Extrahepatic bile duct cancer (EHBDC) is a rare malignancy with poor prognosis [1,2]. Complete surgical resection is considered as the only curative treatment modality, however complete resection is often limited because of advanced stage on presentation [3,4]. Further, even after radical resection, the prognosis still remains poor because of frequent recurrences [5,6]. Therefore, attempts to improve the prognosis through adjuvant treatment have been made, but the benefit of adjuvant treatment was not conclusive and the optimal modality was not determined [7-10].

In a previous multicenter retrospective study (Korean Radiation Oncology Group [KROG] 1814), the role of adjuvant radiotherapy (RT) was evaluated in patients treated with curative surgical resection for EHBDC [11]. Although patients in adjuvant RT group had more poor prognostic factors than in no adjuvant group, adjuvant RT significantly improved the overall survival (OS), locoregional recurrence-free survival (LRFS) and disease-free survival. When adjuvant RT group was analyzed separately, concurrent chemoradiotherapy (CCRT) followed by chemotherapy showed greatest benefit for survival outcome.

In this study, we evaluated risk factors predictive for distant metastasis (DM) in EHBDC patients using KROG 1814 data and identified group of patients who might benefit most from adjuvant chemotherapy.

In current study, tumor location, histologic differentiation, PNI, nodal metastasis, and preoperative CA 19-9 level were identified as significant risk factors for DM, and the prognostic value of these factors were verified in patients undergoing adjuvant CCRT or CCRT followed by chemotherapy.

Because of the high recurrence rate in EHBDC treated with surgical resection, the role of adjuvant treatment has been investigated. But, the evidence supporting adjuvant chemotherapy was not conclusive. Several retrospective studies evaluating the role of chemotherapy with or without RT showed conflicting results [12-14]. Due to the rare incidence, randomized studies testing the optimal adjuvant treatment in EHBDC alone were scarce. BCAT trial, only study which compared observation with adjuvant gemcitabine after surgical resection of EHBDC, failed to demonstrate the difference in relapse-free survival (RFS) and OS between the two groups [15]. However, the BILCAP trial, which included all sites of biliary tract cancer, showed the improved outcome with adjuvant chemotherapy. In this study, patients were randomized into observation versus Capecitabine after surgical resection and capecitabine significantly improved outcome in terms of RFS and OS [16]. Based on these results, adjuvant Capecitabine is recommended for surgically resected biliary tract cancer by the American Society of Clinical Oncology [17]. A recent report on the long-term outcome again showed the improved RFS and OS of the Capecitabine group [18]. However, Capecitabine did not affect local recurrence rate even in patients with involved resection margin, resulting in the local recurrence comprising approximately 50% of the total recurrences in those patients. Notably, involved resection margin was a significant adverse risk factor affecting OS along with nodal involvement and poor differentiation. In our previous study, we reported the benefit of adjuvant RT in local control as well as in OS for patients with EHBDC [11]. In line with the previous study, we aimed to identify prognostic factors for DM in patients with EHBDC and also the subgroup who could benefit from additional chemotherapy after CCRT. We found five risk factors for DM and showed the benefit of additional chemotherapy in patients with high-risk features for DM. Therefore, we believe that results from current analysis could provide additional reliable evidence to supporting the role of adjuvant chemotherapy in patients with EHBDC.

Previously, several studies reported the prognostic factors for survival of resected EHBDC patients. Kim et al. [19] evaluated EHBDC patients treated with curative surgical resection followed by adjuvant CCRT. The major pattern of failure was DM. Hilar tumor location, tumor size ≥ 2 cm, lymph node metastasis, and poorly differentiated tumor histology were identified as prognostic factors for DM. Need for intensified chemotherapy was suggested for patient with multiple risk factors. Lim et al. also compared the outcome of CCRT versus CCRT followed by chemotherapy in patients with EHBDC after resection [20]. They identified that CA 19-9 level, histologic differentiation, nodal status, and pattern of adjuvant treatment were prognostic factors for disease-free survival. CCRT followed by chemotherapy significantly prolonged disease-free survival, especially in subgroup of patients with positive resection margin. Although tumor location was not a significant prognostic factor, patients with proximal tumor benefited from additional chemotherapy after CCRT, while those with distal tumor did not. Another study by Im et al. [21] also evaluated EHBDC patients undergoing curative resection. In their results, preoperative and postoperative CA 19-9 level, histologic grade, and nodal status were prognostic factors for DMFS and adjuvant chemotherapy after surgical resection improved DMFS. Ecker et al. [22] identified curatively resected EHBDC patients from the National Cancer Data Base and evaluated the efficacy of adjuvant therapy after propensity score matching. They showed the benefit of adjuvant chemotherapy with or without RT in patients with high-risk features, including advanced T category, nodal metastasis, lymphovascular invasion, and poor differentiation. Based on these results, it is postulated that patients with high risks should be considered for further adjuvant chemotherapy even after curative resection. Because of the retrospective nature of studies and heterogeneity in adjuvant treatment, nominated risk factors were slightly different across the studies. Additionally, except for the study by Kim et al. [19], the treatment outcome evaluated was mainly disease-free survival or OS and the prognostic factors specific for DM were not evaluated. Contrary to the previous studies, current study evaluated only patients who did not receive any adjuvant treatment after surgical resection and focused on the risk factors for DM. Therefore, the risk factors identified in current study could help to identify the patients who could derive the most benefit from adjuvant chemotherapy with minimal confounding effect.

When compared with the historical reports, the OS rate of the surgery-alone group in our study seems to be better. Although the proportion of resection margin involvement, lymph node metastasis, and other adverse risk factors affecting outcomes were quite different across studies, a recent quality assessment-based meta-analysis reported the pooled locoregional recurrence rate, DM rate, and OS rates of the surgery group not receiving adjuvant RT were 52.1% (crude rate), 39.3% (crude rate), and 25.6% (5-year rate), respectively [23]. Better OS of our surgery-alone group might suggest that patients with adverse features were more likely to receive adjuvant CCRT with or without chemotherapy in the present study. Meanwhile, this observation might also suggest that DM risk is significant in the patients of the surgery-alone group.

There are several limitations in this study including innate retrospective design. The decision on surgical methods and adjuvant treatment was at the discretion of servicing physician or surgeon. Thus, inherent selection bias may have been present. Additionally, not all factors were available from the medical records and thus may have been missed. Despite these limitations, current study is the largest study evaluating the risk factors for DM in patients with surgically resected EHBDC.

In conclusion, proximal tumor location, poor differentiation, presence of PNI, lymph node metastasis, and increased CA 19-9 were risk factors for DM in EHBDC patients after curative resection. Subset of patients with these risk factors may benefit from adjuvant chemotherapy.