Extrahepatic Cholangiocarcinoma
Conditions
Keywords
Extrahepatic Cholangiocarcinoma, Cholangiocarcinoma, Biliary Tract Cancer, Bile Duct Stricture, Endobiliary Radiofrequency Ablation (EB-RFA), Radiofrequency Ablation, Endoscopic Retrograde Cholangiopancreatography (ERCP), Gemcitabine, Cisplatin, Durvalumab, Recurrent Biliary Obstruction (RBO)
Brief summary
This international, multicenter, open-label randomized controlled trial evaluates whether repeated endobiliary radiofrequency ablation (EB-RFA) improves overall survival in patients with unresectable extrahepatic cholangiocarcinoma undergoing first-line systemic therapy with durvalumab plus gemcitabine and cisplatin (GCD). Eligible patients will be randomized 1:1 to EB-RFA with plastic stent placement or standard plastic stenting alone. A scheduled second endoscopic session will be performed at 3 months in both groups (repeat EB-RFA only in the EB-RFA arm). The primary endpoint is overall survival. Secondary endpoints include time to recurrent biliary obstruction, progression-free survival, adverse events, and technical/clinical success.
Detailed description
Extrahepatic cholangiocarcinoma (eCCA) frequently presents as unresectable disease with obstructive jaundice. Although gemcitabine, cisplatin plus durvalumab (GCD) is the global standard first-line regimen, median overall survival remains approximately one year. Endobiliary radiofrequency ablation (EB-RFA) is biologically plausible to enhance local tumor control by inducing coagulative necrosis at the biliary stricture. Retrospective studies, including a multicenter dataset from participating institutions, suggest a survival benefit of repeated EB-RFA, especially when combined with systemic therapy. However, prospective randomized evidence is lacking. This trial (BRAVE) randomizes eligible patients to EB-RFA plus standardized endoscopic stenting or endoscopic stenting alone, followed by GCD. A planned second endoscopic session is performed at Month 3 (window 2-4 months). Additional EB-RFA sessions (≥2-month intervals) are permitted in the EB-RFA arm if imaging shows potentially ablatable lesions and clinical benefit is expected. The study aims to determine whether repeated EB-RFA prolongs survival and improves biliary patency when integrated with modern systemic therapy.
Interventions
DEVICEEndobiliary Radiofrequency Ablation (EB-RFA)
Endobiliary RFA performed using the ELRA® catheter (STARmed) with VIVA combo® generator. Recommended settings: 7-10 W, temperature control 80 °C, 120 seconds per application. Applied along the full stricture length. Repeat procedure at Month 3 (window 2-4 months). Additional sessions every ≥2 months permitted if imaging suggests ablatable residual lesion.
DEVICEPlastic Biliary Stent
Placement of 7Fr or 8.5Fr plastic biliary stent from hepatic side of the stenosis to the duodenum. Bilateral preferred for hilar strictures; unilateral acceptable based on drainage.
Sponsors
Aichi Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Histologically or cytologically confirmed extrahepatic cholangiocarcinoma (eCCA). Unresectable disease (unresectable due to tumor/patient factors, or patient refusal of surgery). Biliary obstruction requiring drainage, demonstrated by abnormal cholestatic liver tests, elevated bilirubin, radiologic evidence, or existing biliary drainage. Planned initiation of first-line systemic therapy with durvalumab + gemcitabine + cisplatin (GCD). Age ≥18 years. Able to provide written informed consent.
Exclusion criteria
Prior radiotherapy or systemic therapy for the current eCCA. Presence of a self-expanding metal stent that cannot be endoscopically removed. Surgically altered anatomy except for Billroth-I; prior biliary reconstruction. History of chronic cholangitis (e.g., primary sclerosing cholangitis, IgG4-related cholangitis). Expected survival \<3 months. Inability to insert an oral endoscope or reach the papilla. Contraindication to endobiliary RFA. Pregnancy or possible pregnancy. Any condition judged unsuitable by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until death from any cause (up to 36 months after last enrollment) | Overall survival is defined as the time from randomization to death from any cause. Participants still alive at the last confirmed contact will be censored at that date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization to radiologic progression or death (up to 36 months) | Progression-free survival is defined per RECIST v1.1 based on imaging performed every 2-4 months. |
| Non-RBO Survival | Up to 36 months | Time alive without recurrent biliary obstruction. |
| Survival Free From Late Biliary-Procedure-Related Adverse Events | Up to 36 months | Late adverse events are defined as events occurring ≥15 days after the procedure (Tokyo Criteria 2024). |
| Incidence and Etiology of Recurrent Biliary Obstruction (RBO) | Up to 36 months | Number and types of RBO events and their causes (sludge, tumor ingrowth/overgrowth, migration, dysfunction). |
| Early Adverse Events (≤14 days) | 14 days | Procedure-related adverse events within 14 days, graded by Tokyo Criteria 2024. |
| Time to Recurrent Biliary Obstruction (TRBO) | From stent placement to RBO or censoring (up to 36 months) | TRBO is defined as the time from stent placement to recurrent biliary obstruction (RBO). |
| Technical Success | At index procedure | Successful completion of the intended procedure: EB-RFA + plastic stent placement in the experimental arm Plastic stent placement in the comparator arm |
| Clinical Success | Within 14 days after stent placement | Defined as: Hyperbilirubinemia: total bilirubin reduction ≥50% or ≤1.5 mg/dL within 14 days Others: normalization of ≥2 abnormal cholestatic/hepatocellular enzymes If baseline values are normal after prior drainage, absence of re-worsening beyond abnormal thresholds. |
| Number of RBO Events | Up to 36 months | Count of recurrent biliary obstruction events per participant. |
| Number of Endoscopic Reinterventions | Up to 36 months | Total number of endoscopic procedures including therapeutic interventions required during follow-up. |
| Late Adverse Events (≥15 days) | Up to 36 months | Procedure-related adverse events occurring ≥15 days post-procedure. |
Countries
Japan, South Korea
Contacts
Primary ContactTadahisa Inoue
Outcome results
None listed