Postradiotherapy Urinary Extracellular Vesicle Concentrations Predict Late Bladder Toxicity in Patients with Prostate Cancer

Purpose: Radiotherapy (RT) is a standard-of-care option for over 50% of patients with prostate cancer (PCa), but up to 25% develop delayed bladder toxicities months to years after treatment. Late radiation cystitis is a form of dose-limiting toxicity that can cause hematuria and other potentially severe symptoms, leading to further morbidity and decisional regret. Additional work is needed to define early biomarkers of late radiation cystitis to better guide patient care. Extracellular vesicles (EVs) are stable membrane-enclosed particles that are released from diverse cell types and are present at high levels in biofluid samples. This study was developed to explore the relationships between late hematuria incidence and urinary and serum EV concentrations analyzed in a cohort of patients with PCa undergoing RT. Materials and Methods: We analyzed EV profiles of preserved urine and serum samples from a longitudinal study of bladder toxicity in 30 patients with PCa undergoing standard-of-care pelvic RT. EVs in these samples were quantified through nanoparticle tracking analyses. EV concentrations at different collection time points were then compared between patients who did and did not develop hematuria. Results: RT was found to significantly increase urinary EV concentrations relative to pre-RT levels in patients who subsequently developed late hematuria, whereas such EV induction was absent in patients without hematuria. The same effect was evident but less robust in patient serum samples. Conclusion: These results suggest that RT-induced changes in EV dynamics may offer value as a robust biomarker that can predict the risk of late radiation cystitis months before overt symptom presentation.