*2.2. Late Radiation Cystitis*

Late radiation cystitis is defined as an adverse event associated with pelvic irradiation that occurs after a minimum of threemonths and possibly even several years after completion of radiation therapy. Toxicities occurring between three and sixmonths are sometimes considered as "early delayed". On average, late radiation cystitis appears within the following 2–3 years. The incidence of late symptomatic radiation cystitis is stable over time at 5–10%, despite improved radiation techniques [8–10]. The clinical presentation can be variable, including bladder pain, urinary urgency, isolated urinary disorders and pollakiuria. Given that these symptoms are nonspecific and appear long after treatment, urine culture, or even cystoscopy may be useful to rule out other differential diagnoses. The most pathognomonic clinical feature is recurrent hematuria, with varying severity. In its most (and rare) severe forms, late radiation cystitis may be life-threatening. The incidence of late radiation cystitis was approximately 5% at 5 years and 10% at 20 years with conventional radiotherapy techniques [9]. It is important to eliminate any local recurrence or new cancer by performing cystoscopy. It should be highlighted that severe late symptoms (e.g., fistulas) may be worsened by inappropriate bladder biopsies, which should therefore be avoided in previously irradiated areas. Patients with a pelvic tumor extending to the bladder are also at high risk of fistulas [11]. A classification of this adverse event was developed (Figure 1). Severe late radiation cystitis is related to the volume and the dose of radiation exposure, the administration schedule and the technique used, but it is also important to identify patients with risk factors for developing a severe form. Marks et al. reported that patients with co-morbidities, such as hypertension, diabetes, a history of abdominal surgery, and patients receiving concomitant chemotherapy were at higher risk of developing radiation cystitis, especially in its late form [12]. Recent data suggested that after high dose exposures (such as after brachytherapy treatment), some anatomic subpart of the bladder may be at higher risk of complication, such as the bladder neck [13]. Although the pathophysiology of late radiation cystitis still remains unclear, endothelial cells appear to play an important role in this mechanism. Indeed, the submucosal vascularity is damaged by fibrosis of the vascular intima resulting in vessel obliteration and submucosal/muscular fibrosis. This is followed by urothelial atrophy, hypoxia with hypovascularization and ischemia of the bladder leading to the development of fibrosis and atrophy of the bladder tissue with the emergence of neovascularization in the form of telangiectasia that may easily bleed [14,15]. At the later stage, reduction in bladder capacity is observed linked to complete bladder fibrosis, mucosal ulcers with the risk of fistulization and spontaneous perforations of the bladder (or fistulae resulting from biopsies).

### **3. Current Treatments and Clinical Trials**

*3.1. Acute and Late Radiation Cystitis with Storage, Voiding Symptoms or Occasional Bleeding*

The clinical management of storage symptoms for acute and late radiation cystitis is largely symptomatic with analgesics and anti-inflammatory drugs. Good hydration is recommended for patients in order to increase diuresis, cleanse the bladder, and avoid urinary obstruction resulting from blood clots [16].

Likewise, anticholinergics, like oxybutynin, trospium chloride, solifenacin, fesoterodine or flavoxate hydrochloride, can be prescribed to help alleviate urgency and increased daytime frequency. Their action is to decrease the contractility of the detrusor and improve symptoms [4].

In some cases, antibiotics may be proposed to prevent the condition from worsening in the event of infection.

Alpha-blockers, 5-reductase inhibitors or phosphodiesterase 5 inhibitors may be useful to alleviate voiding symptoms. Their action is to decrease the tone of the posterior urethra, bladder neck and the volume of the prostate [1]. In severe cases, it is sometimes necessary to hospitalize the patient for transfusions or clot evacuation [4]. In fact, bladder irrigations are performed in order to obtain a dilution of hematuria and drain the clots. It is a sterile technique with lubrication for standard catheter insertion with a large three-way catheter. Blood clot evacuation is performed manually by using a large Toomey or catheter syringe until no further clots and output begin to clear. Then, we use normal saline (0.9%) for continuous irrigation [17].

If acute active bleeding does persist and is refractory to irrigations, electrocoagulation should be discussed, as described by Martinez and colleagues [18]. The procedure was performed with a rigid 22 French cystoscope. It was performed to identify the source of bleeding and rule out any other unidentified pathology. The Green Light laser was used to target any active source of bleeding. These areas were coagulated with the laser. Throughout the procedure, saline irrigation was used, and care was taken to ensure that the ureteral orifices were not injured. At the completion of the procedure, the bladder was drained under direct visualization to ensure adequate hemostasis. Very minimal bladder mucosal damage was reported. Then, a large three-way catheter was placed, and continuous irrigation was maintained overnight and stopped the next morning [18].

These treatments are tailored according to the severity of the symptoms (Figure 1).
