Capecitabine

Cancer Treatment Reviews Cancer Treatment Re-views

Anti-Tumour Treatment

Current standards and future perspectives in adjuvant treatment for biliary tract cancers
Angela Lamarca, Julien Edeline, Mairéad G McNamara, Richard A Hubner, Masato Nagino, John Bridgewater, John Primrose, Juan W Valle
PII: S0305-7372(19)30157-4

Reference: YCTRV 101936

To appear in: Cancer Treatment Reviews Cancer Treatment Re-
views

Contents

Title page 3
Abstract 4
Introduction 5
Patterns of relapse 6
Factors associated with poor outcome 6
Adjuvant scenario prior to 2017 7
Previously available randomised clinical trials exploring the role of adjuvant therapy 7
Other non-randomised studies focused on CCA 8
Other non-randomised studies focused on GBC 8
The urgent need for further randomised studies 9
2017-2019: paradigm shift 9
The era of dedicated randomised trials for patients with CCA and GBC 9
Potential reasons for discrepant results 11
Summary of current guidelines and recommendations 14
Current caveats and future perspectives 15
Conclusion 17
References 18
Conflict of interest 29
Acknowledgement 29
Tables and figures 30
Figure 1: Reported 5-year overall survival rate for patients with resected CCA and GBC during the last 15 years are shown in the figure below 30
Table 1: Main characteristics of available phase III studies exploring the role of adjuvant treatment for GBC and CCA 31
Table 2: Ongoing trials studying the efficacy of adjuvant treatment in cholangiocarcinoma and gallbladder cancer (www.clinicaltrials.gov; last accessed October 2019). 35
Figure 2: Summary of main findings and differences within the ecent phase III trial exploring the role of adjuvant chemotherapy in biliary tract cancer. 36
Figure 3: Future perspectives and unanswered questions 38

Title page

Title: Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Article type: invited review article
Journal: Cancer Treatment Reviews
Reference software: EndNote

Authors:

Angela Lamarca1,2, Julien Edeline3, Mairéad G McNamara1,2, Richard A Hubner1,2, Masato Nagino4, John Bridgewater5, John Primrose6, Juan W Valle1,2

1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

2Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
3Department of Medical Oncology, Centre Eugene Marquis, Rennes, France 4Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan 4Department of Medical Oncology, UCL Cancer Institute, London, United Kingdom 5Department of Surgery, University of Southampton, Southampton, United Kingdom
Corresponding authors

Juan W Valle; Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. E-mail: [email protected]

Angela Lamarca; Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. E-mail: [email protected]

 

Short title; Adjuvant treatment in Biliary Tract Cancer

Abstract
Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60- 70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, including a variety of additional tumours (e.g. pancreatic and ampullary tumours) and most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.

Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.

This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.

Introduction
The term “biliary tract cancer” (BTC) includes tumours of the gallbladder (GBC), cholangiocarcinoma (CCA) and ampullary tumours. Cholangiocarcinomas are subdivided according to location into intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) [eCCA are further divided in hilar cholangiocarcinoma (hCCA) and distal cholangiocarcinoma (dCCA)].

Although BTCs account for only 0.7% of all malignant tumours and 3% of all gastrointestinal malignancies in adults, both incidence and mortality are increasing, predominantly due to a rise in iCCA (1-3). BTCs are characterised by poor prognosis, with a 5-year survival of around 5-15% when all stages are analysed jointly (4, 5).

There is an urgent need to improve outcomes for patients diagnosed with BTC (6), and three main potentially actionable areas are suggested.

First, strategies for early detection are required, since the majority of patients (around 70%) are diagnosed with advanced-stage disease (not suitable for curative surgery) (7, 8). Identification of new diagnostic biomarkers, and definition of populations at risk for development of screening strategies, are areas to explore (9, 10).

Secondly, for patients suitable for resection, the relapse rate following surgery remains high (11, 12). Even though the 5-year survival rate is slowly, but steadily increasing, for CCA and GBC (Figure 1), there is room for further improvement and effort is required not only in the identification of risk factors, but also in the development of new adjuvant strategies.

Thirdly, new strategies for management of advanced disease are urgently needed (79). For many years, cisplatin and gemcitabine has been the standard of care first-line chemotherapy schedule for patients with inoperable disease (80, 81). Triple-chemotherapy combinations are also being explored with promising results in the first-line setting (82, 83) and the combination of oxaliplatin and 5- fluorouracil (FOLFOX) has been recently established as a new second-line strategy (84). Development of new agents (85), liver-directed therapies (86-89), external beam radiotherapy (90) and targeted therapies, with inhibition of fibroblast growth factor receptor (FGFR) fusion rearrangements and isocitrate dehydrogenase (IDH)-1 and -2 mutations (91) are rapidly changing the treatment paradigm in metastatic disease (92, 93).

Until recently, the evidence supporting the role of adjuvant chemotherapy in CCA and GBC was scarce and adjuvant therapy was not considered standard practice in many countries (13). Since 2017, data from phase III randomised studies have been reported and have challenged the role of adjuvant

therapy in resected BTC (65, 77, 78). Even though interpretation of the outcomes of these studies, specifically due to discrepant findings, has not been straight forward (94), current practice has changed based on these results (95). This review summarises and provides an overview of the latest data in the field of adjuvant therapy in CCA and GBC.

Patterns of relapse
Despite potentially curative surgery, frequent relapse is the rule for CCA and GBC (13). There is a predominance for distant metastases for GBC (65, 96), while reported relapse patterns vary between studies for CCA, with some studies supporting a predominance of distant (liver) metastases (65), while others report a higher rate of loco-regional relapse (96). The fact that distant metastases seem to be predominant over local recurrence supports the use of systemic chemotherapy strategies in the adjuvant setting for GBC and CCA. However, radiotherapy is still an option for patients with R1 (microscopically-involved resection margins) disease due to risk of local recurrence; even though level of evidence is low (95).

Factors associated with poor outcome
Some of the factors associated with increased risk of relapse include the presence of R1, high serum carbohydrate antigen (CA) 19-9 and the presence of lymph node metastases (5, 55, 97-105). Some evidence does also support that patients with eCCA have increased risk of tumour recurrence (77).

In a recent series of patients with resected eCCA, the presence of post-operative CA19-9 (Hazard Ratio (HR) 2.26) and presence of lymph node infiltration (HR 2.33) were associated with worse outcomes (overall survival (OS)). Patients with resected eCCA with high pre-and post-operative CA19-9 were shown to have a higher distant metastasis rate and shorter disease-free interval (55). Involvement of adjacent structures, perineural invasion, and poorly-differentiated histology have also been associated with poor outcomes for resected eCCA (5, 103, 104, 106-110).

Factors associated with increased relapse rate and poor prognosis for resected iCCA include R1, lymphatic invasion, vascular invasion and periductal infiltrating disease (5, 98, 99, 101, 102, 106, 111), while R1-resection, depth of mural invasion, lymph node metastasis, extramural extension and perineural invasion have been proposed for GBC (97, 112-114). Prognostic nomograms have been designed for patients with a resected iCCA (11); this nomogram included serum carcinoembryonic antigen (CEA), CA19-9), tumour diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extra-hepatic metastasis, and was superior in prognostic discrimination to five other staging systems for iCCA (p<0.001).

Adjuvant scenario prior to 2017
Prior to 2017, there was a lack of dedicated randomised studies exploring adjuvant therapy in patients with CCA and GBC (105, 115). The use of adjuvant therapy (both in the form of chemotherapy or chemoradiotherapy) was supported by a meta-analysis published in 2012 by Horgan and colleagues (105). This systematic review and meta-analysis included 20 trials; one randomised study, two Surveillance, Epidemiology, and End Results (SEER) registry studies and 17 retrospective series with a total of 6,712 patients (of whom 1,787 received adjuvant treatment). Of the 20 studies included, 9, 3 and 8 included data on adjuvant radiotherapy alone, chemotherapy alone and chemo-radiotherapy, respectively.

When all studies were included (including SEER registry data), adjuvant treatment did not improve survival in the pooled analysis compared to surgery alone (odds ratio (OR) 0.74, 95%CI 0.55-1.0); moreover, no benefit was identified when gallbladder and cholangiocarcinoma were analysed separately. When the SEER registry data were excluded, there was a benefit in favour of adjuvant treatment in the pooled analysis (OR 0.53, 95%CI 0.39-0.72); with benefit for chemotherapy alone (OR 0.39, 95%CI 0.23-0.66) and for chemo-radiotherapy (OR 0.61, 95%CI 0.38-0.99), while no benefit was shown for radiotherapy alone (OR 0.98, 95%CI 0.67-1.43) (105). Horgan and colleagues analysed the benefit of adjuvant therapy in two high risk populations (R1 and presence of lymph node metastases (N1), and showed a benefit of adjuvant therapy in both groups with OR of 0.36 (95%CI 0.19-0.68) and
0.49 (95%CI 0.30-0.80), respectively.

One of the main criticisms of this meta-analysis was the fact that only one randomised study was available at the time, therefore relying on retrospective (with major risk of selection bias) and small phase II studies employing multiple different chemotherapy schedules. It was clear that further prospective studies to define the benefit of adjuvant treatment were required (13, 116) as adjuvant strategies were used variably worldwide.

Previously available randomised clinical trials exploring the role of adjuvant therapy
Only two randomised studies were available prior to 2017 (14, 117), but none were exclusively dedicated to CCA and GBC and did, instead, include a variety of pancreato-biliary tumours.
The first randomised study by Takada and colleagues in 2002 (14) evaluated adjuvant therapy with mitomycin-C and 5-fluorouracil (MF arm) versus surgery alone (control arm). The study recruited a total of 508 patients with resected pancreato-biliary tumours (including fully-resected CCA (n = 118; 58 in the MF group and 60 in the control group, but including less than half with curative-intent resection) and GBC (n = 112; 69 in the MF group and 43 in the control group). The study showed evidence of benefit for the GBC group only, both in terms of OS (5-year OS rate was 26.0% (MF group)

14.4% (control group); p-value 0.0367) and disease-free survival (RFS) (5-year OS rate was 20.3% (MF group) 11.6% (control group); p-value 0.0210). No benefit was identified for patients with CCA, either in terms of OS (5-year OS rate was 26.7 % (MF group) vs 24.1% (control group); p-value >0.05) or RFS (5-year RFS rate was 20.7% (MF group) vs 15.8% (control group); p-value 0.8892) (14). Based on these findings, there was evidence supporting the role of adjuvant chemotherapy for GBC, even though its role remained unclear for CCA.
The ESPAC-3 trial explored the role of adjuvant chemotherapy for resected pancreato-biliary tumours (117). In this trial, 428 patients with periampullary malignancies (a heterogeneous group including 297 ampullary cancers, 96 bile duct cancers and 35 “other” subtypes) were randomised after curative surgery to observation alone, adjuvant 5-FU or adjuvant gemcitabine chemotherapy. In the 96 patients with CCA, adjuvant chemotherapy did not improve OS (27.2 months (95% CI 15.4-31.9) vs 18.3 months (95% CI 12.9-28.7) vs 19.5 months (95% CI 16.2-36.1) for the observation, 5-FU and gemcitabine
groups, respectively) (117).

Other non-randomised studies focused on CCA
The role of adjuvant radiotherapy and chemotherapy has been explored in small phase II and retrospective studies. The available data for adjuvant chemotherapy was based on retrospective studies only (49, 52, 56, 118-122), most of which employed gemcitabine-based regimens with inconsistent findings. Adjuvant radiotherapy, either alone or with radio-sensitising chemotherapy, after resection of CCA had not shown a clear benefit (4) (123-126). Some retrospective and phase II trials appeared to show a benefit compared to surgery alone (119, 127-131), predominantly for incompletely-resected patients. A meta-analysis summarising adjuvant radiotherapy or chemo- radiotherapy studies in eCCA reported that radiotherapy significantly improved OS compared with surgery alone (HR 0.62; 95%CI 0.48-0.78, p<0.001) (132). One of the largest retrospective series exploring the role of adjuvant radiotherapy included a total of 3,839 patients with iCCA from the SEER database (133). The median overall survival was 11 months (95% CI 9-13) for patients treated with surgery followed by adjuvant radiotherapy, versus 6 months (95% CI 5-6) for the group receiving surgery alone; p-value 0.014. Differences were significant when adjusted for other prognostic factors in the multivariable analysis (HR, 0.82 (95% CI, 0.70-0.96)).

Other non-randomised studies focused on GBC
In addition to the randomised phase III study by Takada and colleagues, (14), adjuvant radiotherapy (72, 134-136) and chemo-radiotherapy (45, 69, 74, 137-139) for resected GBC have been explored in multiple phase II and retrospective studies. The largest series was from SEER including 3,187 patients with GBC which showed that adjuvant radiotherapy was associated with improved OS (14 vs. 8

months; p≤0.001) (135). There was also evidence suggesting that those patients with lymph node- positive disease and T2-T3 tumours, appeared to benefit the most from radiotherapy (140) and chemo-radiotherapy (12, 137).

The urgent need for further randomised studies
The two randomised studies available prior to 2017 recruited a wide spectrum of pancreato-biliary malignancies (14, 117), and even though multiple phase II and retrospective studies had been reported, these were heavily influenced by selection bias; and contained a heterogeneous component of radiotherapy and chemotherapy schedules with discrepant findings. Even though some evidence suggested that those patients with poor prognostic factors such as R1 and N1 were the ones deriving the most benefit from adjuvant therapy (105, 141). Therefore, there was an urgent need for dedicated and appropriately powered randomised clinical trials exploring the role of adjuvant strategies following curative resection for patients diagnosed with CCA and GBC (7, 13).

2017-2019: paradigm shift
The era of dedicated randomised trials for patients with CCA and GBC
Three phase III randomised clinical trials were reported and published between 2017 and 2019, all focused on patients with resected BTC (including CCA and GBC) and exploring the role of chemotherapy compared to observation alone after curative surgery (65, 77, 78). Table 1 and Figure 2 provide a summary of the design and main findings of these clinical trials.

The BCAT trial randomised patients to gemcitabine (Gem) versus observation alone (65). A total of 226 patients were randomised to Gem (n=117 patients) and observation alone (109 patients; 1 patient was not eligible and therefore excluded from the analysis). Patient demographics were well balanced between study groups. Only patients with eCCA were included in the BCAT trial, including perihilar and distal CCAs only. Around 35.9% (Gem arm) and 33.3% (observation arm) of patients had N1 disease, and the rate of R1-resection was 9.4% in the Gem arm and 13.0% in the observation arm. Chemotherapy was well tolerated, with 52.1% of patients completing the full course of adjuvant Gem. The primary end point was OS; the study identified no significant differences in OS (median 62.3 months (Gem) vs 63.8 months (observation); HR 1.01 (95% CI 0.70-1.45; p-value 0.964). There was no evidence of benefit in RFS (median 36.0 months (Gem) vs 39.9 months (observation arm); HR 0.93 (95% CI 0.66-1.32); p-value 0.693). Based on these findings, the BCAT study failed to show a benefit from Gem chemotherapy in patients with resected eCCA.

The PRODIGE-12/ACCORD-18 trial randomised patients to gemcitabine and oxaliplatin (GemOx) versus observation alone (78). A total of 196 patients were randomised, and 95 and 99 were included

in the intention-to-treat population in the GemOx and the observation arm, respectively. A high proportion of patients included in the PRODIGE-12/ACCORD-18 trial were diagnosed with iCCA (44%) or had N1 disease (36%) and only 13% had R1 resection; these characteristics were balanced between the study arms. The study was powered to identify differences in terms of RFS, with a pre-specified HR of 0.6. The study failed to show a benefit from GemOx chemotherapy in terms of RFS (HR 0.83 (95% CI 0.58-1.19); p-value 0.31); lack of benefit was confirmed in the per-protocol population. There was also no trend towards improved OS (HR 1.08 (95% CI 0.70-1.66; p-value 0.74). Interestingly, most patients with recurrent disease developed presence of distant metastases and were treated with gemcitabine-based chemotherapy. The authors also described a trend towards worse post-relapse survival in the GemOx arm (median OS 8.0 months) versus patients in the observation arm (median OS 15.2 months); HR 1.55 (95% CI 0.98-2.47); p-value 0.06. The median number of chemotherapy cycles delivered were 12, including 10 with oxaliplatin.

The BILCAP trial randomised 447 patients to capecitabine (Cap) (223 patients) and observation alone (224 patients) and recruited patients with both CCA and GBC (77). Within the BILCAP trial, dCCA were the largest subgroup (34% in the Cap arm, 36% in the observation arm), followed by hCCA (29% in the Cap arm, 28% in the observation arm); only 19% in the Cap arm and 18% in the observation arm were iCCA. Regarding prognostic factors, 38% of the patients in each arm were R1 and 48% in the Cap arm and 46% in the observation arm were N1. The BILCAP trial was powered to identify differences in terms of OS in the intention-to-treat (ITT) population adjusted to stratification factors [institution, primary site (iCCA vs hCCA vs dCCA vs GBC), resection margin, and performance status], with a target HR of 0.69. In addition to the OS analysis in the ITT population, the study had pre-planned a sensitivity analysis of OS in the ITT population adjusting the treatment effect for identified prognostic factors and a separate analysis of OS in the per-protocol population. The median OS (ITT population) was 51.1 months (95% CI 34.6-59.1) and 36.4 months (95% CI 29.7-44.5) in the capecitabine and observation arms, respectively. Even though the BILCAP study did not meet its primary end-point in terms of OS in the ITT population (HR 0.81 (95% CI 0.63-1.04); p-value 0.097), adjuvant capecitabine was beneficial, both in terms of OS in the pre-specified ITT sensitivity analysis adjusted for nodal status, grade of disease and gender (HR 0.71 (95% CI 0.55-0.92); p-value 0.010) and in the per protocol population (HR
0.75 (95% CI 0.58-0.97); p-value 0.028). There was also benefit in terms of RFS (median 24.4 months (95% CI 18.6-35.9) and 17.5 months (95% CI 12.0-23.8); HR 0.75 (95% CI 0.58-0.98); p-value 0.033). In the BILCAP study, capecitabine was well tolerated with an expected toxicity profile and no chemotherapy-related death; 55% of the patients who started capecitabine completed the full 8 cycles of adjuvant therapy and 46% required at least one dose reduction. Median capecitabine dose was 1,250 mg/kg twice daily (inter-quartile range (IQR) 1,061-1250).

Potential reasons for discrepant results

There was variability within study design between the most relevant phase III studies discussed above, which are relevant (65, 77, 78). In addition, it is also appropriate to compare these new studies with the prior Japanese phase III study (14) to put study designs into context and highlight changes in practice over time (Table 1). Studies can be grouped according to the chemotherapy backbone employed: fluoropyrimidine-based (Takada and BILCAP) and gemcitabine-based (BCAT and PRODIGE- 12/ACCORD-18). Only one of the studies tested doublet chemotherapy (PRODIGE-12/ACCORD-18). Overall, the largest study dedicated to CCA/GBC was the BILCAP study, which also recruited patients over a longer time period (total of 11 years).
There are two main differences identified regarding study design when comparing the modern studies (65, 77, 78), with the older Takada study (14). The first is that current study designs allowed time for adequate recovery from surgery before starting adjuvant chemotherapy (maximum 12-16 weeks), whereas Takada et al. administered adjuvant chemotherapy at the time of surgery and continued 1 week after. Such recovery time may confer significant benefit by improving tolerance of adjuvant therapy, as has been shown in another disease group (142). A second difference is the current preference for administering adjuvant therapy for a pre-defined period of time (typically 6 months (65, 77, 78)), rather than continuing chemotherapy until disease progression (14).
The study design included 1:1 randomisation for all studies, with stratification factors, which included main prognostic factors such as the primary site (all studies), resection margins (BCAT, PRODIGE- 12/ACCORD-18) and lymph node metastases (BCAT and PRODIGE-12/ACCORD-18). Even though the BILCAP study did not stratify according to lymph node metastases, such characteristics were well balanced between study arms, and it is unlikely that this had any impact on findings. Similarly, BCAT and PRODIGE-12/ACCORD-18, did not stratify according to performance status but the rate of Eastern Cooperative Oncology Group (ECOG) performance status 2 patients (the group most likely to impact prognosis) was well balanced between study arms. It is worth highlighting that all the studies stratified according to the institution, an important factor to take into account at the time of evaluating treatment strategies that include any form of surgery. In fact, the BILCAP trial required patients to undergo surgery in “specialist hepato-pancreato-biliary centres” which is mandated practice in the United Kingdom; such information in other studies was not specified. This may be of relevance, especially because the number of study sites involved was similar for all the studies, with the corresponding heterogeneity in surgical expertise. Finally, if resection margins are to be used as a stratification factor, it is important to understand its definition, which varies between countries. The College of American Pathologists defines R1 as tumour cells present at the margin, while the Royal

College of Pathologists (United Kingdom) also includes tumour cells within 1 mm of the margin as R1 (143-145); the latter definition was used in the BILCAP trial only.
The primary end-point selected for each study, associated sample size calculations and planned statistical analyses require careful discussion. The majority of studies chose OS as a primary end-point, with the exception of PRODIGE-12/ACCORD-18, which selected RFS. Analysis of primary end-point in the ITT population was selected for both PRODIGE-12/ACCORD-18 and BILCAP. Even though the BCAT study analysed the primary and secondary end-points excluding the non-eligible randomised patients (likely to represent the per-protocol population), the study population only varied by 1 patient in the control arm, and therefore it is unlikely that this impacted on study findings. BILCAP was the only study that pre-specified that the primary end-point would be analysed adjusted for stratification factors, and which also pre-defined a sensitivity analysis adjusting the analysis for additional prognostic factors. For both, PRODIGE-12/ACCORD-18 and BILCAP, there was a plan for analysis of primary and secondary end-points in the per-protocol populations. Definition of such populations vary slightly between both studies, but there was a component of meeting eligibility criteria and receiving a minimum pre-set amount of adjuvant therapy in both. Interestingly, the percentage of patients excluded from the ITT population at the time of defining the per-protocol population was 3.8% in BILCAP but much higher in PRODIGE-12/ACCORD-18 (20.9%). If a proportion of these were due to early post-operative recurrence, it may highlight the need for better selection of patients for resection. Some recent work has been done in this area, and additional imaging prior to surgery in the form of 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18FDG-PET) may have a role, especially for identification of occult metastatic disease (146).
Regarding the sample size and assumptions related to these sample size calculations, it is worth highlighting that some of the studies aimed for a very ambitious benefit, such as the PRODIGE- 12/ACCORD-18 (study powered for HR of 0.6 for RFS) or the study by Takada study (aimed to identify an absolute difference in 5-year OS rate of 20%). This resulted in studies underpowered to identify small but perhaps still clinically meaningful differences, which would require larger, longer duration, and more costly studies to reliably confirm of refute.
In addition to the sample size, the maturity of the data is of relevance. Only two of these studies had actually reached the maturity of the data for analysis of the pre-defined primary end-point: PRODIGE- 12/ACCORD-18 and BILCAP. Therefore, the other two studies are underpowered for any further conclusions, including the primary end-point for which the study was theoretically powered.
When analysing RFS and comparing between studies, one wonders why capecitabine showed a benefit in term of RFS while GemOx did not. As mentioned above, the PRODIGE-12/ACCORD-18 study was adequately-powered and data maturity in terms of RFS events was appropriate. In fact, median RFS in

the control arms are similar (18.5 (PRODIGE-12/ACCORD-18) vs 17.5 (BILCAP) months), suggesting that both study populations were comparable, at least with respect to RFS time. One of the potential explanations may be in the length of follow-up. When reporting HRs, the separation of the respective curves in the Kaplan-Meier graph is relevant. In the BILCAP trial, the separation of the curves for RFS initiated at the beginning of follow-up and runs in parallel throughout (HR 0.75 in the ITT population). In contrast, in the PRODIGE-12/ACCORD-18 study, the curves converge at month 48. This may reflect the fact that the median follow-up for PRODIGE-12/ACCORD-18 trials was shorter (median 46.5 months) than BILCAP (median follow-up 60 months). This could also explain why the median RFS for the GemOx arm in this study was longer than for capecitabine in the BILCAP study (30.4 (PRODIGE- 12/ACCORD-18) vs 24.4 (BILCAP) months), which, despite overlapping 95% CIs, may represent overoptimistic estimations due to shorter follow-up for censored patients in PRODIGE-12/ACCORD-
18. The fact that median RFS in PRODIGE-12/ACCORD-18 was “achieved at a plateau with the largest separation between the curves” could also make the median RFS less representative of the true difference (78). The fact that radiological assessment was more frequently performed for the PRODIGE-12/ACCORD-18 trial (3-monthly during the first 2 years, 6-monthly thereafter) than for the BILCAP trial (6-monthly during the first 2 years, annually thereafter) is unlikely to have impacted on the above-mentioned differences, since it would have skewed the findings in the contrary direction. In terms of OS, both the control and the experimental median OS were longer in the PRODIGE- 12/ACCORD-18 study when compared to BILCAP. Once again, it is unlikely that this represents a real effect or any differences between study populations, and is more likely to be a reflection of overoptimistic estimations due to limitations derived from shorter follow-up and lack of OS data maturity. In addition to differences in follow-up time, power and data maturity, there are some imbalances in the subpopulations of BTCs recruited between studies. The BCAT study limited recruitment to eCCA alone, with almost half split between hCCA and dCCA; this was also the most prevalent population in BILCAP. The PRODIGE-12/ACCORD-18 had a predominance of iCCA. Whether this impacts on findings cannot be fully excluded, since there is some evidence suggesting that iCCA may have a more favourable natural history (147), likely reflective of different molecular biology (91). It has also been suggested that in view of worse response to GemOx in previous studies for the GBC population (148), the fact that resected GBC were included in PRODIGE-12/ACCORD-18 could have negatively affected the findings (78).In addition to the differences in the subtypes of BTC recruited into the different studies, there was also a higher proportion of patients harbouring poor prognosis factors (such as R1 and N1 disease, previously reported to be the subgroups benefiting the most from chemotherapy (105, 141)) in the BILCAP study and could maybe also explain the positive findings of this study (78).

One of the main criticisms of the BILCAP study is the limited absolute reduction in relapse rate (65% vs 60%) when the study did not show a benefit in RFS after the 24 months from randomisation (HR
1.48 (95% CI 0.80-2.77); p-value 0.21), raising the possibility “that capecitabine only defers recurrence” (149). Relapse rate reported in all studies was similar, highlighting that this is an ongoing issue to resolve. The 5-year survival data from the BILCAP trial is awaited; if 5-year OS benefit is confirmed, a potential real effect of capecitabine increasing the rate of cure and not only delaying recurrence may then be confirmed
The fact that recurrent disease is mainly in the form of distant metastases was already known and is the rationale for adjuvant strategies with systemic chemotherapy. However, at the time of recurrence, clinicians and patients are facing among others, two main issues. Firstly, the majority of patients will have recurrent disease which is not amenable to surgical options, therefore entering a palliative pathway with the implications on prognosis that this implies. Secondly, the selection of the first-line palliative chemotherapy is often influenced by which adjuvant therapy the patient previously received, and the time between the adjuvant therapy and recurrence. Data on palliative treatment were not recorded in the BILCAP study but were reported in the PRODIGE-12/ACCORD-18 study and highlight an important message. Choice of first-line chemotherapy was most frequently gemcitabine- based regimens in the observation arm and fluoropyrimidine-based regimens in the GemOx arm; interestingly, post-relapse OS tended to be worse in the GemOx arm (median OS 8.0 months) vs observation arm (median OS 15.2 months); HR 1.55 (95% CI 0.98-2.47); p-value 0.06. Current evidence supports use of cisplatin and gemcitabine as the standard of care in the first-line setting for advanced disease. However, the evidence for fluoropyrimidine-based chemotherapy is reserved for the second line setting. Patients who received adjuvant GemOx potentially did not receive the most effective first- choice palliative treatment. Additional questions include: are adjuvant strategies that potentially compromise first-line advanced disease chemotherapy adequate? Are we selecting clones of cells resistant to gemcitabine and oxaliplatin when these patients recur? These will require further research and need to be taken into account in further study design.

Summary of current guidelines and recommendations
ESMO guidelines (last updated in 2016) have not yet been updated and adjusted to include the latest evidence (65, 77, 78). Therefore, statements regarding adjuvant recommendations do not provide strong recommendations in favour of a specific strategy and do, in fact, highlight the lack of quality evidence at the time of these being issued. Authors concluded that “adjuvant therapy (radiotherapy, chemo-radiotherapy or chemotherapy alone) may be offered to patients on the understanding that the evidence base is weak, and only after risk–benefit assessment; participation in clinical trials should be encouraged” (7).

National Comprehensive Cancer Network (NCCN) guidelines were updated January 2019 (150), prior to the publication of the BILCAP study (77). Current NCCN guidelines support the use of adjuvant chemotherapy and chemo-radiotherapy for CCA and GBC, regardless of R0/1 and N0/1 status for GBC and eCCA. The only exception is for patients with completely resected (R0) iCCA, for whom chemo- radiotherapy is not recommended. However, the NCCN guidelines do not specify a recommended chemotherapy schedule and do suggest that schedules active in the metastatic setting could be employed: “There are phase II trials that support the following combinations: gemcitabine/cisplatin, gemcitabine/capecitabine, capecitabine/cisplatin, capecitabine/oxaliplatin, 5-fluorouracil/oxaliplatin, 5-fluorouracil/cisplatin and the single agents gemcitabine, capecitabine, and 5-fluorouracil in the unresectable or metastatic setting. The phase III BILCAP study shows improved overall survival for adjuvant capecitabine in the per-protocol analysis, but the study is not yet published, and the overall survival did not reach statistical significance in the intent-to-treat analysis”.

Following the latest evidence published, an urgent need for updated guidelines was recognised. Based on this, the ASCO guidelines were updated (95) and, based on the BILCAP trial results, recommended adjuvant capecitabine for a period of six months following curative resection of BTCs (CCA and GBC) as a new standard of care (95). Authors stated that the role of chemo-radiotherapy remained unclear and suggested its use for patients with eCCA with R1 resection (95, 151) or other high-risk factors.

Current caveats and future perspectives
We have learned multiple lessons from past clinical trials. Researchers agree on the fact that a recovery time period is required post-surgery prior to starting adjuvant therapy; based on findings from the BILCAP trial, it does seem that a maximum period of 12-16 weeks is sufficient, without adversely impacting on patient outcomes. In addition, administration of chemotherapy during a limited period of time (rather than until disease recurrence) is accepted as standard practice in the adjuvant setting and has been shown to be safe, with very limited long-term toxicity. Finally, based on the data available, chemotherapy based on fluoropyrimidines seems to be preferable, since this was used in the only two positive studies to date (14, 77). However, emerging data on molecular targets in BTC may result in novel future adjuvant designs incorporating these findings.
There are multiple clinical trials ongoing to further explore the role of adjuvant chemotherapy for BTC (Table 2). However, multiple questions remain unanswered (Figure 3).
There is a need to standardise the definition of some of the risk factors (such as R1), and also an urgent need to include these as stratification factors and to pre-plan adjusted statistical analysis. Typical risk factors such as primary tumour site, resection margins and lymph node metastases are the most important ones, but have not, yet, resulted in design alteration. Should these be used as stratification

to enrich for patients at risk of relapse in future studies? Is adjuvant therapy a “one size fits all”, as it seems at the moment? The institution should also be included as a stratification factor in studies exploring an experience-dependent intervention, such as surgery.
Similar to the need for identification and use of risk factors for tailored treatment strategies, we are in urgent need of biomarkers to better select which patients are more likely to benefit from specific adjuvant strategies. In addition, there is a need for in-depth translational research to understand mechanisms of resistance and disease recurrence. In order for researchers to learn from every patient and every trial (even if negative), it is crucial to include tissue banking and translational research questions in future studies.
In addition, adequate patient selection is key, not only for adjuvant therapy but also for surgery. There is evidence supporting the use of 18FDG-PET for identification of occult metastases in BTC and this is of huge relevance in this setting (146); to reduce the number of patients undergoing unnecessary surgery and to avoid delays in initiating systemic therapy in patients with “occult” metastatic disease. Adequate study design is crucial. The time for small phase II studies has passed and the community is now in need of further phase III randomised studies, comparing experimental arms with an active (non-observational) control arm (currently: capecitabine). Clinically-meaningful but achievable assumptions are required at time of sample size calculations; to design adequately-powered studies able to provide mature and quality data to answer the question that is being asked. Sample size calculations may require revision during the study period to ensure that assumptions made at the time of study design are still accurate and relevant. Over the years, there has been some discrepancy regarding the most adequate primary end-point for adjuvant studies (RFS vs OS). The caveats of these two are to be taken into account, since we probably need power to show benefit in both of them; unfortunately, RFS may not a good surrogate for OS due to the impact of subsequent lines of therapy on OS. Related to the study design, we have reached a point in which the feasibility of performing dedicated adjuvant trials in BTCs has been shown, despite their infrequency. However, long study durations cannot be ignored. Length of studies does not only depend on required follow-up per patient (directly related to primary end-point selected), but also the fact that all studies until now have been performed in single countries. The rationale for this approach has been related to funding and the fact that they were all investigator-led studies. Securing funding for performing multi-national studies is challenging, if not impossible. As a clinical community, we need to re-think how we collaborate in future studies. Biliary tract researchers have been successful at recruiting to randomised phase III trials in the advanced setting, when performed with adequate funding, to allow sites to open in multiple countries, even when small subpopulations of a rare cancer have been targeted (92). It is likely that researchers have to be imaginative and find ways around these issues, since it is unlikely

that third-parties (e.g. industry) will be interested in adjuvant trials exploring well-known chemotherapy agents and radiotherapy.
Relapse rate remains high, with 60% reported with capecitabine in the BILCAP study (77). New chemotherapy agents and novel combinations are probably required to overcome this issue, together with the additional challenge of how to implement some of the emerging targeted therapies in the adjuvant scenario. In addition, the role of radiotherapy is still to be elucidated, and randomised phase III studies adequately powered to answer these questions are urgently required. It is likely that patients with a higher risk of local recurrence (R1 disease) are likely to benefit more from these approaches. Emerging strategies such as peri-operative treatment and neo-adjuvant strategies are also to be explored. As previously mentioned, the schedule chosen in the adjuvant setting may impact on the first-line palliative chemotherapy that patients are exposed to, and on occasions there has been an apparent detrimental effect (78). It will be interesting to see whether a similar effect will be demonstrated in the ongoing ACTICCA-1 clinical trial (cisplatin and gemcitabine versus capecitabine; NCT02170090) and if so, this will need to be addressed in future study design, to ensure that first-line palliative treatment choice is not compromised.

Conclusion
Despite the reservations regarding the findings of the BILCAP trial, this study has changed the paradigm of adjuvant therapy, establishing capecitabine as the new standard of care for resected CCA and GBC. Unfortunately, the relapse rate remains high and it is clear that not all patients benefit from such adjuvant therapy, necessitating further randomised studies exploring the role of novel strategies. Adequately-designed and properly powered studies with sufficient follow-up are required for development of adjuvant tools which will increase the cure rate for patients with CCA and GBC.

References
1. Patel T: Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33:1353-1357, 2001

2. Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al.: Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut 48:816-820, 2001

3. Vauthey JN, Blumgart LH: Recent advances in the management of cholangiocarcinomas. Semin Liver Dis 14:109-114, 1994

4. Anderson C, Kim R: Adjuvant therapy for resected extrahepatic cholangiocarcinoma: a review of the literature and future directions. Cancer Treat Rev 35:322-327, 2009

5. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al.: Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245:755-762, 2007

6. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al.: Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS- CCA). Nat Rev Gastroenterol Hepatol 13:261-280, 2016

7. Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D: Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27:v28-v37, 2016

8. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvise M, Lamarca A: Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int:10, 2019

9. Macias RIR, Kornek M, Rodrigues PM, Paiva NA, Castro RE, Urban S, et al.: Diagnostic and prognostic biomarkers in cholangiocarcinoma. Liver Int 39 Suppl 1:108-122. doi: 10.1111/liv.14090.:108-122, 2019

10. Bailey A, Shah SA: Screening high risk populations for cancer: Hepatobiliary. J Surg Oncol 120:847-850, 2019

11. Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, et al.: Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol %20;31:1188-1195, 2013

12. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al.: Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol 29:4627-4632, 2011

13. Lamarca A VJ: Should patients with resected bile duct cancer receive an adjuvant treatment?
The Journal of OncoPathology, Volume 2, Number 4, November 2014, pp 57-68(12), 2014

14. Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al.: Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective

randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95:1685-1695, 2002

15. Zhu HF, Li J, Huang L, Yan YQ: Intrahepatic cholangiocarcinoma: a clinicopathologic study of 37 resected cases. Hepatogastroenterology 60:263-267, 2013

16. Nagino M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, et al.: Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg 258:129-140, 2013

17. Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nimura Y, et al.: Hepatopancreatoduodenectomy for cholangiocarcinoma: a single-center review of 85 consecutive patients. Ann Surg 256:297-305, 2012

18. Glazer ES, Liu P, Abdalla EK, Vauthey JN, Curley SA: Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg 16:1666-1671, 2012

19. Giuliante F, Ardito F, Vellone M, Nuzzo G: Liver resections for hilar cholangiocarcinoma. Eur Rev Med Pharmacol Sci 14:368-370, 2010

20. Ercolani G, Zanello M, Grazi GL, Cescon M, Ravaioli M, Del Gaudio M, et al.: Changes in the surgical approach to hilar cholangiocarcinoma during an 18-year period in a Western single center. J Hepatobiliary Pancreat Sci 17:329-337, 2010

21. Nagino M, Nimura Y, Nishio H, Ebata T, Igami T, Matsushita M, et al.: Hepatectomy with simultaneous resection of the portal vein and hepatic artery for advanced perihilar cholangiocarcinoma: an audit of 50 consecutive cases. Ann Surg 252:115-123, 2010

22. Lee SG, Song GW, Hwang S, Ha TY, Moon DB, Jung DH, et al.: Surgical treatment of hilar cholangiocarcinoma in the new era: the Asan experience. J Hepatobiliary Pancreat Sci 17:476- 489, 2010

23. Zhao HL, Wei ZG, He JF, Liu JS, Zhao Y, Bao MS: [Experience of surgical resection of Bismuth- Corlette type I and II hilar cholangiocarcinoma]. Zhonghua Wai Ke Za Zhi 47:1145-1147, 2009

24. Igami T, Nishio H, Ebata T, Yokoyama Y, Sugawara G, Nimura Y, et al.: Surgical treatment of hilar cholangiocarcinoma in the “new era”: the Nagoya University experience. J Hepatobiliary Pancreat Sci 17:449-454, 2010

25. Saiura A, Yamamoto J, Kokudo N, Koga R, Seki M, Hiki N, et al.: Intrahepatic cholangiocarcinoma: analysis of 44 consecutive resected cases including 5 cases with repeat resections. Am J Surg 201:203-208, 2011

26. Allen PJ, Reiner AS, Gonen M, Klimstra DK, Blumgart LH, Brennan MF, et al.: Extrahepatic cholangiocarcinoma: a comparison of patients with resected proximal and distal lesions. HPB (Oxford) 10:341-346, 2008

27. Yedibela S, Demir R, Zhang W, Meyer T, Hohenberger W, Schonleben F: Surgical treatment of mass-forming intrahepatic cholangiocarcinoma: an 11-year Western single-center experience in 107 patients. Ann Surg Oncol 16:404-412, 2009

28. Konstadoulakis MM, Roayaie S, Gomatos IP, Labow D, Fiel MI, Miller CM, et al.: Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery 143:366-374, 2008

29. Hidalgo E, Asthana S, Nishio H, Wyatt J, Toogood GJ, Prasad KR, et al.: Surgery for hilar cholangiocarcinoma: the Leeds experience. Eur J Surg Oncol 34:787-794, 2008

30. Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI: What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 23:766-770, 2008

31. Mansfield SD, Barakat O, Charnley RM, Jaques BC, O’Suilleabhain CB, Atherton PJ, et al.: Management of hilar cholangiocarcinoma in the North of England: pathology, treatment, and outcome. World J Gastroenterol 11:7625-7630, 2005

32. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ: Surgical management of hilar cholangiocarcinoma. Ann Surg 241:693-699, 2005

33. Kawarada Y, Yamagiwa K, Das BC: Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg 183:679-685, 2002

34. Lillemoe KD, Cameron JL: Surgery for hilar cholangiocarcinoma: the Johns Hopkins approach. J Hepatobiliary Pancreat Surg 7:115-121, 2000

35. Harrison LE, Fong Y, Klimstra DS, Zee SY, Blumgart LH: Surgical treatment of 32 patients with peripheral intrahepatic cholangiocarcinoma. Br J Surg 85:1068-1070, 1998

36. Su CH, Tsay SH, Wu CC, Shyr YM, King KL, Lee CH, et al.: Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg 223:384-394, 1996

37. Muller B, Sola JA, Carcamo M, Ciudad AM, Trujillo C, Cerda B: Adjuvant chemoradiation for resected gallbladder cancer: Treatment strategies for one of the leading causes of cancer death in Chilean women. Indian J Cancer 50:184-188, 2013

38. Yang XW, Yang J, Li L, Man XB, Zhang BH, Shen F, et al.: Analysis of the relationships between clinicopathologic factors and survival in gallbladder cancer following surgical resection with curative intent. PLoS One 7:e51513, 2012

39. Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, et al.: Postoperative chemoradiotherapy for gallbladder cancer. Strahlenther Onkol 188:388-392, 2012

40. Regimbeau JM, Fuks D, Bachellier P, Le Treut YP, Pruvot FR, Navarro F, et al.: Prognostic value of jaundice in patients with gallbladder cancer by the AFC-GBC-2009 study group. Eur J Surg Oncol 37:505-512, 2011

41. Miura F, Asano T, Amano H, Toyota N, Wada K, Kato K, et al.: New prognostic factor influencing long-term survival of patients with advanced gallbladder carcinoma. Surgery 148:271-277, 2010

42. Park JS, Yoon DS, Kim KS, Choi JS, Lee WJ, Chi HS, et al.: [Analysis of prognostic factors after curative resection for gallbladder carcinoma]. Korean J Gastroenterol 48:32-36, 2006

43. Balachandran P, Agarwal S, Krishnani N, Pandey CM, Kumar A, Sikora SS, et al.: Predictors of long-term survival in patients with gallbladder cancer. J Gastrointest Surg 10:848-854, 2006

44. Onoyama H, Ajiki T, Takada M, Urakawa T, Saitoh Y: Does radical resection improve the survival in patients with carcinoma of the gallbladder who are 75 years old and older? World J Surg 26:1315-1318, 2002

45. Kresl JJ, Schild SE, Henning GT, Gunderson LL, Donohue J, Pitot H, et al.: Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 52:167-175, 2002

46. Fong Y, Jarnagin W, Blumgart LH: Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 232:557-569, 2000

47. Tsukada K, Hatakeyama K, Kurosaki I, Uchida K, Shirai Y, Muto T, et al.: Outcome of radical surgery for carcinoma of the gallbladder according to the TNM stage. Surgery 120:816-821, 1996

48. Roos E, Strijker M, Franken LC, Busch OR, van Hooft JE, Klumpen HJ, et al.: Comparison of short- and long-term outcomes between anatomical subtypes of resected biliary tract cancer in a Western high-volume center. HPB (Oxford):10, 2019

49. Akahoshi K, Ban D, Kuboki R, Oba A, Ono H, Mitsunori Y, et al.: Orotate phosphoribosyltransferase as a predictor of benefit from S-1 adjuvant chemotherapy for cholangiocarcinoma patients. J Gastroenterol Hepatol 34:1108-1115, 2019

50. Ebata T, Mizuno T, Yokoyama Y, Igami T, Yamaguchi J, Onoe S, et al.: Predictive performance of Blumgart T staging for perihilar cholangiocarcinoma in a Japanese center. J Hepatobiliary Pancreat Sci:10, 2019

51. Akashi K, Ebata T, Mizuno T, Yokoyama Y, Igami T, Yamaguchi J, et al.: Surgery for perihilar cholangiocarcinoma from a viewpoint of age: Is it beneficial to octogenarians in an aging society? Surgery 164:1023-1029, 2018

52. Hester C, Nassour I, Adams-Huet B, Augustine M, Choti MA, Minter RM, et al.: Improved Survival in Surgically Resected Distal Cholangiocarcinoma Treated with Adjuvant Therapy: a Propensity Score Matched Analysis. J Gastrointest Surg 22:2080-2087, 2018

53. Jun SY, Sung YN, Lee JH, Park KM, Lee YJ, Hong SM: Validation of the Eighth American Joint Committee on Cancer Staging System for Distal Bile Duct Carcinoma. Cancer Res Treat 51:98- 111, 2019

54. Komaya K, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T, et al.: Recurrence after curative-intent resection of perihilar cholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach. Surgery 163:732-738, 2018

55. Kim BH, Kim E, Kim K, Jang JY, Kim SW, Oh DY, et al.: The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma. J Surg Oncol 117:380-388, 2018

56. Reames BN, Bagante F, Ejaz A, Spolverato G, Ruzzenente A, Weiss M, et al.: Impact of adjuvant chemotherapy on survival in patients with intrahepatic cholangiocarcinoma: a multi- institutional analysis. HPB (Oxford) 19:901-909, 2017

57. Higuchi R, Yazawa T, Uemura S, Izumo W, Furukawa T, Yamamoto M: High-grade dysplasia/carcinoma in situ of the bile duct margin in patients with surgically resected node- negative perihilar cholangiocarcinoma is associated with poor survival: a retrospective study. J Hepatobiliary Pancreat Sci 24:456-465, 2017

58. Im JH, Seong J, Lee IJ, Park JS, Yoon DS, Kim KS, et al.: Surgery Alone Versus Surgery Followed by Chemotherapy and Radiotherapy in Resected Extrahepatic Bile Duct Cancer: Treatment Outcome Analysis of 336 Patients. Cancer Res Treat 48:583-595, 2016

59. Mao K, Liu J, Sun J, Zhang J, Chen J, Pawlik TM, et al.: Patterns and prognostic value of lymph node dissection for resected perihilar cholangiocarcinoma. J Gastroenterol Hepatol 31:417- 426, 2016

60. Okuno M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T, et al.: Evaluation of inflammation-based prognostic scores in patients undergoing hepatobiliary resection for perihilar cholangiocarcinoma. J Gastroenterol 51:153-161, 2016

61. Ercolani G, Dazzi A, Giovinazzo F, Ruzzenente A, Bassi C, Guglielmi A, et al.: Intrahepatic, peri- hilar and distal cholangiocarcinoma: Three different locations of the same tumor or three different tumors? Eur J Surg Oncol 41:1162-1169, 2015

62. Sakata J, Wakai T, Matsuda Y, Ohashi T, Hirose Y, Ichikawa H, et al.: Comparison of Number Versus Ratio of Positive Lymph Nodes in the Assessment of Lymph Node Status in Extrahepatic Cholangiocarcinoma. Ann Surg Oncol 23:225-234, 2016

63. Hakeem AR, Marangoni G, Chapman SJ, Young RS, Nair A, Hidalgo EL, et al.: Does the extent of lymphadenectomy, number of lymph nodes, positive lymph node ratio and neutrophil- lymphocyte ratio impact surgical outcome of perihilar cholangiocarcinoma? Eur J Gastroenterol Hepatol 26:1047-1054, 2014

64. Onoe S, Shimoyama Y, Ebata T, Yokoyama Y, Igami T, Sugawara G, et al.: Prognostic delineation of papillary cholangiocarcinoma based on the invasive proportion: a single-institution study with 184 patients. Surgery 155:280-291, 2014

65. Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, et al.: Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg 105:192-202, 2018

66. Kim TH, Woo SM, Lee WJ, Oh ES, Youn SH, Moon SH, et al.: Benefit of Adjuvant Chemoradiotherapy in Resected Gallbladder Carcinoma. Sci Rep 9:11770-48099, 2019

67. Manterola C, Grande L, Otzen T, Conejeros R: Extension of surgical treatment and adjuvant chemotherapy in patients with incidental gallbladder cancer. Cir Cir 87:313-320, 2019

68. Mizukami T, Kamachi H, Mitsuhashi T, Einama T, Hatanaka Y, Kamiyama T, et al.: Cytoplasmic CD133 expression correlates with histologic differentiation and is a significant prognostic factor in extrahepatic bile duct cancer and gallbladder cancer. Oncol Lett 16:6423-6430, 2018

69. Gu B, Qian L, Yu H, Hu J, Wang Q, Shan J, et al.: Concurrent Chemoradiotherapy in Curatively Resected Gallbladder Carcinoma: A Propensity Score-Matched Analysis. Int J Radiat Oncol Biol Phys 100:138-145, 2018

70. Go SI, Kim YS, Hwang IG, Kim EY, Oh SY, Ji JH, et al.: Is There a Role for Adjuvant Therapy in R0 Resected Gallbladder Cancer?: A Propensity Score-Matched Analysis. Cancer Res Treat 48:1274-1285, 2016

71. Palanisamy S, Patel N, Sabnis S, Palanisamy N, Vijay A, Palanivelu P, et al.: Laparoscopic radical cholecystectomy for suspected early gall bladder carcinoma: thinking beyond convention. Surg Endosc 30:2442-2448, 2016

72. Wang J, Narang AK, Sugar EA, Luber B, Rosati LM, Hsu CC, et al.: Evaluation of Adjuvant Radiation Therapy for Resected Gallbladder Carcinoma: A Multi-institutional Experience. Ann Surg Oncol 22 Suppl 3:S1100-6. doi: 10.1245/s10434-015-4685-y. Epub;%2015 Jul 30.:S1100- S1106, 2015

73. Yamaguchi J, Kaneoka Y, Maeda A, Takayama Y, Onoe S, Isogai M: Benefit of extended radical surgery for incidental gallbladder carcinoma. Surg Today 46:453-459, 2016

74. Agrawal S, Gupta PK, Rastogi N, Lawrence A, Kumari N, Das KJ, et al.: Outcomes of adjuvant chemoradiation and predictors of survival after extended cholecystectomy in gall bladder carcinoma: a single institution experience from an endemic region. J Gastrointest Cancer 46:48-53, 2015

75. Pais-Costa SR, Farah JF, Artigiani-Neto R, Martins SJ, Goldenberg A: Evaluation of P53, E- cadherin, Cox-2, and EGFR protein immunoexpression on prognostic of resected gallbladder carcinoma. Arq Bras Cir Dig 27:126-132, 2014

76. Matsumoto N, Morine Y, Utsunomiya T, Imura S, Ikemoto T, Arakawa Y, et al.: Role of CD151 expression in gallbladder carcinoma. Surgery 156:1212-1217, 2014

77. John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019

78. Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, et al.: Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12- ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol 37:658-667, 2019

79. Lamarca A, Barriuso J, McNamara MG, Valle JW: Biliary Tract Cancer: State of the Art and potential role of DNA Damage Repair. Cancer Treat Rev 70:168-177. doi: 10.1016/j.ctrv.2018.09.002. Epub;%2018 Sep 8.:168-177, 2018

80. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al.: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273-1281, 2010

81. Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al.: Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 103:469-474, 2010

82. Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, et al.: Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol 5:824-830, 2019

83. Sakai et al: Randomized phase III study of Gemcitabine, Cisplatin plus S-1 (GCS) versus Gemcitabine, Cisplatin (GC) for Advanced Biliary Tract Cancer. 2018

84. Angela Lamarca et al: ABC-06 | A randomised phase III, multi-centre, open-label study of Active Symptom Control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol 37, 2019 (suppl; abstr 4003), 2019 (abstr)

85. McNamara et al: A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08). Presented at the ESMO Annual Meeting 2018; Annals of Oncology (2018) 29 (suppl_8): viii205-viii270. 10.1093/annonc/mdy282, 2018

86. Al-Adra DP, Gill RS, Axford SJ, Shi X, Kneteman N, Liau SS: Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol 41:120-127, 2015

87. Burger I, Hong K, Schulick R, Georgiades C, Thuluvath P, Choti M, et al.: Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 16:353-361, 2005

88. Ibrahim SM, Mulcahy MF, Lewandowski RJ, Sato KT, Ryu RK, Masterson EJ, et al.: Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer 113:2119-2128, 2008

89. J.Edeline et al: Radioembolisation plus chemotherapy for first-line treatment of locally- advanced intrahepatic cholangiocarcinoma:a phase 2 clinical trial. JAMA Oncol 2019 oct 31. doi 10.1001/jamaoncol.2019.3702.

90. Hong TS, Wo JY, Yeap BY, Ben-Josef E, McDonnell EI, Blaszkowsky LS, et al.: Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol 34:460-468, 2016

91. Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX: New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov:10-8290, 2017

92. G.K.Abou-Alfa TMMMJRKKSLea: ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Annals of Oncology (2019) 30 (suppl_5): v851- v934 10 1093/annonc/mdz394, 2019 (abstr)

93. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, et al.: Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J Clin Oncol %20;36:276-282, 2018

94. Lamarca A, Gambardella V, Cejalvo JM, Fleitas-Kanonnikoff T, Cervantes A: In the literature: June 2019. ESMO Open %20;4:e000547, 2019

95. Shroff RT, Kennedy EB, Bachini M, Bekaii-Saab T, Crane C, Edeline J, et al.: Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J Clin Oncol:JCO1802178, 2019

96. Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, Dematteo RP, et al.: Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 98:1689-1700, 2003

97. Weber SM, Dematteo RP, Fong Y, Blumgart LH, Jarnagin WR: Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg 235:392-399, 2002

98. Madariaga JR, Iwatsuki S, Todo S, Lee RG, Irish W, Starzl TE: Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg 227:70-79, 1998

99. Hanazaki K, Kajikawa S, Shimozawa N, Shimada K, Hiraguri M, Koide N, et al.: Prognostic factors of intrahepatic cholangiocarcinoma after hepatic resection: univariate and multivariate analysis. Hepatogastroenterology 49:311-316, 2002

100. Tanaka S, Hirohashi K, Tanaka H, Yamamoto T, Kubo S, Shuto T, et al.: Prognostic factors in patients with carcinoma of the papilla of Vater. Hepatogastroenterology 49:1116-1119, 2002

101. Miwa S, Miyagawa S, Kobayashi A, Akahane Y, Nakata T, Mihara M, et al.: Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery. J Gastroenterol 41:893-900, 2006

102. Jan YY, Yeh CN, Yeh TS, Hwang TL, Chen MF: Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg 29:894- 898, 2005

103. Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, et al.: Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma–part 3: update on 5-year survival. J Gastrointest Surg 9:1191-1204, 2005

104. Wade TP, Prasad CN, Virgo KS, Johnson FE: Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987-1991. J Surg Oncol 64:242-245, 1997

105. Horgan AM, Amir E, Walter T, Knox JJ: Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 30:1934-1940, 2012

106. Aljiffry M, Walsh MJ, Molinari M: Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol 15:4240-4262, 2009

107. Seiler CA, Wagner M, Bachmann T, Redaelli CA, Schmied B, Uhl W, et al.: Randomized clinical trial of pylorus-preserving duodenopancreatectomy versus classical Whipple resection-long term results. Br J Surg 92:547-556, 2005

108. Seiler CA, Wagner M, Sadowski C, Kulli C, Buchler MW: Randomized prospective trial of pylorus-preserving vs. Classic duodenopancreatectomy (Whipple procedure): initial clinical results. J Gastrointest Surg 4:443-452, 2000

109. Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF: Outcome of treatment for distal bile duct cancer. Br J Surg 83:1712-1715, 1996

110. Chen CY, Shiesh SC, Tsao HC, Lin XZ: The assessment of biliary CA 125, CA 19-9 and CEA in diagnosing cholangiocarcinoma–the influence of sampling time and hepatolithiasis. Hepatogastroenterology 49:616-620, 2002

111. Hirohashi K, Uenishi T, Kubo S, Yamamoto T, Tanaka H, Shuto T, et al.: Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes. Hepatogastroenterology 49:326-329, 2002

112. AJCC Cancer Staging Manual, Seventh Edition, in , 2010

113. Kondo N, Furuya H, Yamamoto S, Nakano A, Sakashita Y: Diffuse large B-cell lymphoma in the ampulla of vater causing obstructive jaundice: report of a case. Surg Today 38:76-80, 2008

114. Eckel F, Brunner T, Jelic S: Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21 Suppl 5:v65-v69, 2010

115. Zhu AX, Knox JJ: Adjuvant therapy for intrahepatic cholangiocarcinoma: the debate continues. Oncologist 17:1504-1507, 2012

116. Bariani GM, Braghiroli MI, Riechelmann RP: Poor evidence to standardize adjuvant treatment for patients with biliary tract cancer. J Clin Oncol 30:4173, 2012

117. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al.: Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 308:147-156, 2012

118. Kelley ST, Bloomston M, Serafini F, Carey LC, Karl RC, Zervos E, et al.: Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy. Am Surg 70:743- 748, 2004

119. Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, et al.: Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 46:581-587, 2000

120. Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, et al.: Gemcitabine- based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg 13:1470-1479, 2009

121. Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Sakabe R, et al.: Adjuvant chemotherapy with gemcitabine and S-1 after surgical resection for advanced biliary carcinoma: outcomes and prognostic factors. J Hepatobiliary Pancreat Sci 19:306-313, 2012

122. Yubin L, Chihua F, Zhixiang J, Jinrui O, Zixian L, Jianghua Z, et al.: Surgical management and prognostic factors of hilar cholangiocarcinoma: experience with 115 cases in China. Ann Surg Oncol 15:2113-2119, 2008

123. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al.: Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224:463-473, 1996

124. Gonzalez GD, Gouma DJ, Rauws EA, van Gulik TM, Bosma A, Koedooder C: Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma. Ann Oncol 10 Suppl 4:215-220, 1999

125. Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, et al.: Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 221:788-797, 1995

126. Vern-Gross TZ, Shivnani AT, Chen K, Lee CM, Tward JD, MacDonald OK, et al.: Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys 81:189-198, 2011

127. Kraybill WG, Lee H, Picus J, Ramachandran G, Lopez MJ, Kucik N, et al.: Multidisciplinary treatment of biliary tract cancers. J Surg Oncol 55:239-245, 1994

128. Borghero Y, Crane CH, Szklaruk J, Oyarzo M, Curley S, Pisters PW, et al.: Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol 15:3147-3156, 2008

129. Kim S, Kim SW, Bang YJ, Heo DS, Ha SW: Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys 54:414-419, 2002

130. Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ, et al.: Improved survival in resected biliary malignancies. Surgery 132:555-563, 2002

131. Nelson JW, Ghafoori AP, Willett CG, Tyler DS, Pappas TN, Clary BM, et al.: Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 73:148-153, 2009

132. Bonet BM, Allal AS, Gich I, Sole JM, Carrio I: Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. Cancer Treat Rev 38:111-119, 2012

133. Shinohara ET, Mitra N, Guo M, Metz JM: Radiotherapy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas. Int J Radiat Oncol Biol Phys 74:1191-1198, 2009

134. Bosset JF, Mantion G, Gillet M, Pelissier E, Boulenger M, Maingon P, et al.: Primary carcinoma of the gallbladder. Adjuvant postoperative external irradiation. Cancer 64:1843-1847, 1989

135. Mojica P, Smith D, Ellenhorn J: Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease. J Surg Oncol 96:8-13, 2007

136. Mehta A, Bahadur AK, Aranya RC, Jain AK: Role of radiation therapy in carcinoma of the gall bladder–a preliminary indian experience. Trop Gastroenterol 17:22-25, 1996

137. Cho SY, Kim SH, Park SJ, Han SS, Kim YK, Lee KW, et al.: Adjuvant chemoradiation therapy in gallbladder cancer. J Surg Oncol 102:87-93, 2010

138. Gold DG, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH, et al.: Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience. Int J Radiat Oncol Biol Phys 75:150-155, 2009

139. Czito BG, Hurwitz HI, Clough RW, Tyler DS, Morse MA, Clary BM, et al.: Adjuvant external- beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 62:1030-1034, 2005

140. Wang SJ, Fuller CD, Kim JS, Sittig DF, Thomas CR, Jr., Ravdin PM: Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol 26:2112-2117, 2008

141. McNamara MG, Walter T, Horgan AM, Amir E, Cleary S, McKeever EL, et al.: Outcome of adjuvant therapy in biliary tract cancers. Am J Clin Oncol 38:382-387, 2015

142. Valle JW, Palmer D, Jackson R, Cox T, Neoptolemos JP, Ghaneh P, et al.: Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol %20;32:504-512, 2014

143. Hermanek P, Wittekind C: Residual tumor (R) classification and prognosis. Semin Surg Oncol 10:12-20, 1994

144. Deeter M, Dorer R, Kuppusamy MK, Koehler RP, Low DE: Assessment of criteria and clinical significance of circumferential resection margins in esophageal cancer. Arch Surg 144:618- 624, 2009

145. O’Neill JR, Stephens NA, Save V, Kamel HM, Phillips HA, Driscoll PJ, et al.: Defining a positive circumferential resection margin in oesophageal cancer and its implications for adjuvant treatment. Br J Surg 100:1055-1063, 2013

146. Lamarca A, Barriuso J, Chander A, McNamara MG, Hubner RA, O’Reilly D, et al.: 18F- fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: systematic review and meta-analysis. J Hepatol %20. pii: S0168-8278:10, 2019

147. Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, et al.: Advanced intrahepatic cholangiocarcinoma: post-hoc analysis of the ABC-01, -02 and -03 clinical trials. J Natl Cancer Inst:5488118, 2019

148. Andre T, Reyes-Vidal JM, Fartoux L, Ross P, Leslie M, Rosmorduc O, et al.: Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer 99:862-867, 2008

149. D Malka JE: Adjuvant capecitabine in biliary tract cancer: a standard option? Lancet Oncol 2019, 2019

150. NCCN (National Comprehensive Cancer Network): NCCN Guidelines.

151. Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, et al.: SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol %20;33:2617-2622, 2015

Conflict of interest
Angela Lamarca: Travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath. Speaker honoraria from Merck, Pfizer, Ipsen and Incyte. Advisory honoraria from EISAI, Nutricia Ipsen, and QED. Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.
Julien Edeline: Travel grant from Ipsen, Amgen, Roche. Advisory honoraria from MSD, BMS, Ipsen, Eisai, Bayer, BTG, Roche. All outside the scope of this work.
Mairéad G McNamara: Received research grant support from Servier, Ipsen and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana and Mylan. She has served on advisory boards for Celgene, Ipsen, Sirtex and Baxalta; all outside the scope of this work.
Richard Hubner: no conflict of interest to declare

Masato Nagino: no conflict of interest to declare

John Bridgewater: Consulting or Advisory role for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD oncology, Merck Serono, Servier and BMS.
John Primrose: no conflict of interest to declare

Juan W Valle: Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited Ipsen Novartis Nucana; and Travel Grants from Celgene and Nucana.

Acknowledgement
Dr Angela Lamarca has received funding from The Christie Charity.

Tables and figures
Figure 1: Reported 5-year overall survival rate for patients with resected CCA and GBC during the last 15 years are shown in the figure below
Adapted and updated from (13). Data extracted from studies reporting 5-year survival rate for patients with resected disease (last updated October 2019) (5, 14-76). Studies which included data jointly for CCA and GBC were not included (77, 78). CCA: cholangiocarcinoma; GBC: gallbladder cancer; CI: confidence interval.

Table 1: Main characteristics of available phase III studies exploring the role of adjuvant treatment for GBC and CCA.
iv: intravenously; CCA: cholangiocarcinoma, GBC, gallbladder cancer; dCCA: distal cholangiocarcinoma; hCCA: hilar cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; iCCA: intrahepatic cholangiocarinoma; OS: overall survival; RFS: relapse-free survival; TTD: time to definitive deterioration; HRQOL: health- related quality of life; ITT: intention-to-treat; IDMC: independent data monitoring committee; Mod dif: moderately differentiated; Poorly dif: poorly differentiated; Gem: gemcitabine, GemOx: gemcitabine and oxaliplatin; Cap: capecitabine; IQR: interquartile range; obs: observation; n: number of patients; %: percentage; R1: positive resection margins; R0: clear resection margins: N0: negative lymph nodes; N1: presence of metastatic regional lymph nodes.

Takada et al (14) BCAT (65) PRODIGE-12/ACCORD-18 (78) BILCAP (77)
Study design Randomised phase III; open label Randomised phase III; open label Randomised phase III; open label Randomised phase III; open label
Study arms Mitomycin C (MMC; 6 mg/m2 at the time of surgery) and 5-fluorouracil (5-FU; 310mg/m2 (iv) during 5 consecutive days on week 1 and 3 after surgery followed by daily oral 100mg/m2 from week 5 until disease recurrence) (MF arm) versus surgery alone (control arm) Gemcitabine (Gem arm; 1000mg/m2, administered iv on days 1, 8 and 15 every 4weeks for 6 cycles) vs surgery alone (control arm); time of chemo initiation not specified Gemcitabine and oxaliplatin (GemOx arm; iv Gem 1,000mg/m2 on day 1 and Ox 85mg/m2 on day 2 every 2 weeks for 12 cycles) vs surgery alone (control arm); randomisation had to take place within 3 months of surgery and GemOx started within 1 week from randomisation. Capecitabine (Cap arm; 1250mg/m² orally twice daily on days 1–14 of a 21-day cycle, for 8 cycles) vs surgery alone (control arm)
Cap started up to 12 weeks from surgery, with a maximum extension to 16 weeks from surgery.
Recruitment period April 1986-June 1992 September 2007-31 January 2011 July 2009-February 2014 March 2006-December 2017
Number of sites 31 48 33 44
country Japan Japan France United Kingdom
Randomisation; Stratification factors 1:1; stratified according to institution and primary site (CCA, GBC, pancreas, ampullary). 1:1; stratified according to lymph node status, resection margin status, primary site (hCCA vs dCCA) and institution. 1:1 random; stratified according to primary site (iCCA vs eCCA vs GBC), resection margin, lymph node involvement, and institution. 1:1; stratified according to
institution, primary site (iCCA vs hCCA vs dCCA vs GBC), resection margin, and performance status.
Sample size (randomised pts; ITT population) 508 patients randomised: CCA (n=139), GBC (n=140) 226 patients randomised (Gem (n=117) vs control (n=109)) 196 patients: 97 (GemOx; 95 included;
2 withdrew consent) vs 99 (control) 447 patients; 223 (Cap) vs 224 (control)
Sample size (per- protocol population) CCA: n=118: MF group (n=58) vs control (n=60) group)
GBC: n=112: MF group (n=69) vs control (n=43) group) 225 patients (Gem (n=117) vs control (n=108))
1patient excluded: 0.4% of total population 155 patients: 73 (GemOx) vs 82 (control)
41patient excluded: 20.9% of total population 430 patients; 210 (Cap) vs 220 (control)
17 patient excluded: 3.8% of total population
Primary end-point OS (time from the day of surgery to death from any cause) OS (time from randomization to death from any cause) RFS (time from randomization
to relapse or death from any cause) OS (time from to death from any cause or cancer-related death)

Co-primary end-point: time to definitive deterioration (TDD) of HRQOL
Pre-planned analysis (primary end-point) Per protocol population; primary end- point analysed separately for each disease group separately Per-protocol population; including all eligible randomised patients
Pre-specified subgroup analysis according to margin status, lymph node status and primary tumour site ITT population; including all randomised patients
Pre-specified exploratory per-protocol analysis was planned including patients who met inclusion criteria and who had received at least 50% of the chemotherapy dose during the first six cycles) ITT population; including all
randomised patients; adjusted to stratification factors excluding surgical centre
Pre-specified sensitivity analysis in the ITT population, adjusting the treatment effect for identified prognostic factors
Secondary end- points RFS RFS, subgroup analysis and toxicity OS, toxicity, and exploratory translational end points Per-protocol analysis (excluding ineligible patients and those failing to complete at least one cycle of Cap) of OS/RFS, RFS (ITT population), toxicity, health economics, and quality of life
Frequency of imaging assessment Not specified Every 3 months during the first 3 years after enrolment, and every 6 months thereafter until the end of follow-up (at least 5 years from registration). Every 3 months from randomization for 2 years, and then every 6 months for the next 3 years. Every 6 months for the first 24 months and at annual intervals with clinical review for up to 5 years.
Assumptions for sample size calculation A minimum of 60 patients per group required;
Assumed 5-year OS rate 15% in the control group; postulated 5-year OS increase by 20% (35%) MF arm; 5% alpha
(two-sided), power 80%.
Number of events at time of analysis: A total of 300 patients (189 events) required;
Postulated HR OS 0.85; 5% alpha (two- sided), power 80%.
Interim analysis: performed when enrolled 200 patients; alpha error adjusted (<5%) to control for multiplicity for the primary endpoint; patient recruitment early terminated due to lack of recruitment.
Number of events at time of analysis: total 119: 62 (Gem) and 57 (observation) RFS was considered as the
primary endpoint for statistical power calculation; A total of 190 patients (126 events) required;
Postulated HR OS 0.6; 5% alpha (two- sided), power 80%.
Power to show a difference in global HRQOL of at least 5 points with 180 patients included was 80%.
Number of events at time of analysis: total 126: 59 (GemOx) and 67 (observation) A minimum of 360 patients (270 events) required;
Assumed 24-month OS rate 20% in the control group; postulated 24- month OS increase by 12% (32%) Cap arm; equivalent to HR 0.71; 5% alpha (two-sided), power 80%.
IDMC recommended that the final
analyses be done once 234 events had accrued. Revisited OS rate (60%) in the control group; increase by 11% (71%); equivalent to HR 0.69; 5% alpha (two-sided), power 80%.
Number of events at time of analysis: total 243: 114 (Cap) and 131 (observation)
BTC subtype CCA (n = 118; 58 in the MF group and 60 in the control group) and GBC (n = 112; 69 in the MF group and 43 in the control group) All eCCA: 102 hCCA and 123 dCCA Any CCA/GBC: predominance of iCCA (44%) CCA/GBC: most patients had dCCA followed by hCCA; only 19% in the Cap arm and 18% in the observation arm were iCCA.
Stage and distribution of prognostic factors GBC:
stage III (33% MF vs 33% observation) stage IV (46% MF vs 60% observation) Curative surgery (45% MF vs 47% observation)
CCA:
stage III (48% MF vs 37% observation) stage III (26% MF vs 43% observation) N1 (35.9% Gem vs 33.3% observation)
stage II (51.3% Gem vs 55.6% observation)
stage III (14.5% Gem vs 13.0% observation)
R1 (9.4% Gem vs 13.0% observation)
Mod dif (45.3% Gem vs 59.3% observation) Predominance of iCCA (44%); N1 (36%) and R1 (13%); these
characteristics were balanced between the study arms
iCCA (43% GemOx vs 46% observation)
hCCA (11% GemOx vs 5% observation)
dCCA (28% GemOx vs 28% observation)
GBC (18% GemOx vs 21% observation)
N1 (35% GemOx vs 36% observation) iCCA (19% Cap vs 19% observation)
hCCA (29% Cap vs 28% observation)
dCCA (34% Cap vs 36% observation)
GBC (17% Cap vs 18% observation)
N1 (48% Cap vs 46% observation)
R1 (38% Cap vs 38% observation) Stage II (61% Cap vs 64% observation) Stage III (13% Cap vs 8% observation)

Curative surgery (59% MF vs 63% observation)
R0/1 not reported Poorly dif (12.8% Gem vs 12.0% observation) R1 (14% GemOx vs 12% observation)
Completion of chemotherapy and toxicity profile Good compliance ( 80%) was achieved with MF 61 patients (52.1%) completed chemotherapy (with (32.8%) or without (67.2%) dose reduction);
18 patients stopped Gem due to need for dose reduction to below 60% and 6 due to delay >28 days Gem median 10 cycles (mean 9.7); Ox median 10 cycles (mean 8.5)
At 12 months, prevalence of sensory neuropathy was: grade 1 (10%), grade
2 (6%), and grade 3 (4%) in the GEMOX arm. 44% of patients had at least one grade 3 toxicity; <1% had grade 4 cardiac ischaemia or infarction
Serious adverse events (21%)
55% of patients completed chemotherapy course; 10 patients (4%) had 0 cycles; median Cap dose was 1250mg/m2 twice daily (IQR 1061
- 1250mg/m2)
46% had at least one dose reduction; 32% discontinued treatment because of toxicity (hand-foot syndrome (14%), diarrhoea (13%)
Median follow-up and maturity of data All patients were followed-up for 5 years; median follow-up not provided Median follow-up was 79.4months
OS: During follow-up 62/117=52.9% (Gem) and 57/108=52.8% (observation) died.
Relapse: data maturity not reported. Median follow-up of 46.5 months
OS: During follow-up 41/95=43.2% (GemOx) and 41/99=41.4% (observation) died.
Relapse: During follow-up 59/95=62.1% (GemOx) and 67/99=67.7% (observation) progressed. Median follow-up of 60 months
OS: During follow-up 114/223=51% (Cap) and 131/224=58% (observation) died.
Relapse: During follow-up 134/223=60% (Cap) and 146/224=65% (observation) progressed.
Results primary end point OS (GBC): 5-year survival rate in gallbladder carcinoma patients was significantly better in the MF group (26.0%) compared with the control group (14.4%); p-value 0.0367
OS (CCA): not reported; p-value >0.05 OS: No significant differences
in OS (median 62.3 months (Gem) vs
63.8 (observation); HR 1.01 (95% CI 0.70-1.45; p-value 0.964 RFS: No differences in RFS (median 30.4 months (95% CI 15.4-43.0)
(GemOx) vs 18.5 (95% CI 12.6-38.2)
(observation); HR 0.88 (95% CI 0.62-
1.25); p-value 0.48
The per-protocol analysis confirmed the findings (HR, 0.86 (95% CI 0.59-
1.27); p-value 0.45.
No difference in TTD of global HRQOL OS: Primary analysis, ITT OS (adjusted for minimisation factors other than surgical centre): median was 51.1 months (95% CI 34.6-59.1) (Cap) vs 36.4 (95% CI 29.7-44.5) (observation); HR 0.81 (95% CI 0.63-
1.04); p-value 0.097
ITT OS, sensitivity analysis (adjusted for stratification factors and other prognostic factors such as nodal status, grade of
disease and sex): HR 0.71 (95% CI 0.55-0.92); p-value 0.010
Per protocol OS, sensitivity analysis (adjusted for minimisation factors other than surgical centre): median was 53.0 months (95% CI 40-not reached) (Cap) vs 36.0 (95% CI 33-44) (observation); HR 0.75 (95% CI
0.58-0.97); p-value 0.028
Subgroup analysis (primary end- point) Not reported Trend towards a benefit for women, and lack of benefit among patients with ECOG performance status 1. Group with less benefit was GBC
No specific group benefited from adjuvant GEMOX More marked benefit of Cap in men (HR 0.70 (95% CI 0.50-0.99) and poorly differentiated disease (HR 0.60 (95% CI 0.39-0.93).
Secondary end- points RFS (GBC): 5-year RFS rate 20.3% (MF
group) vs 11.6% (observation); median
11.9 months (MF group) vs 12.3 (observation); p-value 0.0210
RFS (CCA): 5-year RFS rate 26.7% (MF
group) vs 24.1% (observation); p-value
>0.05 RFS: median 36.0 months (Gem arm) vs
39.9 (observation); HR 0.93 (95% CI 0.66-1.32); p-value 0.693 OS: median of 75.8 months
(95% CI 34.4-not reached) (GemOx) vs
50.8 (95% CI 38.0-not reached); HR 1.08 (95% CI 0.70-1.66); p-value 0.74 RFS (first 24 month period), ITT (adjusted for minimisation factors other than surgical centre): median 24.4 months (95% CI 18.6-35.9) (Cap) vs 17.5 (95% CI 12.0-23.8); HR 0.75 (95% CI 0.58-0.98); p-value
0.033
RFS (first 24 month period), per-protocol (adjusted for minimisation factors other than surgical centre): median 25.9 months (95% CI 19.8- 46.3) (Cap) vs 17.4 (95% CI 12.0-23.7); HR 0.70 (95% CI 0.54-0.92); p-
value 0.0093

RFS (period from 24-60 months), ITT (adjusted for minimisation factors other than surgical centre): HR 1.48 (95% CI 0.80-2.77); p- value 0.21
Relapse rate 79.7% (MF arm; GBC)
88.4% (observation; GBC) 53.8% (Gem)
56.5% (Obs) 62.1% (GemOx)
67.7% (observation) 60% (Cap)
65% (Obs)
Relapse pattern Not reported Location of first relapse similar between both groups: liver (most frequent), local site, peritoneum, and lymph nodes Similar proportion of metastatic recurrence in both arms: 75% (GemOx) and 71% (observation) Not reported
Subsequent therapy Not reported Of the 124 patients with relapse: 92 chemotherapy, 9 radiotherapy, 8 surgical resection. Most frequently gemcitabine-based regimens in the surveillance arm and fluoropyrimidine-based regimens in the GemOx arm
Post-relapse OS tended to be worse in the GemOx arm (median OS 8.0 months) vs observation arm (median OS 15.2 months); HR 1.55 (95% CI 0.98-
2.47); p-value 0.06 Follow-up treatment for patients who had disease recurrence was not recorded.

Table 2: Ongoing trials studying the efficacy of adjuvant treatment in cholangiocarcinoma and gallbladder cancer (www.clinicaltrials.gov; last accessed October 2019).
Study/Country (registration number) Patient number Population Arms Primary endpoint Expected completion
Germany – 781 Cholangiocarcinoma and Capecitabine vs Relapse-free April 2023
ACTICCA-1 gallbladder Cisplatin-Gemcitabine survival
NCT02170090 Phase III
South Korea 100 Extrahepatic Capecitabine vs. 2-year disease-free April 2022
NCT03079427 cholangiocarcinoma Cisplatin-Gemcitabine survival
Phase II
China 286 Intrahepatic Capecitabine vs. Relapse-free December 2018
NCT02548195 cholangiocarcinoma Gemcitabine-Oxaliplatin survival
Phase III
China 40 Intrahepatic Gemcitabine-Nab-paclitaxel Relapse-free September 2022
NCT04077983 cholangiocarcinoma Phase II survival
China – AdBTC-1 460 Cholangiocarcinoma and Gemcitabine vs Capecitabine Relapse-free December 2023
NCT03779035 gallbladder Phase III survival
China 138 Gallbaldder cancer Apatinib with SOX (Tegafur, Progression-free August 2020
NCT03702491 Oxaliplatin) vs SOX alone survival

Figure 2: Summary of main findings and differences within the ecent phase III trial exploring the role of adjuvant chemotherapy in biliary tract cancer.
Three phase III trials have been recently published exploring the role of adjuvant chemotherapy in resected cholangiocarcinoma and gallbladder cancer. The trials differ in some of the baseline characteristics which may explain why only the BILCAP trial (capecitabine vs observation) was the only study showing benefit in favour of adjuvant chemotherapy in resected biliary tract cancer. Figure 2.A shows main differences in study characteristics. Figure 2.B provides a graphic representation of HR for Relapse-free and Overall survival, with further details summarised in Figure 2.C.

iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; GBC: gallbladder cancer; N0: no evidence of lymph node metastases; N1: presence of lymph node metastases; R0: clear resection margins; R1: affected resection margins (including tumour within 1 mm for the BILCAP trial); Cap: capecitabine, Gem: gemcitabine; GemOc: gemcitabine and oxaliplatin; HR: Hazard Ratio; CI: confidence interval. *Hazard Ratio in the ITT (intention-to-treat) population (sensitivity analysis) is presented for the BILCAP trial (Overall Survival).
Figure 3: Future perspectives and unanswered questions
N1: lymph node positivity; R1: positive resection margins; CCA: cholangiocarcinoma; GBC: gallbladder cancer; 18FDG-PET: 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography; RT: radiotherapy;
Highlights

 

Capecitabine is the new standard of care for resected CCA and GBC.

Relapse rate remains high and not all patients benefit from such adjuvant therapy. There is an urgent need for further adequately-designed and properly powered studies

Graphic abstract:

Three phase III trials have been recently published exploring the role of adjuvant chemotherapy in resected cholangiocarcinoma and gallbladder cancer. The trials differ in some of the baseline characteristics which may explain why only the BILCAP trial (capecitabine vs observation) was the only study showing benefit in favour of adjuvant chemotherapy in resected biliary tract cancer. Panel A shows main differences in study characteristics. Panel B provides a graphic representation of HR for

Conflict of interest
Angela Lamarca: Travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath. Speaker honoraria from Merck, Pfizer, Ipsen and Incyte. Advisory honoraria from EISAI, Nutricia Ipsen, and QED. Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.
Julien Edeline: Travel grant from Ipsen, Amgen, Roche. Advisory honoraria from MSD, BMS, Ipsen, Eisai, Bayer, BTG, Roche. All outside the scope of this work.
Mairéad G McNamara: Received research grant support from Servier, Ipsen and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana and Mylan. She has served on advisory boards for Celgene, Ipsen, Sirtex and Baxalta; all outside the scope of this work.
Richard Hubner: no conflict of interest to declare

Masato Nagino: no conflict of interest to declare

John Bridgewater: Consulting or Advisory role for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD oncology, Merck Serono, Servier and BMS.
John Primrose: no conflict of interest to declare

Juan W Valle: Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED and Capecitabine Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited Ipsen Novartis Nucana; and Travel Grants from Celgene and Nucana.