*3.2. Late Radiation Cystitis with Persistent or Recurrent Hematuria*

## 3.2.1. Intravesical Instillations

Different molecules have been used for this indication, with different mechanisms of action. Their objectives are sterilization, cleansing and arrest of focal bleeding points.

*Aluminum salt:* Intravesical aluminous salts are considered astringent agents. They exert their action through protein precipitation on the cell surface and in interstitial spaces. They decrease blood vessel diameter and stiffness of capillary endothelium [9,19]. Aluminum salts are typically delivered as a 1% concentration of alum mixed with sterile water. Westerman et al. evaluated the benefit of alum instillations in 40 patients with hematuria, which was linked in 95% of patients to radiation cystitis [20]. These instillations led to a reduction in transfusion requirements (82% before instillation vs. 59% after instillation, *p* = 0.05). Moreover, 32.5% of patients did not require additional treatment after a median follow-up of 17 months. Tolerance was generally good. The main side effect reported was bladder spasm in 35% of patients [20].

*Formalin*: Formalin action consists of precipitating cellular proteins in the mucosa of the bladder. The consequence is to create occlusion within telangiectatic tissue. It appears to be the most effective intravesical agent with complete resolution rates ranging from 70 to 89%. However, the safety profile for this treatment is mediocre. First of all, its instillation is quite painful and must therefore be performed under general anesthesia. In addition, formalin has a high rate of morbidity and mortality (31%), with risks of vesicoureteral reflux complicated by severe bilateral pyelonephritis, ureteral stenosis and fibrosis of the bladder with reduced capacity and increased urinary frequency [21]. To date, its use remains very limited due to its poor safety profile.

*Hyaluronic acid*: Hyaluronic acid is a mucopolysaccharidethathelps to repair the normal glycosaminoglycan layer of the bladder when administrated through intravesical instillations. It has immunomodulatory properties that enhance connective tissue healing. Shao et al. evaluated the efficacy of intravesical hyaluronic acid (HA) instillation and hyperbaric oxygen (HBO) in the management of hemorrhagic radiation cystitis [22]. The clinical benefit was identical in the 2 groups but was maintained over time significantly in the HA arm. Indeed, complete resolution of hematuria was noted in 88%, 75%, and 50% of HA patients and in 75%, 50%, and 45% of patients in the HBO group, at 6-, 12- and 18-months following therapy, respectively. Hyaluronic acid appears to be an interesting therapeutic alternative, though this must be confirmed in a larger cohort.

Other agents have shown interesting results but have been studied only in small cohorts, like botulinum toxin, chondroitin sulfate, polydeoxyribonucleotides, early placental extract [23–26].
