Surgical resection is the only curative treatment for biliary tract cancer. Resectability is considered an important prognostic factor in many studies [16–18]. The resectability rate of EHBTC has been reported to range between 10% and 47%, despite differences in resectability rate according to tumor location [19–22]. Following complete surgical resection, the most common relapse pattern is loco-regional, with subsequent bile duct obstruction, liver failure, and recurrent sepsis . Therefore, in considering postoperative local control, many studies have reported the role of RT with or without chemotherapy. However, there have been conflicting results for the role of adjuvant RT after radical resection, especially R0 resection, and no randomized controlled trial has resolved the inconsistent findings.
Many retrospective studies and small phase II studies have shown a benefit with adjuvant RT, especially for the control of microscopic residual tumor [8–10, 12, 23]. Oh et al. showed that adjuvant RT was useful in patients with microscopic residual tumor . A recent study by Todoroki et al. revealed that an adjuvant RT group had a higher 5-year survival rate (33.9%) than a group with resection alone (13.5%), especially for patients with R1 resection . Also, Todoroki et al. reported the efficient eradication of microscopic local-regional tumor residue by adding intraoperative RT to postoperative RT appeared to result in prolonging survival by preventing distant metastasis. Kim et al. reported the results of adjuvant CCRT with and without adjuvant chemotherapy after radical resection in 84 patients with EHBTC . In this study, patients with microscopically positive resection margins had a 5-year survival rate of 35%, and patients with microscopically negative margins had a 5-year survival rate of 36%. This result suggested that despite no significant difference between the survival rates of the two groups, adjuvant CCRT might play a role in patients with R1 resection. Serafini et al. reported that median survival (41 months) of patients with distal cholangiocarinoma receiving adjuvant CCRT was significantly longer than that (25 months) of patients not receiving adjuvant CCRT .
However, some studies have shown no benefit with adjuvant RT in patients with EHBTC [2, 7, 24]. One prospective study showed that surgical resection and RT in 50 patients with perihilar tumors had no beneficial effect on survival or quality of survival, although the fact that lymph node evaluation was done in only 15 patients and no information was gathered concerning T stage might reduce the value of this prospective study . Another small randomized trial conducted in 207 patients with pancreatic or periampullary malignancies failed to demonstrate a survival benefit for postoperative CCRT compared to surgery alone , but the study was limited in that there were fewer than 100 patients with periampullary cancers in this trial, only some of which were of biliary origin. Twenty percent of the patients in the treatment arm received no adjuvant treatment because of postoperative complications or refusal.
Many hospitals have carried out CCRT as a practical treatment option for patients with positive resection margins, advanced T stage, or lymph node metastasis, although this adjuvant treatment has not been demonstrated to be the standard through randomized prospective study. Our institution recommended adjuvant CCRT with or without further adjuvant chemotherapy in some patients, based on assumptions that loco-regional disease recurrence rates are high and that improving loco-regional disease control improves survival [7, 12, 26, 27].
In this study, we reviewed 120 patients treated with adjuvant treatment after R0 and R1 resection. Adjuvant CCRT followed by adjuvant chemotherapy was significantly different with regard to DFS (p = 0.04) and OS (p < 0.01), compared with CCRT alone. Patients that had either R1 resection or negative node status experienced more benefits with CCRT followed by adjuvant chemotherapy. However, there was no significant difference in DFS and OS between the CCRT alone and CCRT followed by adjuvant chemotherapy groups for patients with R0 resection (p = 0.43, p = 0.15) or positive nodal status (p = 0.96, p = 0.23). The local failure rate was not different between the CCRT alone (5 out of 30, 16.7%) and CCRT followed by adjuvant chemotherapy (17 out of 90, 18.9%) groups. Furthermore, the rate of distant metastasis was no different between the CCRT alone (14 out of 30, 46.7%) and CCRT followed by adjuvant chemotherapy (31 out of 90, 34.4%) groups. However, even though it was not statistically significant, CCRT followed by adjuvant chemotherapy showed a tendency to prevent the development of distant metastasis.
The results of our study showed that adjuvant CCRT might be as effective in controlling microscopic residual tumor as some previous studies have suggested, and there is the possibility that further adjuvant chemotherapy could reduce recurrence, especially systemic relapse, after CCRT for patients with R1 resection. The loco-regional relapse rate in our study was lower than that seen in previous studies , because we classified a concomitant relapse at loco-regional and distant sites as a systemic recurrence.
Although tumor location had no prognostic impact on survival on univariate analysis in this study, patients with proximal EHBTC had better DFS and OS when treated with CCRT followed by adjuvant chemotherapy. Patients with distal EHBTC had no significant difference in survival when treated with CCRT alone or CCRT followed by adjuvant chemotherapy.
Radiosensitization with cytotoxic agents has become standard practice in the treatment of gastrointestinal malignancies. 5-FU is known to be one of the most active single agents in biliary tract cancer and is frequently used in a combined modality approach because of its potential radiosensitization effect. In general, these regimens are well tolerated. However, the number of patients treated with adjuvant RT alone in this study was small, and direct comparison was not done.
Adjuvant chemotherapy after adjuvant CCRT has not been routinely applied to patients with EHBTC and has not yet been studied. The role of further adjuvant chemotherapy remains unclear. 5-FU and gemcitabine-based regimens are used universally and are known to be active in metastatic EHBTC. 5-FU-based regimens include 5-FU alone, 5-FU in combination with other agents, uracil-tegafur, capecitabine, and S-1. In the palliative setting, these 5-FU-based chemotherapy yields response rates of 10-40% and overall survival somewhat better than best supportive therapy alone [14, 28–30]. On the basis of this background, the group in our study treated with adjuvant chemotherapy showed a longer DFS and OS than did the group without adjuvant chemotherapy, especially for patients with R1 resection, patients with more than T3 or patients with negative nodal status. No beneficial effects of further adjuvant chemotherapy were shown in the lower risk patients, such as those with R0 resection or those who were less than T2. Furthermore, there was no significant difference in survival between the two groups with positive nodal status, despite the assumption that adjuvant chemotherapy would reduce local and systemic relapse and result in a survival advantage. The implications of these results should be considered. First, current nodal status simply classifies N0 and N1, regardless of the number and location of involved nodes, and cannot reflect the exact extent of disease. Second, some incomplete lymph node dissections could have been done. Third, the efficacy of 5-FU was still low, in spite of its active agency in biliary tract cancer. This suggests a need for intensification of adjuvant treatment through the use of novel agents in cases with node metastasis.
Prognostic factors such as extent of surgical procedure, T stage, nodal status, tumor location, and others have been identified in many reports [3, 9, 10, 12, 22, 24, 30]. In our study, the pattern of adjuvant treatment, elevated CA 19-9 level, and histologic grade were significant prognostic factors for DFS and OS on multivariate analysis.
By its nature, our study was subject to several limitations. First, the study is a retrospective series, which could have shortcomings such as selection bias. Second, adjuvant chemotherapy was not identical. We did not consider factors such as differences in efficacy between 5-FU alone and combination 5-FU therapy or duration of chemotherapy. The effect of these differences on the study outcome is unknown. Third, as a small portion of patients was included in subgroup analysis as R1 resection, our results should be interpreted with caution.
Despite these shortcomings, our study is valuable for many reasons. First, this study is one of largest reports to date comparing CCRT and CCRT followed by adjuvant chemotherapy. Second, unlike previous reports, the population in our study was characterized by a homogeneous disease representation. Previous studies looked at a combination of extrahepatic cholangiocarcinoma and other diseases, such as gallbladder and periampullary cancer. They also looked at diverse disease status, including R0, R1, and R2 resection, whereas the current study enrolled only patients with extrahepatic cholangiocarcinoma and a history of curatively radical surgery, such as R0 or R1 resection, and excluded patients with gallbladder cancer or intrahepatic cholangiocarcinoma. Therefore, in our study, CCRT with or without adjuvant chemotherapy was done only as an adjuvant treatment, not as a palliative treatment.