STRONG II trial: stereotactic body radiation therapy following chemotherapy for unresectable perihilar cholangiocarcinoma - a single-arm multicentre phase II study.

Anne Demols, Lydi M J W van Driel, Yvette Seppenwoolde, Martijn Intven, Eva Versteijne, Anna M Bruynzeel, Freek Brandts, Harm Westdorp, Pètra M Braam, Christelle Bouchart, Ferry Eskens, Jeroen Buijsen, Ines Joye, Timon Vandamme, Derk Jan de Groot, Margriet Dieters, Fred J F Ubbels, Ben Heijmen, Alejandra Méndez Romero, Joris I Erdmann, Marjolein Y V Homs, Nadia Haj Mohammad, Joep de Bruijne, Eric T T L Tjwa, Erik van Werkhoven, Bas Groot Koerkamp, Judith de Vos-Geelen, Luisa Vonghia, Frederik J H Hoogwater, Maxime Dewulf, Akos Gulyban, Dirk de Ruysscher, Rianne D W Vaes, Suus Y van Loosbroek, Maaike T W Milder, Wilhelm den Toom, François Willemssen

Journal: BMJ open 2025;15(7):e097545

PMID: 40669914

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Abstract

INTRODUCTION

For patients with perihilar cholangiocarcinoma (pCCA), surgical resection remains the sole treatment modality that can potentially result in cure. Unfortunately, the majority of patients present with unresectable tumours or are excluded from surgical treatment due to complications like cholangitis affecting their performance status. In the Netherlands, recommended first-line treatment for patients with unresectable pCCA is palliative chemotherapy with gemcitabine and cisplatin. This regimen yields an estimated median overall survival (OS) of 11.7-15.2 months, highlighting the urgent need for novel treatment options. The STRONG I trial, a phase I study in patients with unresectable pCCA, was completed in 2020. Its aim was to assess the feasibility and toxicity profile of adding stereotactic body radiation therapy (SBRT) to chemotherapy. SBRT, delivered in 15 fractions of 4.0 Gray (Gy), was considered to be feasible and safe, with no dose-limiting toxicity being observed. The 1-year local tumour control rate was 80% and the 1-year OS rate 100%, with maintenance of quality of life (QoL). These results encouraged us to initiate the STRONG II trial, aiming to investigate the efficacy of adding SBRT to chemotherapy in a larger patient cohort.

METHODS AND ANALYSIS

STRONG II is a single-arm, multicentre phase II study. Patients with non-metastatic unresectable pCCA (T1-4, N0-2) are eligible. A total of 30 patients will be enrolled in six academic centres in the Netherlands and two in Belgium. SBRT will be delivered in 15 fractions of 4.0-4.5 Gy. The primary endpoint is local tumour control, defined by Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1. Secondary endpoints include toxicity, biliary stent-related events, progression-free survival, OS and QoL using the EuroQoL five-dimensional, five-level (EQ-5D-5L) questionnaire, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) and the EORTC Biliary Module (QLQ-BIL21). In addition, we will explore the predictive value of the peripheral immunological status (immune-related proteins and serum functional immunological status assay) and its dynamics in determining survival outcomes. For this explorative translational study, two blood samples will be collected, one before the start of chemotherapy and another after completing chemotherapy.

ETHICS AND DISSEMINATION

Approval of the study was obtained on 5 June 2024 by the Medical Ethics Review Committee of Erasmus Medical Center Rotterdam, the Netherlands (ID: NL86210.078.24). The anticipated time frame for patient enrolment is July 2024 to December 2027. The main study findings will be published in peer-reviewed medical journals, and presented at national and international conferences.

TRIAL REGISTRATION NUMBER

NCT06493734 (ClinicalTrials.gov).

Address: Department of Radiotherapy, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands [email protected].; Department of Radiotherapy, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands.; Department of Radiotherapy, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands.; Department of Radiation Oncology (Maastro), GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.; Department of Radiation Oncology (Maastro), GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Medical Oncology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Surgery, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Radiation Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.; Department of Medical Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.; Department of Surgery, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Radiation Oncology, Hôpital Universitaire de Bruxelles (H.U.B.) - Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.; Department of Gastroenterology, Hepatology, and Digestive Oncology, Hôpital Erasme and Institut Jules Bordet HUB, Université Libre de Bruxelles, Brussels, Belgium.; Department of Medical Physics, Hôpital Universitaire de Bruxelles (H.U.B.) - Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.; Department of Internal Medicine, Division of Medical Oncology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.; Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands.; Department of Radiation Oncology, Iridium Netwerk, Wilrijk - Antwerp, Belgium.; University of Antwerp, Centre for Oncological Research (CORE)-IPPON, Faculty of Medicine and Health Sciences, Wilrijk - Antwerp, Belgium.; Department of Oncology, University Hospital Antwerp, Edegem, Belgium.; Center for Oncological Research, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium.; Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands.; Department of Radiation Oncology, University Medical Centre Groningen, Groningen, The Netherlands.; Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Centre Groningen, Groningen, The Netherlands.

DOI: 10.1136/bmjopen-2024-097545

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MeSH Terms: Humans, Radiosurgery, Bile Duct Neoplasms, Klatskin Tumor, Gemcitabine, Quality of Life, Netherlands, Clinical Trials, Phase II as Topic, Deoxycytidine, Male, Combined Modality Therapy, Female, Cisplatin, Multicenter Studies as Topic, Middle Aged, Antineoplastic Combined Chemotherapy Protocols