In-vivo laser induced urethral stricture animal model for investigating the potential of LDR-brachytherapy (2015)

Purpose: Treatment of urethral strictures is a major challenge in urology. For investigation of different treatment methods an animal model was developed by reproducible induction of urethral strictures in rabbits to mimic the human clinical situation. By means of this model the potential of endoluminal LDR brachytherapy using &beta;-irradiation as prophylaxis of recurrent urethral strictures investigated. Material and Methods: A circumferential urethral stricture was induced by energy deposition using laser light application (wavelength λ=1470 nm, 10 W, 10 s, applied energy 100 J) in the posterior urethra of anaesthetized New Zealand White male rabbits. The radial light emitting fiber was introduced by means of a children resectoscope (14F). The grade of urethral stricture was evaluated in 18 rabbits using videourethroscopy and urethrography at day 28 after stricture induction. An innovative catheter was developed based on a &beta;-irradiation emitting foil containing 32P, which was wrapped around the application system. Two main groups (each n=18) were separated. The "internal urethrotomy group" received after 28days of stricture induction immediately after surgical urethrotomy of the stricture the radioactive catheter for one week in a randomized, controlled and blinded manner. There were 3 subgroups with 6 animals each receiving 0 Gy, 15 Gy and 30 Gy. In contrast animals from the “De Nuovo group” received directly after the stricture induction (day 0) the radioactive catheter also for the duration of one week divided into the same dose subgroups. In order to determine the radiation tolerance of the urethral mucosa, additional animals without any stricture induction received a radioactive catheter applying a total dose of 30 Gy (n=2) and 15 Gy (n=1). Cystourethrography and endoscopic examination of urethra were performed on all operation days for monitoring treatment progress. Based on these investigation a classification of the stricture size was performed and documented for correlation. At further 28 days after catheter removal the animals were euthanasized and the urethra tissue was harvested. Histological examination of tissue with assessment of radiation damage, fibrotic and inflammatory changes were performed. After deblinding histological finding were correlated with the applied dose. Results: All animals developed a stricture, while 15/18 (83,3%) showed a significant, high grade stricture with more than 90% lumen narrowing. Histopathological examination including evaluation of urethral inflammation, fibrosis and collagen content were investigated in additional 6 rabbits confirming the former findings. No rabbits died prematurely during the study. The experiments showed that the procedure of the application of radioactive catheter was safe without any problems in contamination and protection handling. The combination of internal urethrotomy and LDR-brachytherapy results in a stricture free rate of 66.7% in the 15-Gy group, compared with only 33.3% among animals from the 0- and 30-Gy groups. Furthermore histological classification of inflammation and fibrosis of 0 Gy and 15 Gy showed similar extent. Conclusion: This new method of laser induced urethral stricture was very efficient and showed a high reproducibility, thus being useful for studying stenosis treatments. The experiments showed that application of local &beta;-irradiation by means of radioactive catheters modulated the stenosis development. This kind of LDR-brachytherapy shows potential for prophylaxis of urethral stricture. As this was an animal pilot experiment a clinical dose response study is needed.