Distant Metastasis After Chemoradiation and Image Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer

Johannes Knoth; Remi A Nout; Richard Pötter; Umesh Mahantshetty; Ina Jürgenliemk-Schulz; Christine Haie-Meder; Israel Fortin; Lars U Fokdal; Alina Sturdza; Peter Hoskin; Barbara Segedin; Kjersti Bruheim; Fleur Huang; Bhavana Rai; Rachel Cooper; Marie A D Haverkort; Erik van Limbergen; Bradley R Pieters; Li Tee Tan; Daniela Boryshchuk; Robin Ristl; Rohini Hawaldar; Sadhana Kannan; Astrid A C de Leeuw; Nicole Eder-Nesvacil; Kari Tanderup; Christian Kirisits; Jacob C Lindegaard; Maximilian P Schmid; EMBRACE Collaborative Group

doi:10.1016/j.ijrobp.2025.04.037

Distant Metastasis After Chemoradiation and Image Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer

Int J Radiat Oncol Biol Phys. 2025 May 10:S0360-3016(25)00436-5. doi: 10.1016/j.ijrobp.2025.04.037. Online ahead of print.

Authors

Johannes Knoth¹, Remi A Nout², Richard Pötter¹, Umesh Mahantshetty³, Ina Jürgenliemk-Schulz⁴, Christine Haie-Meder⁵, Israel Fortin⁶, Lars U Fokdal⁷, Alina Sturdza¹, Peter Hoskin⁸, Barbara Segedin⁹, Kjersti Bruheim¹⁰, Fleur Huang¹¹, Bhavana Rai¹², Rachel Cooper¹³, Marie A D Haverkort¹⁴, Erik van Limbergen¹⁵, Bradley R Pieters¹⁶, Li Tee Tan¹⁷, Daniela Boryshchuk¹⁸, Robin Ristl¹⁸, Rohini Hawaldar³, Sadhana Kannan³, Astrid A C de Leeuw⁴, Nicole Eder-Nesvacil¹, Kari Tanderup¹⁹, Christian Kirisits¹, Jacob C Lindegaard²⁰, Maximilian P Schmid²¹; EMBRACE Collaborative Group

Affiliations

¹ Department of Radiation Oncology, Comprehensive Cancer Center, Medical University/General Hospital of Vienna, Vienna, Austria.
² Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
⁴ Department of Radiation Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁵ Department of Radiotherapy, Gustave-Roussy, Villejuif, France.
⁶ Department of Radiation Oncology, Maisonneuve-Rosemont Hospital, Université de Montréal, Montréal, Québec, Canada.
⁷ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark.
⁸ Mount Vernon Hospital, Mount Vernon Cancer Centre, Northwood, United Kingdom.
⁹ Department of Radiotherapy, Institute of Oncology Ljubljana, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁰ Department of Oncology, Oslo University Hospital, Oslo, Norway.
¹¹ Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
¹² Postgraduate Institute of Medical Education and Research, Department of Radiotherapy and Oncology, Chandigarh, India.
¹³ Leeds Cancer Centre, St James's University Hospital, Leeds, United Kingdom.
¹⁴ Department of Radiotherapy, Radiotherapiegroep Arnhem, Arnhem, The Netherlands.
¹⁵ Department of Radiation Oncology, UZ Leuven, Leuven, Belgium.
¹⁶ Department of Radiation Oncology, Amsterdam University Medical Center, Location University of Amsterdam, The Netherlands; Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, The Netherlands.
¹⁷ Department of Oncology, Addenbrooke´s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom.
¹⁸ Center for Medical Data Science, Institute of Medical Statistics, Medical University of Vienna, Vienna, Austria.
¹⁹ Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²⁰ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
²¹ Department of Radiation Oncology, Comprehensive Cancer Center, Medical University/General Hospital of Vienna, Vienna, Austria. Electronic address: maximilian.schmid@akhwien.at.

PMID: 40354949
DOI: 10.1016/j.ijrobp.2025.04.037

Abstract

Purpose: This study aimed to assess patterns and risks of distant metastasis (DM) in patients with cervical cancer treated with chemoradiation therapy and MR-image guided adaptive brachytherapy (IGABT) and to explore a potential dose-effect relationship of concomitant cisplatin.

Methods and materials: Data were derived from EMBRACE I, an international, prospective, and multicenter cohort study conducted at 24 centers across Europe, Asia, and North America from July 30, 2008, to December 29, 2015. The study included 1416 patients with biopsy-confirmed cervical cancer (International Federation of Gynecology and Obstetrics [FIGO₂₀₀₉] stage IB-IVA or stage IVB limited to paraaortic lymph nodes below the L1/L2 interspace). Treatment involved external beam radiation therapy (45-50.4 Gy), weekly cisplatin (40 mg/m², 30 mg/m², or paused), and IGABT. DM was defined as extra-pelvic recurrence excluding paraaortic nodes.

Results: The analysis included 1318 patients with a median age of 49 years and a median follow-up of 52 months. The 5-year cumulative incidence of DM was 14%, with the lungs (26%), mediastinal lymph nodes (15%), and bones (10%) identified as the most common metastatic sites. Key risk factors for DM included nonsquamous histology (HR, 1.89; 95% CI, 1.30-2.75), nodal involvement at diagnosis (pelvic-only nodes: HR, 1.56; 95% CI, 1.07-2.26; paraaortic nodes: HR, 3.15; 95% CI, 1.93-5.16), and large target volume at brachytherapy (HR, 1.93; 95% CI, 1.21-3.08). Patients receiving fewer than 4 cycles of chemotherapy demonstrated a significantly higher risk of DM (HR, 1.52; 95% CI, 1.08-2.13).

Conclusion: DM is a substantial burden in patients with locally advanced cervical cancer, with the lungs, distant lymph nodes, and bones being the most frequent sites. Risk factors such as nonsquamous histology, nodal involvement, and large target volumes at brachytherapy are critical considerations for identifying high-risk patients in future studies. These findings highlight the need for tailored strategies to mitigate DM in this patient population.