Clinically effective biliary drainage and systemic therapy rather than intraductal radiofrequency ablation improve overall survival for inoperable perihilar cholangiocarcinoma patients:results of the COMBO-RFA randomized clinical trial

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Aims Intraductal radiofrequency ablation (RFA) has been proposed as a useful therapeutic method for patients with inoperable perihilar cholangiocarcinoma (pCCA), with emerging data suggesting improvement of both stent patency and overall survival (OS). However, it remains unclear whether increased OS is a result of prolonged stent patency or a consequence of RFA effect on local and systemic disease progression. We aimed to assess the intrinsic benefit of intraductal RFA for inoperable pCCA in the setting of an aggressive biliary drainage protocol using scheduled plastic stent exchange sessions. Methods We conducted a single center randomized clinical trial (NCT05563870) in a tertiary referral center for therapeutic endoscopy. Consecutive patients presenting with pCCA and biliary obstruction who were not candidates for curative resection were evaluated for inclusion in this trial. Native-papilla patients were randomized 1:1 to biliary plastic stenting aiming to drain all the viable liver territories (control) or drainage plus RFA of the entire length of the tumor (active arm). After the index procedure, patients were scheduled for iterative stent exchange at 8-10 weeks intervals with additional RFA treatment in the active arm only. Patients received systemic therapy at the discretion of their oncologist. The primary outcome of the study was OS; secondary outcomes included clinical efficacy defined as bilirubin levels<3mg/dL at 4 weeks after index ERCP and safety outcomes, with a particular focus on biliary events (cholangitis and cholecystitis). Results We included 27 patients (14 in the active arm) undergoing a total of 119 procedures (72 in the RFA arm) for a median follow-up of 7 months (range 1-24). Most patients received either 2 (11/27) or 3 (3/27) PS at index ERCP and 25/27 of the patients achieved clinically effective biliary drainage according to study protocol. Despite adequate drainage, only 11/27 patients received some form of palliative systemic therapy (chemotherapy and/or immunotherapy). There was no significant difference in median OS between the RFA group (270 days (95% CI 104-435)) and the control arm (150 days (95%CI 81-218)) (p=0.385). However, patients receiving any form of systemic therapy had a significantly higher OS (450 days (95%CI 222-677) vs 90 days (95%CI 31-148), p=0.009). There was no difference in the rate of early or delayed adverse events between the two study groups [ 1 ] [ 2 ]. Conclusions Early and extensive biliary drainage with multiple RFA applications followed by scheduled PS exchange and retreatment seems clinically effective, feasible and safe for the palliation of biliary obstruction in pCCA patients. However, in the setting of early stent exchange aimed at lowering the risk of stent occlusion, RFA seems to carry no additional intrinsic survival benefit compared to our aggresive drainage protocol alone. Further studies are needed to explore the correct positioning of RFA in the management of this vulnerable patient population. Publication History Article published online: 27 March 2025 © 2025. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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