Variation in clinical target volume delineation in postoperative radiotherapy for biliary tract cancer.

We aimed to evaluate the inter-clinician variability in the clinical target volume (CTV) for postoperative radiotherapy (PORT) for biliary tract cancer (BTC) including extrahepatic bile duct cancer (EBDC) and gallbladder cancer (GBC). Nine experienced radiation oncologists delineated PORT CTVs for distal EBDC (pT2N1), proximal EBDC (pT2bN1) and GBC (pT2bN1) patients. The expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) was used to quantify expert agreements. We generated volumes with a confidence level of 80% to compare the maximum distance to each CTV in six directions. The degree of agreement was moderate; overall kappa values were 0.573 for distal EBDC, 0.513 for proximal EBDC, and 0.511 for GBC. In the distal EBDC, a larger variation was noted in the right, post, and inferior direction. In the proximal EBDC, all borders except the right and left direction showed a larger variation. In the GBC, a larger variation was found in the anterior, posterior, and inferior direction. The posterior and inferior borders were the common area having discrepancies, associated with the insufficient coverage of the paraaortic node. A consensus guideline is needed to reduce inter-clinician variability in the CTVs and adequate coverage of regional lymph node area.

Irradiation stent insertion for distal biliary obstruction secondary to primary common biliary cancer.

PURPOSE: To assess the effectiveness and safety of irradiation stent insertion for patients with distal biliary obstruction (DBO) secondary to primary common biliary cancer. MATERIAL AND METHODS: Eighty-two consecutive patients with DBO secondary to primary common biliary cancer were treated via either normal (n = 45) or irradiation stenting (n = 37) between January 2013 and December 2019. The instant and long-term outcomes were compared. RESULTS: Technical success rates of normal and irradiation stenting were both 100%. Clinical success rates of normal and irradiation stenting were 91.1 and 100%, respectively (p = .179). Stent reobstruction was observed in 13 and 7 patients in the normal and irradiation stenting groups, respectively (p = .295). The median stent patency was 162 and 225 days in the normal and irradiation stenting groups, respectively (p < .001). The median survival was 178 and 250 days in the normal and irradiation stenting groups, respectively (p < .001). Cholangitis was, respectively, observed in 8 and 12 patients in normal and irradiation stenting groups (p = .124). CONCLUSION: Irradiation stenting is effective and safe for patients with DBO secondary to primary common biliary cancer and can prolong stent patency and survival.

Role of adjuvant and neoadjuvant therapy for resectable biliary tract cancer.

Introduction: Although the safety of biliary tract cancer resection has improved over the years, the recurrence rate is still high, and the postoperative prognosis remains low after biliary tract cancer resection. Therefore, the development of effective adjuvant therapy is essential to improve treatment outcomes. Because biliary tract cancer is rare compared with other gastrointestinal cancers, there have been only a small number of clinical trials of adjuvant therapy. However, in recent years, the results of several large-scale randomized controlled trials have been published, and clinical trials investigating the efficacy of new regimens are currently ongoing.Areas covered: This review presents the results of previously published important phase II and III clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and discusses their interpretation. The future direction of new research on resectable biliary tract cancer treatment is also discussed.Expert opinion: The foundations of large-scale clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer are underway, and new trials will establish evidence of their effectiveness. Additionally, breakthroughs in treatment through genetic and molecular research are expected.

Suboptimal outcome for patients with biliary rhabdomyosarcoma treated on low-risk clinical trials: A report from the Children's Oncology Group.

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The biliary tract is classified as a favorable primary site. Therefore, patients with localized biliary RMS were included in two consecutive low-risk studies, D9602 and ARST0331, by the Children's Oncology Group (COG). The outcome for these patients treated with low-risk therapy has not been reported. PROCEDURE: Patients with biliary RMS enrolled on COG low-risk trials D9602 or ARST0331 were analyzed. All patients received systemic chemotherapy and those with Group II (microscopic residual) or Group III (macroscopic residual) disease received 36-50.4 Gy adjuvant radiotherapy (RT). Delayed primary excision (DPE) was allowed on both studies. RESULTS: Seventeen patients with biliary RMS were treated on D9602 (n = 7) or ARST0331 (n = 10). Median age was 3.5 years (range 1.7-10.3). Ten (59%) patients had tumors >5 cm and 14 (82%) had Group III disease. Fifteen (88%) patients received RT. The 5-year event-free survival (EFS) and overall survival (OS) were 70.6% (95% confidence interval [CI]: 46.9-94.3%) and 76.5% (95% CI: 54.6-98.4%), respectively. The majority of patients (80%) who received RT did not have disease recurrence while both patients who did not receive RT had local relapse. Five (36%) of 14 patients with Group III disease underwent DPE; two experienced a local relapse. In the nine patients without DPE, two developed local relapse. CONCLUSIONS: Patients with localized biliary RMS treated on low-risk studies had suboptimal outcomes. These patients may benefit from therapy on intermediate-risk studies.

Impact of breath-hold level on positional error aligned by stent/Lipiodol in Hepatobiliary radiotherapy with breath-hold respiratory control.

BACKGROUND: Respiratory motion management with breath hold for patients with hepatobiliary cancers remain a challenge in the precise positioning for radiotherapy. We compared different image-guided alignment markers for estimating positional errors, and investigated the factors associated with positional errors under breath-hold control. METHODS: Spirometric motion management system (SDX) for breath holds was used in 44 patients with hepatobiliary tumor. Among them, 28 patients had a stent or embolized materials (lipiodol) as alignment markers. Cone-beam computed tomography (CBCT) and kV-orthogonal images were compared for accuracy between different alignment references. Breath-hold level (BHL) was practiced, and BHL variation (ΔBHL) was defined as the standard deviation in differences between actual BHLs and baseline BHL. Mean BHL, ΔBHL, and body-related factors were analyzed for the association with positional errors. RESULTS: Using the reference CBCT, the correlations of positional errors were significantly higher in those with stent/lipiodol than when the vertebral bone was used for alignment in three dimensions. Patients with mean BHL > 1.4 L were significantly taller (167.6 cm vs. 161.6 cm, p = 0.03) and heavier (67.1 kg vs. 57.4 kg, p = 0.02), and had different positional error in the craniocaudal direction (- 0.26 cm [caudally] vs. + 0.09 cm [cranially], p = 0.01) than those with mean BHL < 1.4 L. Positional errors were similar for patients with ΔBHL< 0.03 L and > 0.03 L. CONCLUSION: Under rigorous breath-hold respiratory control, BHL correlated with body weight and height. With more accurate alignment reference by stent/lipiodol, actual BHL but not breath-hold variation was associated with craniocaudal positional errors.

Adjuvant chemotherapy in biliary tract cancer: state of the art and future perspectives.

PURPOSE OF REVIEW: Biliary tract cancers (BTCs) have a poor prognosis; most patients present with advanced disease and, even after surgical resection for early-stage disease local and distant relapses are frequent. Involved resection margins and lymph node involvement are the most relevant known adverse prognostic factors. Historically clinicians have made clinical decisions based on data from institutional series and uncontrolled studies, with their inherent limitations. In this review, data from recently-reported prospective randomized trials are reviewed and clinical implications discussed. RECENT FINDINGS: Results from prospective randomized phase III trials (namely BILCAP, PRODIGE-12, and BCAT) are reviewed: none of the studies met their primary endpoint by intention-to-treat analysis. However, following a per-protocol sensitivity analysis of the BILCAP study, adjuvant capecitabine (for 6 months) showed a clinically-relevant improvement in overall survival and provides reference data for future clinical trials. SUMMARY: Adjuvant chemotherapy with capecitabine should be considered following curative resection of BTC. Identification of benefit in anatomical subgroups is ongoing and future trials should also consider the implication of molecular subtypes of BTC (for prognostic impact and on-target therapeutic options).

Treatment and outcome of the patients with rhabdomyosarcoma of the biliary tree: Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. METHODS: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). RESULTS: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7-202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45-71) and 47% (34-50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22-54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. CONCLUSION: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.

Role of Radioembolization for Biliary Tract and Primary Liver Cancer.

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are often amenable to locoregional therapy, including percutaneous ablation, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE). TARE is a technique that delivers a high dose of radiation to the tumor, while limiting the dose to the normal liver parenchyma and the adjacent organs. It has been shown to effectively provide disease control with relatively few toxicities, and in certain cases results in a complete response. It is the preferred therapy as a bridge to liver transplant and can provide necessary compensatory future liver remnant hypertrophy before planned surgical resection.

Nodal CTV selection according to primary tumour location and pT stage for biliary tract cancer.

INTRODUCTION/PURPOSE: To assist radiation oncologists in determining the elective nodal CTV for biliary tract cancer, we aimed to provide the rules for selection of the CTV for each subsite of biliary tract with respect to the pT stage, based on the analysis of the incidence and location of metastatic lymph nodes. METHODS: Systematic review and meta-analysis was performed to determine the rate of pathological nodal involvement of each individual lymph node station (LNS) as a function of the primary tumour pT stage (pT1-2 vs. pT3-4) separately for right intrahepatic cholangiocarcinoma (rIHC), left/hilar intrahepatic cholangiocarcinoma l/hIHC), proximal extrahepatic cholangiocarcinoma (pEHC), middle extrahepatic cholangiocarcinoma (mEHC), distal extrahepatic cholangiocarcinoma (dEHC) and gall bladder cancer (GBC). A 5% or higher risk of involvement was assumed to justify inclusion of the LNS in the CTV. RESULTS: Coeliac LNS, which is usually included in the CTV in clinical practice, has a low risk of involvement and can presumably be omitted for pT1-2 GBC, for dEHC irrespective of pT stage and for mEHC. Para-aortic and superior mesenteric artery (SMA) LNS that are usually omitted have a high risk of involvement. Para-aortic LNS should be considered for inclusion for all the subsites except for pT1-2 dEHC, and SMA LNS for all the subsites except for pT1-2 dEHC, pT1-2 GBC and pEHC. Left gastric artery, lesser curvature and paracardial LNS should be considered for inclusion for l/hIHC. CONCLUSION: This systematic review provides an evidence-based strategy for nodal CTV selection in biliary tract cancer according to primary tumour location and pT stage.

[Helical tomotherapy using simultaneously integrated boost and simultaneous integrated protection technique for unresectable biliary tract cancer].

Objective: To evaluate the safety and efficacy of helical tomotherapy using simultaneously integrated boost and simultaneous integrated protection technique in the treatment of unresectable biliary tract cancers. Methods: The data of 23 patients with unresectable biliary tract cancer who received tomotherapy-based hypofractionated radiotherapy at Comprehensive Cancer Centre of Drum Tower Hospital,the Affiliated Drum Tower Clinical College of Nanjing Medical University between February 2015 and October 2017 were analyzed. There were 10 males and 13 females, aged from 40 to 85 years(median:58 years). Pathological type included intrahepatic cholangiocarcinomas(n=11), gallbladder cancers(n=6),extrahepatic cholangiocarcinomas(n=6). The irradiated sites covered primary tumors and areas of local invasion,including metastatic lymph nodes which were confined to the abdominal or retroperitoneal space. Dose escalation was achieved using simultaneously integrated boost(SIB) technique, and simultaneous integrated protection(SIP)technique was used to protect gastrointestinal tracts and other adjacent organs. Cox regression modal and Kaplan-Meier analysis were used to analyze the associations between patients' characteristics and overall survival(OS). Results: The median total radiation dose was 54 Gy(range: 28-72 Gy)and median biologically effective dose(BED)was 74.4 Gy(range: 37.8-115.2 Gy).The median planning target volume(PTV)was 445.79 cm(3)(range:126.02-950.12 cm(3)). Based on the various PTV,patients received 2.4-6.0 Gy/fraction with 8-28 fractions. The local control rate was 65.2% and the median OS was 11.3 months(range:2.1-31.9 months).The most common cause of death was out-field failure and only 3 patients died of in-field failures. The longest survival was 31.9 months. BED≥70 Gy significantly improved OS,compared to BED<70 Gy(16.8 months vs.5.1 months)(HR=0.146, 95%CI:0.028-0.762, P=0.022). No patients developed grade ≥4 toxicities. Conclusions: Helical tomotherapy-based hypofractionated radiotherapy is effective and well tolerated for patients with unresectable biliary tract cancer. The dose escalation with higher BED could improve the survival for such patients.

Radiotherapy for Biliary Tract Cancers.

Biliary tract cancers (BTCs), including intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder cancers, are a heterogeneous cohort of tumors that tend to present with advanced stage and with high rates of recurrence after surgical resection. While liver-directed radiotherapy was traditionally restricted to the palliative setting given concerns over hepatotoxicity, modern radiotherapy techniques have enabled safe and effective treatment of a variety of hepatic tumors, thereby expanding the role of liver-directed radiotherapy in the management of BTCs. For resected BTCs, adjuvant chemoradiotherapy is recommended for patients with involved lymph nodes and positive resection margins. For patients with hilar cholangiocarcinomas, neoadjuvant chemoradiotherapy is recommended prior to orthotopic liver transplantation. Finally, for patients with unresectable disease, definitive radiotherapy in addition to systemic therapy represents a potential opportunity to maximize both local control and overall survival. In this review, we will discuss the evidence supporting the use of liver-directed radiotherapy for BTCs, as well as ongoing clinical investigations.

Hyperfractionated abdominal reirradiation for gastrointestinal malignancies.

BACKGROUND: We sought to determine the role of abdominal reirradiation for patients presenting with recurrent or new primary gastrointestinal (GI) malignancies. At our institution, we have established a hyperfractionated, accelerated reirradiation regimen consisting of 39 Gray (Gy) in 26 twice-daily fractions. Although this regimen is used frequently in the pelvis, we sought to determine its toxicity and efficacy for abdominal tumors. METHODS: Twenty-four patients who received abdominal reirradiation with a hyperfractionated, accelerated approach from 2000 to 2017 were identified. Overall survival (OS) and local progression-free survival (LPFS) were calculated using the Kaplan-Meier method. Several patient, tumor and treatment characteristics were evaluated on univariate analyses for association with OS and LPFS using a Cox proportional hazards model. RESULTS: Of the twenty-four patients identified, the majority (n = 11, 46%) had pancreatic adenocarcinoma as their primary disease but also included upper GI adenocarcinoma (n = 4), colon adenocarcinoma (n = 3), hepatobiliary cancers (n = 4) and other malignancies (n = 2). The majority of patients received 45-50.4Gy in 1.8Gy fractions as their initial abdominal radiation course. The median reirradiation dose was 39Gy in 26 twice-daily fractions with a minimum six hour interval. The median [interquartile range (IQR)] interval between the courses of radiotherapy was 28 [18.6-38.9] months. Only palliative reirradiation intent was associated with decreased OS. While colon adenocarcinoma primary was significantly associated with increased LPFS, the sample size was small (n = 3). The 1-yr rate of LPFS was 38%. The median [IQR] duration of freedom from local progression was 8 [3.8-19.2] months. The 1-year OS was 50% and the median (IQR) OS was 14 [6.3-19.6] months. Thirteen patients (54%) had acute side effects with one patient experiencing G3 nausea and one experiencing a G4 bleed; the remaining patients experienced G1-G2 symptoms. CONCLUSION: Hyperfractionated, accelerated reirradiation to the abdomen was relatively well-tolerated but provided limited local control to recurrent or second primary abdominal malignancies. Reirradiation could play a role in treating these patients with palliative or curative intent, but alternative strategies for delivering increased biologically effective dose should be further explored.

Preliminary clinical application of integrated 125I seeds stents in the therapy of malignant lower biliary tract obstruction.

PURPOSE: To evaluate the clinical efficacy of percutaneous trans-hepatic integrated 125I seed stents implantation for malignant lower biliary tract obstruction. METHODS: Thirty-two patients with malignant lower biliary obstruction were randomly divided into two groups. One group underwent the therapy with integrated 125I seed stents (Test group, n = 13), and another group received conventional metal stents implantation for treatment (Control group, n = 19). The pre- and post-operative changes in biochemical indices, white blood cell count, IgG level, stent patency, survival time, tumor size and complications were compared between the two groups. RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) was used to evaluate therapeutic effects. The average follow-up time was 12.3 months. RESULTS: The differences between pre- and post-operative (30 days) intragroup biochemical indices had statistically significant difference (P < 0.05), but there were no significant differences (P > 0.05) in leukocyte counts and IgG levels. As to the median time of stent patency and patients' survival, there were significant differences (P < 0.05) between Control and Test groups (3.9 months vs. 8.1 months, 139 days vs. 298 days, respectively). Three months after the operation, the average tumor size was reduced in the Test group, but was increased in the Control group (P < 0.05). There was no significant difference in the incidence of complications between the two groups. The evaluation results using RECIST 1.1 showed that there were statistically significant differences between the two groups in terms of the rates of remission, control, and progression (χ2 = 17.5, P < 0.05). CONCLUSIONS: The study indicates that integrated 125I seed stents are effective in reducing jaundice symptoms, inhibiting tumor growth, improving stent patency and prolonging patient survival, which may serve as a safer and more feasible method in treating malignant lower biliary obstruction with minimal invasiveness.

Nodal areas of potential geographic error in adjuvant radiotherapy for biliary tract cancer.

PURPOSE: To determine the areas of potential geographic error in adjuvant radiotherapy (RT) for biliary-tract cancer (BTC) by comparing pathological-surgical data on the pattern of nodal spread with the extent of elective nodal CTV used in published RT studies in this setting. MATERIAL/METHODS: A literature search was performed to select articles on: 1/adjuvant RT for BTC, that provided information on the lymph node stations (LNS) included in the CTV; 2/the pathological-surgical data on the patterns of nodal involvement/recurrence in BTC. Risk of nodal involvement/recurrence and frequency of inclusion in the CTV in RT studies for each of the LNS were compared to determine the areas of potential geographic misses and unnecessary irradiation, separately for intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC) and gallbladder-cancer (GBC). RESULTS: Areas of potential geographic misses include: for right IHC: paraaortic and superior mesenteric artery (SMA) LNS; for left or hilar IHC: left gastric, lesser gastric curvature, paraaortic, and SMA LNS; for proximal EHC: paraaortic LNS; for middle EHC: paraaortic and SMA LNS; for distal EHC: paraaortic, SMA, and anterior pancreatico-duodenal LNS; for GBC: paraaortic, SMA, and posterior pancreatico-duodenal LNS. Celiac-LNS is unnecessarily irradiated for middle/distal EHC. CONCLUSIONS: In view of discrepancies between pathological-surgical data and the CTVs used in common practice, there is an obvious need for international consensus guidelines.

Clinical outcomes of salvage chemoradiotherapy for locally recurrent biliary tract cancer.

PURPOSE: The purpose of this study was to investigate the clinical outcomes and prognostic factors of concurrent chemoradiotherapy (CCRT) for locally recurrent biliary tract cancer (BTC) after curative surgical resection. METHODS: We performed a retrospective cohort study of patients with locally recurrent BTC treated with CCRT between October 2004 and December 2013. The study included and analyzed 42 patients with a history of curative-intent surgical resection of confirmed adenocarcinoma originating from the biliary tract. RESULTS: The median time to recurrence after surgery was 16.1 months (range, 4.5-77.8 months). Median follow-up after CCRT was 26.9 months (range, 5.2-81.9) with no grade 3 or higher gastrointestinal toxicities. Analysis of the first site of failure showed local progression (LP) developed in 20 patients (47.6%); among these, 16 (38.1%) had isolated LP. The median values were 15.8 months (range, 1.7-81.7) for LP-free survival (LPFS), 10.6 months (range, 1.7 - 81.7) for progression-free survival (PFS) and 41.2 months (range, 5.2-81.9) for overall survival (OS). Multivariate analysis showed that the level of pre-CCRT carbohydrate antigen (CA) 19-9 and the chemotherapy regimen were significant prognostic factors for LPFS and PFS; pT stage was the only significant prognostic factor for OS. CONCLUSIONS: CCRT for locally recurrent BTC showed promising outcomes as a salvage modality, but LP was still frequent. The pre-CCRT CA 19-9 level and the chemotherapy regimen were prognostic factors for LPFS and PFS.

Study of self-expandable metallic stent placement intraluminal 125I seed strands brachytherapy of malignant biliary obstruction.

OBJECTIVE: To evaluate the safety and efficacy of self-expandable metallic stent placement combined with or without intraluminal 125I seed strands brachytherapy in patients with malignant biliary obstruction. METHODS: Participants were randomly assigned to receive treatment with a self-expandable metallic stent (SEMS) placement combined with intraluminal 125I seed strands brachytherapy (brachytherapy group) or a SEMS without brachytherapy (control group). The outcomes were measured in terms of technical success, clinical success, stent patency, complications related to the procedure, and patient survival. A P value of less than 0.05 indicated a significant difference. Results There were no significant differences in technical and clinical success between brachytherapy and control group (100 vs. 100%-100 vs. 93.3%). During the median 273.4 ± 154.6 days follow-up time, the median stent patency time in the brachytherapy group was longer than those in the control group (368.0 ± 42.4 vs. 220.0 ± 34.8 days), and the duration of survival in the brachytherapy groups was higher than those in the control group (355.0 ± 71.5 vs. 209.0 ± 17.2 days). There were no significant differences in the complications between the two groups. Conclusions SEMS placement combined with intraluminal 125I seed strands brachytherapy are feasible and effective for malignant biliary obstruction, and seems to prolong the stent patency and survival time.

Radiation therapy for biliary tract tumors: the joint experience of three centers.

BACKGROUND/AIM: This study presents the joint experience of three centers in the treatment of patients with biliary tract tumors with radiation therapy (RT). MATERIALS AND METHODS: The records of 27 patients were retrospectively reviewed. All of the patients who had undergone surgical resection received postoperative adjuvant RT, whereas all of the patients who had not undergone a surgical resection received RT with palliative intent. Twenty patients with adequate performance status were treated with RT and chemotherapy, while the remaining seven patients were treated with RT alone. RESULTS: Follow-up ranged from 1 to 44 months. Local control was not achieved in 10 out of 11 patients who had received RT with palliative intent. Systemic failure was observed in eight patients at 5 to 16 months. Fifteen patients died due to disease-related causes at 1 to 22 months. At 2 years, overall survival was 33% and disease-free survival was 19%. A surgical resection with curative intent predicted improved local failure-free survival and improved disease-free survival. CONCLUSION: Since local recurrence is still the leading cause of failure following postoperative RT and the outcome following palliative RT is far from satisfactory, the indications, the target volume, and the doses for RT should be reconsidered.

Clinical Target Volume in Biliary Carcinoma: A Systematic Review of Pathological Studies.

BACKGROUND/AIM: Radiotherapy is a treatment option for both adjuvant and neo-adjuvant settings for biliary tract cancer. Guidelines on the delineation of the target volume of lymph nodes are lacking; only generic indications are available, without specific recommendations for different primary tumour locations (e.g. intrahepatic, extrahepatic biliary tract or gallbladder cancer). The aim of this study was to systematically review available literature to provide recommendations on lymph node target volume delineation in patients with unresectable biliary tumour. MATERIALS AND METHODS: A systematic search of electronic databases was performed up to July 2016. The primary outcome measure was the rate of lymph node involvement according to the location of primary biliary tumour. Sites with ≥5% of nodal metastases were considered in the clinical target volume for radiotherapy planning. RESULTS: Twelve studies (1075 patients) were included. The most frequent site of lymph node metastasis in intrahepatic biliary tree carcinoma was retroportal (61.1%, 95% confidence interval (CI)=50.7-70-6%). Other frequently involved lymph nodes were along the hepatoduodenal ligament [frequency=38.7%, 95% CI=31.0-47.0%], those along the common hepatic artery (17.0%, 95% CI=8.2-31.9%) and the hilar nodes (16.9%, 95% CI=13.2-21.4%). In extrahepatic biliary tree cancer, the most frequently involved lymph nodes were the pericholedochal (42.7%, 95% CI=33.8-52.1%) and those along the hepatoduodenal ligament (40.3%, 95% CI=32.4-48.8%). Other commonly involved nodal regions included retroportal lymph nodes (30.9%, 95% CI=23.0-40.1%), pancreaticoduodenal anterior and posterior nodes (30.1%, 95% CI=12.2-57.1%), those along the common hepatic artery (19.7%, 95% CI=11.8-31.0%) and para_aortic nodes (15.2%, 95% CI=8.0-27.0%). The most common site of metastases in gallbladder cancer were the pericholedochal nodes (25.2%, 95% CI=18.6-33.2%), those along the cystic duct (23%, 95% CI=16.6-30.8%), and retroportal nodes (17.1%, 95% CI=11.6-24.5%). CONCLUSION: Biliary tract cancer has a high propensity for regional lymphatic metastases. An evidence-based nodal target definition of biliary tract cancer based on primary tumour location was proposed.