Cholangiocarcinoma (CCA) is one of the most lethal cancer types, with a 5-year survival rate of <5% (1,2). Mostly consisting of adenocarcinomas, CCAs are topographically categorized into two major subtypes, namely intrahepatic and extrahepatic CCAs, with the hilar subtype also being considered as extrahepatic. CCA is rare in developed countries, with an incidence of ~0.5–2 per 100,000 individuals; however, intra- as well as extrahepatic CCA is common in southeast Asia, particularly Thailand. Compared with liver cancer, the prevalence of CCA is considered to account for 10–25% of liver cancer cases in the country, particularly in the northeastern region, where incidence rates of 36.3 and 87.7 per 100,000 individuals have been reported in women and men, respectively (3–6). The exact cause of bile duct cancer remains unknown; however, infection with the southeast Asian liver fluke (Opisthorchis viverrini) is considered a major risk factor for the development of intrahepatic CCA. Furthermore, liver cirrhosis, chronic hepatitis C virus infection, hepatolithiasis, smoking and obesity, as well as mutations of the K-ras and p53 genes, may also contribute to the development of intrahepatic CCA (7–11). While the risk factors for hilar and extrahepatic CCA largely remain elusive, excessive alcohol consumption has been reported to be a major risk factor for the development of extrahepatic CCA (12).

At present, complete surgical resection is considered as the only effective treatment available for CCA. Negative histological margins and well-differentiated tumor histology are associated with long-term survival of patients following tumor resection (13,14). Liver transplantation combined with neoadjuvant chemoradiotherapy is another available option for effective CCA treatment (15,16). In unresectable CCA, conventional treatment modalities, including chemotherapy and radiotherapy, may prolong patient survival; however, the results thus far are discouraging (17–19). An alternative radiation modality, stereotactic body radiation therapy, has also failed to improve the survival of unresectable CCA patients (20). Tumor -related hepatic failure due to disease recurrence is the leading cause of patient mortality, exceeding that of other causes combined, such as distant metastasis, infection or angiocholitis (21). For patients with resectable CCA, the effectiveness of postoperative adjuvant radiotherapy remains controversial, as diverse studies report either positive or null results. Although the debate regarding the benefit of radiotherapy for patients with CCA is ongoing, certain factors have been shown to affect treatment outcomes and patient survival (18,22–26). Age, ethnicity, tumor stage and year of diagnosis, as the numbers of patients receiving radiotherapy were growing, have been associated with the prognosis of CCA patients following radiotherapy (22). Negative margins, lymph node metastasis and tumor histopathology are also significant prognostic factors following treatment (27). The aim of the present study was to evaluate clinical factors which may affect the survival of CCA patients receiving radiotherapy treatment.

CCA is a lethal cancer that predominantly affects individuals in developing countries; to date, means to reduce its incidence have not been implemented. Numerous potential prognostic factors have been suggested for patients with CCA. Orthotopic liver transplantation along with chemoradiotherapy have significantly improved overall survival in CCA patients, with fewer complications of locoregional dissemination and tumor recurrence; thus, this approach is considered as standard treatment procedure for CCA (29,30). However, this option may not be feasible for all patients; conventional therapies, including surgical resection, chemotherapy and radiotherapy, may remain useful for CCA patients with certain characteristics.

The clinical condition of affected patients provides an initial indicator regarding the prediction of survival; as previously reported, the ECOG status and clinical symptoms provide information regarding the severity of the disease and treatment outcome (31). It has been reported that patients considered suitable for surgery also have a higher survival rate (32). However, in the present study, neither lymph node involvement nor histological grading were predictive factors for patient survival according to the statistical analysis.

The efficacy of radiotherapy in the treatment of CCA has been questioned; it has previously been reported that postoperative radiotherapy exerts a limited effect on the survival of patients with hilar CCA (33). However, radiation as an adjuvant or palliative treatment appears to confer a survival advantage in patients with intra- or extrahepatic CCA (22,24,33,34). Radiotherapy has been shown to prolong patient survival by ~4 months in unresectable intrahepatic CCA (35). It has also been suggested that liver transplantation with neoadjuvant chemoradiotherapy may achieve improved survival rates in patients with hilar CCA in comparison with surgical resection (36).

In the present study, retrospective analysis of the data of CCA patients who had received radiotherapy was performed. Although TNM-staging did not provide any prognostic information, PTV, which was adjusted according to the tumor size, was a significant predictive factor (P<0.05). From this, it can be deduced that a smaller tumor size is associated with a higher survival rate. In addition, although patient survival was not significantly associated with the total therapeutic dose, once the total radiation doses and fractionation frequencies were converted into BED, the difference in survival became significant between patients who received a BED >60 vs. those who received a lower BED. The BED is prescribed based on the clinicopathological condition of each patient and corresponds with the tumor status, including its resectability or whether there is residual tumor following surgery; thus, a larger BED was associated with poor patient prognosis. The fact that a larger BED translated to a poorer prognosis also indicated that current radiotherapy protocols may not address the severity of the disease, and that radiotherapy is ineffective against CCA as previously hypothesized (37). It has been reported that SBRT may achieve higher survival rates for selected patients (38); SBRT concurrent with gemcitabine has also been suggested to be a promising approach (39).

Based on logistic regression analysis, treatment response at 3 months was considered to be of prognostic value (P=0.047); however, when analyzed using the Fisher's exact test, this factor could no longer be used to predict between-group differences (P=0.056). Re-grouping between complete and partial response vs. stable and progressive disease also revealed no significant difference (P=0.325). Thus, based on the findings of the present study, initial treatment response may be of limited value in determining patient prognosis. Future studies using a larger patient cohort may help determine whether patient response at 3 months after treatment may be used to predict the prognosis.

CCA is a heterogeneous cancer type and complete surgical resection is the most effective treatment for either perihilar or peripheral CCA. In addition to surgery, the majority of the patients undergo postoperative adjuvant treatment. Although these adjuvant treatments have conferred certain survival benefit, the actual standard protocols vary, particularly regarding radiotherapy; at present, there is no consensus regarding the optimal definition of target contouring, radiation dose and fractionation schedule. Novel radiological modalities, including dynamic computed tomography (CT), magnetic resonance cholangiopancreatography and positron emission tomography/CT, have been developed and have become useful for target contouring. Moreover, liver motion is a critical factor that requires consideration during contouring (40–42). Fluoroscopy or 4D-CT have been proven to be useful in the precise definition of the internal target volume. All these technologies enhance the accuracy of radiation delivery and improve local tumor control. Further development of these procedures may improve the efficacy of radiotherapy for CCA.

Besides standard external beam radiotherapy, yttrium-90 radioembolization is currently used as an alternative procedure for radiation delivery. It may be employed for the treatment of intrahepatic CCA and has appeared to confer survival benefits to patients. Radioembolization has also been reported to transform unresectable into resectable tumors (43,44). Therefore, the effectiveness of this approach for treating intrahepatic CCA should also be further investigated.

In conclusion, the present study investigated clinical characteristics of CCA patients, such as performance status, clinical symptoms and resectability of the tumor, as predictive factors of prognosis. Tumor volume, represented by PTV, and radiation dose delivered to the tumor, expressed as the BED, may be used as predictors of survival. CCA patients subjected to radiotherapy with a lower PTV and BED had higher 2-year survival rates. However, as these factors were adjusted based on tumor size and the clinicopathological status, increased survival rates may have been due to the lower degree of disease progression. Further studies involving larger patient numbers are required to further validate the findings of the present study.