Patterns of failure after resection of extrahepatic bile duct cancer: implications for adjuvant radiotherapy indication and treatment volumes

In developed countries, bile duct cancers are rare. Although the prevalence rates are gradually increasing, bile duct cancer is only the sixth most commonly occurring alimentary tract cancer in the United States of America [1]. However, higher incidence rates have been reported in northeast Thailand, and other Asian countries such as China and Korea [2, 3].

Bile duct cancers can be classified into 3 groups according to their locations: intrahepatic, perihilar, and distal bile duct cancers [4]. Most bile duct cancers occur in the perihilar bile duct (approximately 65–70%) followed by in the distal bile duct, which includes the ampulla of Vater (AOV) (approximately 25–30%) [2]. Intrahepatic bile duct cancer is relatively uncommon, accounting for approximately 5–10% of all bile duct cancers, and is associated with lower rates of lymph node (LN) metastases than cancers of the extrahepatic bile duct (EHBD) [2]. The EHBD (including the perihilar, and distal bile ducts, and the AOV) has a rich lymphatic network along the submucosa, and similar pathways of lymph drainage.

Surgical resection is the only cure for EHBD cancer patients, but the rates of resectability are not very high [5]. In addition, the 5-year survival rates after resection were still found to be poor, at approximately 10–40%, due to the high rates of loco-regional (LR) recurrence and distant metastasis (DM) [6]. Theoretically, when a patient has a high probability of recurrence, adjuvant therapy may be beneficial in improving outcomes. Nowadays, radiotherapy (RT) is often considered as adjuvant treatment in clinics when patients have positive resection margins (RMs) or pathologic LN metastases [7, 8]. However, there is a lack of randomized trials which focus on establishing which group of patients benefit from adjuvant RT; in addition, there are no definite guidelines in terms of proper RT target volumes.

The purpose of this study was to analyze the patterns of failure, especially LR failure, after surgical resection of EHBD cancer, and the prognostic factors for LR recurrence. This information can be used to guide the indication and treatment volumes for adjuvant RT.

EHBD cancer has high rates of LR recurrence, even in patients who have undergone radical resection. These poor outcomes suggest that there is a requirement for adjuvant RT, with or without chemotherapy. However, due to the rarity in the occurrence of EHBD cancer, the role of adjuvant RT is poorly proven. Our study was implemented to evaluate the prognostic factors for recurrence and patterns of failure, particularly those associated with LR recurrence in patients with EHBD cancer who underwent surgical resection without adjuvant RT.

The role of adjuvant therapy in the treatment of EHBD cancer is poorly defined. Sikora et al. [10] reported that adjuvant chemoradiotherapy did not improve the survival or decrease the recurrence rates in AOV cancer patients who had undergone surgical resection. In another analysis of perihilar cholangiocarcinoma, performed by Henry et al. [11], it was reported that adjuvant RT did not prolong survival after radical resection. In contrast, several studies suggested that adjuvant therapy might be beneficial. Michael et al. [12] evaluated the outcome of adjuvant chemoradiotherapy after surgery in 34 patients with distal bile duct cancer, and found that adjuvant therapy improved local control and survival. Robert et al. [13] showed that adjuvant chemoradiotherapy may improve overall survival after resection, in a study of 125 AOV cancer patients. Recently, Kim et al. [14] reported the long-term outcomes of distal cholangiocarcinoma after surgery followed by adjuvant chemoradiotherapy; They reported slightly better outcomes in terms of 5-year LR-recurrence-free survival, disease-free survival, and overall survival rates (70.7%, 49.4%, and 48.1%, respectively) compared to other surgery alone studies. The above-mentioned studies showing improved outcomes reported that poor histologic differentiation, LN metastasis, positive RM status, and a higher primary tumor stage were the main factors behind LR recurrence; therefore, the use of adjuvant therapy targeted at these factors may reduce the recurrence rates. A systematic review and meta-analysis by Jennifer et al. [7] studied the benefit of adjuvant therapy for biliary tract cancer. They reported that the use of adjuvant therapy provided the greatest benefit in biliary tract cancer patients with an LN positive status (odds ratio, 0.49; p = 0.004) and R1 status (odds ratio, 0.36; p = 0.002). In our study, we observed an LR recurrence rate of 40.9%, which is higher than the reported rate of 25.8% (Kim et al.) after resection followed by adjuvant chemoradiotherapy [14]; this difference suggests the role of adjuvant therapy in LR recurrence. The multivariable analysis, performed to predict any type of recurrence, showed that positive LN metastasis and RM status were significant factors. Regarding the prediction of LR recurrence, in the univariable and multivariable analysis, RM status remained significant. Therefore, we suggest that the addition of adjuvant therapy may improve outcomes in patients with positive LN metastases and RM status; in particular, in patients with a positive RM status, adjuvant RT may improve LR control.

DM is also a major pattern of failure in patients with EHBD cancer who have undergone resection. Several studies have attributed the inefficiency of adjuvant therapy to the fact that DM accounts for a large portion of recurrence [15]. Kim et al. [14] reported that DM is still a major pattern of failure for EHBD cancer patients who have undergone adjuvant chemoradiotherapy, and the pattern seems to shift from LR recurrence to DM. In our study, DM occurred in 38.7% of the patients and LR recurrence was observed in 40.9%. Concomitant LR recurrence and DM was observed in 20 (21.5%) patients. To control DM, further advances in chemotherapy are needed, which focus on defining when chemotherapy should be used, and the identification of novel agents.

Recently, similar to our study, a retrospective study about LR recurrence patterns and prognostic factors in patients with cholangiocarcinoma who underwent surgical resection without RT was reported by Ghiassi-Nejad et al. [16]. Their study included a total of 145 patients and median followed up 41.6 months, and reported recurrence in 59% of patients (LR recurrence, 51%; DM, 16.3%). In addition, they reported the presence of satellite nodule and stage 3/any LN status were significant prognostic factors of overall recurrence. Compared with our results, a similar rate of any type of recurrence event was observed, but the detailed LR recurrence and DM were somewhat different. These differences may be due to differences in the proportion of patients with intrahepatic tumors (0% vs. 70.3%), who did not received LN dissection (2.2% vs. 31%) or who underwent adjuvant chemotherapy (18.3% vs. 26%).

Currently, the treatment volumes for adjuvant RT are poorly defined. In the modern era, three-dimensional conformal RT, intensity-modulated RT, or stereotactic radiosurgery are conducted in hepatobiliary cancer patients for reduced treatment-related toxicity, while maintaining the quality of treatment [17, 18]. With changes in RT, precise target delineation has become more important. Traditionally, the RT target volume for EHBD cancers in adjuvant setting varied, and roughly included the tumor bed and LN basin (porta hepatis, hepatic artery, pancreaticoduodenal, celiac, and superior mesenteric artery lymph node). Several studies [10, 12, 13, 15, 18‐21] have focused on adjuvant RT in EHBD cancer patients, and their RT volumes are shown in Table 5. Sikora et al. [10] conducted adjuvant RT in AOV cancer patients including the tumor bed and porta hepatis. Another study by Robert et al. [13] which implemented RT included the tumor bed, porta hepatis, peripancreatic, superior mesenteric, and para-aortic nodes from approximately the T11/12 to L2/3 vertebral body levels. In our study, the first site of LR recurrence was analyzed. Our results suggest that the tumor bed and the following LN stations should be included in the RT target volume, due to the associated high rate of LR recurrence: LN stations No. 8 (frequency = 14.1%), No. 9 (12.7%), No. 12 (12.7%), No. 14 (21.1%), and No. 16 (14.1%). With regards to LN station No. 16, 16a2 (frequency = 11.3%) should be included in the treatment volume, but 16a1 (1.4%), 16b1 (1.4%), and 16b2 (0%) may be omitted for reduced RT-related toxicity. As shown in Fig. 2, while the patterns were similar for the different primary tumor locations, we observed a gradual downward trend, by tumor location, from the perihilar bile duct to the AOV. For the coverage of these areas, we suggest the superior border at the T10/11 interspace to cover the tumor bed, inferior border at the L1/2 interspace to cover the proper paraaortic LN adjacent to the renal hilum, and lateral border 1 cm from the vertebra body to cover the left lateralized metastatic paraaortic LN in the anteroposterior/posteroanterior RT field. With this sophisticated target setting, dose escalation through the intensity-modulated RT technique may be possible to overcome the poor treatment outcomes.

There are several limitations to this study. First, its retrospective nature may have influenced the heterogeneous patient characteristics, especially the small number of patients who received adjuvant chemotherapy and the relatively small number of cancer patients. Second, the criteria for the judgment of recurrence by a diagnostic radiologist, and surgical technique used by a general surgeon were not constant, as this study was performed in 2 medical centers. Future multicenter randomized trials with a large number of patients are needed to confirm the role of adjuvant RT and definite RT target volume in preventing recurrence.

In conclusion, our results suggest that a close or R1 RM status may be predictive of high LR recurrence rates. For patients with these risk factors, adjuvant RT may be required. If adjuvant RT is conducted, the treatment field should encompass the tumor bed, and LN stations No. 8, No. 9, No. 12, No. 14, and No. 16 in order for the frequently affected LR recurrence areas to be covered.