiving 5FUbased chemotherapy. Between two groups of patients, the median times to progression were not staistically significant (p=0.06) (Figure 3 and 4).

Toxicity
Toxicity data were shown in Table 3. There was one treatment-related death in a 55-years old woman with locally advanced disease receiving gemcitabine

Discussion
Cholangiocarcinoma has been the leading cancer in Thailand, especially in northern and northeastern regions (Khuntikao, 2005;Khuhaprema et al., 2010;Sararat, 2010). Generally, more than 80% of primary liver cancer in Thailand is cholangiocarcinoma. The treatment outcome in this biliary tract cancer is poor. Tumor removal is the main treatment modality. In general, patients with cholangiocarcinoma present with advanced disease which are basically beyond surgery. Chemotherapy was therefore given to probable cases of having cholangiocarcinoma. Unfortunately, there is no chemotherapy with approved superior efficacy. In addition, there has been limited numbers of studies in histologically verified patient. All patients included in this study were histologically confirmed. As of our recent knowledge, no randomized controlled trial demonstrated the efficacy of gemcitabinebased chemotherapy and 5FU-based regimens in unresectable and metastatic cholangiocarcinoma. Most previous data seem to elicit that gemcitabine-based may be superior than 5FU-based chemotherapy. In our study, four out of five patients have been treated with 5FU based regimen because of patients' affordability. The median overall survival of all our patients received chemotherapy was 7.77 months. It is slightly longer than historically data that showed 6 months overall survival while comparing with 2.5 months in best supportive care group (Glimelius et al., 1996).
In our study, majority of patients received 2 drugs. 5FU-based regimens achieved overall response rate (tumor control) 23.81% and a median survival 7.2 month. Gemcitabine-based regimens achieved overall response rate (tumor control) 19.05% and a median survival 9.97 month. All were identical to historical data (Thongprasert, 2005;Hezel et al., 2008). These survival data were not statistically different.
According to this retrospectively collected data, we are unable to draw any conclusion whether gemcitabine or 5FU-based regimens showed better efficacy in the treatment of unresectable or metastatic cholangiocarcinoma. With less cost, this 5FU-based chemotherapy may be efficient to treat advanced cholangiocarcinoma and an appropriate use in resource-limited country.