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

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.