Extrahepatic bile duct (EHBD) cancer is an uncommon disease in Western countries; however, about 5,000 cases are newly diagnosed every year in Korea (crude incidence rate, 10.6 per 100,000 in 2013) [1]. Although there have been considerable advancements in surgical management and multidisciplinary approaches, its aggressive nature has not been changed. Despite curative resection, which is typically pancreaticoduodenectomy (PD) for distal EHBD, more than half of patients can experience recurrence pancreaticoduodenectomy, leading to poor overall 5-year survival rates ranging from 20% to 50% [2-7]. Because there have been no randomized trials, adjuvant strategies for EHBD cancer following resection have been controversial, particularly with respect to the application of postoperative radiotherapy. However, as we previously reported, our institution has consistently provided adjuvant chemoradiotherapy (CRT) for locoregionally advanced diseases (T2-4 or node positive) and microscopic residual disease (R1 resection) after surgery [8].

Tumor location is of clinical importance and may affect survival outcomes. Distal cholangiocarcinoma (DCC) is defined as bile duct tumors between the cystic duct and the ampulla of Vater (except Klatskin tumors and ampulla of Vater cancer), which include mid common bile duct tumors (between the junction with the cystic duct and the junction with the pancreas) and distal (intrapancreatic) bile duct tumors. DCC usually shows improved outcomes compared with perihilar tumors, which may be because of earlier clinical symptoms. Nevertheless, its prognosis remains poor. Moreover, the prognostic factors for these rare tumors have not been widely established because they only comprise about 30% of EHBD cancer occurrences [9,10]. Many previous studies showed weakness in heterogeneous treatments and insufficient follow-up duration [2-7]. Therefore, we evaluated the long-term outcome of patients undergoing PD followed by adjuvant CRT for DCC in a high-volume center to identify the prognostic impact of clinicopathological factors.

This retrospective study was conducted to evaluate the long-term outcome of DCC in patients who underwent PD followed by adjuvant CRT. Although our study only analyzed a selected group of patients, the results suggest that adjuvant CRT for DCC following PD is an effective and tolerable treatment strategy without significant side effects.

As expected, long-term survival was still unsatisfactory; nevertheless, our finding of a 5-year OS rate of 48.1% was comparable or slightly better than the results of previously reported studies [2-5,7,11]. Tumor differentiation and LN metastases were identified as important predictors of survival in our study, as demonstrated in other studies [2-5,7,12]. In particular, a meta-analysis conducted by Zhou et al. [13] revealed that LN metastasis was associated with shorter OS (risk ratio, 2.35; 95% confidence interval, 1.89 to 2.93; p < 0.0001). Most studies included in this meta-analysis reported that LN metastasis has a powerful negative effect on survival. In our study, the frequency of LN metastasis was 32.6%, and patients with LN metastasis had worse survival rates than those without it (5-year OS, 53.9% vs. 36.0%; p=0.001). Node-positive disease appeared to be incurable even after adjuvant CRT; however, the LN-positive group in our study was relatively favorable, with only a median of one metastatic LN. The dissection of regional LNs in our patients (median number, 15) appears to be sufficient according to a recent study that evaluated the optimal extent of LN dissection in cholangiocarcinoma and suggested that a total LN count of 11 or more be used as the threshold for recommendation of DCC [14]. Therefore, the number of metastatic LNs in our patients may not be an underestimated value. The poor outcome after surgery and adjuvant CRT suggests that approaches other than upfront surgery may need to be considered, especially in cases of LN-positive disease at the time of preoperative work-up. Even after curative resection, there may be a need for more effective adjuvant strategies for patients with LN metastasis.

A positive resection margin has been considered as an adverse prognostic factor in some studies [6,7,11,13]; however, its prognostic impact has not been fully determined because of inconsistent results among studies and diverse definitions. Incidences of a positive resection margin in EHBD cancer after curative resection can vary from 10% to as high as 70%, which can be explained by differences between surgeons regarding the principle of the operation or the definition of a positive resection margin, such as whether to include carcinoma in situ [15-19]. Despite the controversy, the effects of R1 resection on survival outcomes was not significant in our DCC patients who underwent adjuvant CRT. Previous studies of adjuvant CRT also demonstrated that a comparison between patients with R0 and R1 resection showed no significant differences in OS and LRRFS [20,21]. These findings corresponded with the results of our study. Therefore, adjuvant CRT may improve outcome with R1 resection in EHBD cancer and also in DCC.

Our study had a LRR rate of 25.8%, lower than the reported range from 35% to 74% even after complete resection in the previous studies [3,7,22,23], demonstrating the important role of radiotherapy in terms of locoregional control. However, the major pattern of failure was shifted to DM, as we previously reported for EHBD cancer patients who underwent adjuvant CRT [8]. Even after maintenance chemotherapy, the DM rate was too high, which worsened patient survival and quality of life. Conversely, in the era of targeted therapy, newly developed targeted agents and immunotherapeutic agents have shown some promising results [24,25]. Therefore, to treat DM, which is not well controlled by conventional chemotherapy, and to further improve treatment outcome of this lethal disease, our efforts should be focused on incorporating new chemotherapeutic agents in a combined perioperative approach with radiotherapy.

To the best of our knowledge, no randomized controlled trials have evaluated the role of adjuvant CRT in EHBD cancer and in DCC. Given the lack of evidence supporting the application of adjuvant CRT, our favorable long-term results could help researchers establish the application of adjuvant CRT. A recent multicenter study in Korea also demonstrated that adjuvant CRT was associated with significantly improved relapse-free survival and OS in patients with R0-resected DCC [26]. Moreover, our findings showed that acute gastrointestinal toxicity caused by adjuvant radiotherapy was mild, and that late toxicity (grade 3 or more) only occurred in one patient (0.8%), even after a long-term follow-up. Other recent studies also reported that few cases of severe gastrointestinal complications were associated with radiotherapy [21,27]. Unlike perihilar tumors, radiosensitive adjacent organs such as the liver may be less affected by adjuvant radiotherapy in the case of DCC. Recent advances in radiotherapy techniques may further lower its unintended toxicity. However, further prospective trials are needed to evaluate the efficacy and safety of adjuvant CRT for DCC.

For a median follow-up of 57 months, about three-fifths of our patients had a recurrence but recurrence 5 years after surgery was rarely observed. These results were somewhat different from those of a previous study by Jang et al. [28], who reported that late recurrence after 5 years was not uncommon in EHBD cancer. However, about one-third of the patients in that study received hepatobiliary resection or bile duct resection for proximal EHBD tumor, while only one-third of the patients received adjuvant treatments. Unfortunately, further comparison of this aspect with other retrospective series was difficult because a limited number of studies have mentioned late recurrences after 5 years, possibly due to insufficient follow-up. Furthermore, some studies have suggested that late recurrence likely resulted from residual carcinoma in situ after resection, which had less malignancy and slower growth than invasive carcinoma [19,29]. However, the effects of residual carcinoma in situ on postoperative recurrence or survival have not been described in most studies and thus remain unclear. Accordingly, further studies of the characteristics of late recurrence after PD are required for the adequate management of DCC patients during a long-term follow-up.

It should be noted that there are several limitations to this study. Specifically, its retrospective nature might be a significant weakness; however, we thought that it would be difficult to conduct a prospective study because of the rarity of DCC. Moreover, although our institution offered adjuvant CRT to almost all patients who underwent PD, the patients evaluated in this study were selected ones who both underwent surgery and received adjuvant therapy. In addition, treatment-related toxicity might be underestimated because it was not considered prospectively. Finally, heterogeneous details of adjuvant CRT during a relatively long study period (for example, radiotherapy dose or type of maintenance chemotherapy) might also influence clinical outcomes.

In conclusion, we reported the actual long-term outcome of DCC in patients who underwent PD followed by adjuvant CRT. During long-term follow-up, we found that prognosis of DCC after PD was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.