Advances in the management of radiation-induced cystitis in patients with pelvic malignancies

Abstract Objective Radiotherapy plays a vital role as a treatment for malignant pelvic tumors, in which the bladder represents a significant organ at risk involved during tumor radiotherapy. Exposing the bladder wall to high doses of ionizing radiation is unavoidable and will lead to radiation cystitis (RC) because of its central position in the pelvic cavity. Radiation cystitis will result in several complications (e.g. frequent micturition, urgent urination, and nocturia) that can significantly reduce the patient’s quality of life and in very severe cases become life-threatening. Methods Existing studies on the pathophysiology, prevention, and management of radiation-induced cystitis from January 1990 to December 2021 were reviewed. PubMed was used as the main search engine. Besides the reviewed studies, citations to those studies were also included. Results and discussions In this review, the symptoms of radiation cystitis and the mainstream grading scales employed in clinical situations are presented. Next, preclinical and clinical research on preventing and treating radiation cystitis are summarized, and an overview of currently available prevention and treatment strategies as guidelines for clinicians is provided. Treatment options involve symptomatic treatment, vascular interventional therapy, surgery, hyperbaric oxygen therapy (HBOT), bladder irrigation, and electrocoagulation. Prevention includes filling up the bladder to remove it from the radiation field and delivering radiation based on helical tomotherapy and CT-guided 3D intracavitary brachytherapy techniques.


Introduction
Radiation-induced complications are unavoidable due to the widespread employment of radiotherapy. Radiation treatment for pelvic malignancies (e.g. cervical, prostate, and rectal cancer) can cause lasting damage to the bladder and even radiation cystitis (RC). One example of lasting damage is hemorrhagic cystitis, which involves bleeding of the bladder lining. Martin et al. calculated that approximately 11.1% of patients developed RC in a population of 709 prostate cancer patients ). An earlier Chinese trial that studied 472 uterine cervical cancer patients suggested that the percentage of Grade 2 cystitis cases was 14.9% (age <60) and 9.5% (age >75) (Wang et al. 2017). If the bladder receives a high dose of ionizing radiation, radiation-induced cystitis and even a vesical fistula may happen. It is generally recognized that radiation-induced bladder injury is more likely to occur when the total dose to the bladder exceeds 60 Gy. Specific dose limits are as follows: V5 < 74Gy, V20 < 70Gy, V25 < 65Gy, and V50 < 40-60Gy (Brossard et al. 2022). Hemorrhagic cystitis, a more severe type of RC, occurred at radiation doses ranging from ab 45-74 Gy (Pascoe et al. 2019). Accordingly, to minimize the above side effects, radiation therapists, medical physicists, and radiation oncologists should consider the bladder as one of the main organs at risk and strictly limit the dose-volume of radiation to the bladder when making radiotherapy plans.
In this review, background information about radiation cystitis is summarized including common symptoms, pathological alteration of radiation-induced bladder lesions, and clinically used assessments for evaluating the severity and burden of radiation cystitis. Preclinical and clinical strategies to prevent and treat radiation cystitis will be discussed, and some clinical guidelines will be suggested.

Pathophysiology of radiation cystitis
For pelvic radiotherapy complications, gastrointestinal and urologic toxicity is most observed during clinical practice and research. Modern radiobiology has suggested that the radiosensitivity of tissue is not correlated with mitotic rate. Besides, highly proliferative tissues (e.g. bladder mucosa) tend to show their damage quickly in developing into acute reactions. Histologically, the bladder wall is divided into four layers, which from adjacent to the lumen to deeper tissues are urothelium, lamina propria, submucosa, and detrusor muscle. When ionizing radiation reaches the bladder, the transitional epithelium comprising rapidly dividing cells shows damage first with cells dying through miotic catastrophe (Joiner and Van der Kogel 2018). At a later stage, inflammation in the smooth muscle layer shows edema, followed by cell destruction, fibroblast proliferation, and collagen deposition (Smit and Heyns 2010). The major cause of this result is radiation-induced prostaglandin metabolism, and the metabolic alterations cause changes in the tone of the bladder wall (Joiner and Van der Kogel 2018). Acute or subacute radiation cystitis happens during or up to 6 months after being irradiated. When patients develop the acute phase of radiation cystitis, their symptoms include frequent micturition, urgent urination, dysuria or nocturia, and hematuria (Helissey et al. 2020). Most mild reactions usually self-resolve after 4-6 weeks and rarely last longer than 3 months. In other words, acute RC tends to be self-limiting.
With increased irradiated dose, late radiation-induced tissue injury with different mechanisms from acute one would occur. In the case of chronic reactions, the pathogenesis of radiation cystitis primarily starts from the destruction of the mucosa, and then ulcers and even fistulas are gradually formed (Joiner and Van der Kogel 2018). Once a considerable number of mucosa epithelium cells die, they stop continuing regeneration, followed by superior layers sloughing off (Smit and Heyns 2010). Radiation creates a hypovascular, hypocellular, and hypoxic environment causing tissue breakdown. Such an ischemic environment leads to the formation of secondary bladder wall fibrosis (Joiner and Van der Kogel 2018). Besides, irradiated capillaries, mostly in mucous membranes, may develop into telangiectasia or cause bleeding (Smit and Heyns 2010). The above finding explains why hematuria, urothelial lesions, and bladder ulceration happen.
Chronic RC happens 1-10 years after being irradiated (Liem et al. 2015;Pascoe et al. 2019). However, developing late RC will cause much more severe symptoms, even death. The incidence of chronic RC is related to the total dose, dose per fraction, and irradiated volume of the bladder (Marks et al. 1995;Helissey et al. 2020). Just as the pathology of late RC explained, submucosa fibrosis leads to a decreased bladder capacity and vascular telangiectasia (Helissey et al. 2020). Besides, the radiation-induced inflammatory response of the vesicles leads to occlusion of the small arteries, thus creating a local hypoxic environment. Endarteritis obliterans results in hematuria or even lifethreatening hemorrhaging (Smit and Heyns 2010;Helissey et al. 2020). Hence, timely and accurate evaluation of RC is essential for patients undergoing pelvic radiotherapy (Rigaud et al. 2004).
The degree of RC severity varies from mild functional abnormalities to refractory symptoms with significant effects on patients' quality of life as captured in measures such as the Common Terminology Criteria for Adverse Events (CTCAE) (Freites-Martinez et al. 2021). CTCAE V5 comprises two parts, including cystitis noninfective and hematuria. The former is graded by the severity of symptoms (e.g. hematuria, urgency, nocturia, and incontinence, and the treatment measures taken). The latter is only based on the severity of hematuria and the corresponding recommended measures for grading. Included with objective and subjective signs, CTCAE has been extensively employed in clinical practice (Smit and Heyns 2010;Liem et al. 2015). Moreover, the Radiation Therapy Oncology Group (RTOG) and the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale have been widely used in relevant clinical trials and case reports (Herst et al. 2020;Small et al. 2021). RTOG is authoritative in evaluating radiological damage since it has compiled several severity scales of other radiation-induced organ damage (Brand et al. 2019;Widmark et al. 2019). Besides, one of the factors making RTOG a common use in clinical practice is its simplicity in grading acute and late hemorrhagic RC. Based on RTOG, LENT-SOMA is much more comprehensive than evaluating the effect from four dimensions (e.g. subjective and objective indicators). Its use in daily practice by clinicians is troublesome due to numerous indicators (Power 2005). All the above criteria are evaluated by the clinician, whereas the patients' subjective feelings are not involved. There are also some Patient-reported Measures (PROMS), including the validated O'Leary interstitial cystitis symptom, problem scale (IC), and radiation-induced cystitis assessment scale (RICAS). The problem scale (IC) is primarily used to evaluate IC symptoms. It can be applied since both conditions can be speculated as symptoms of bladder irritation. However, since RC also has some specific symptoms (e.g. hematuria), the efficacy of IC in evaluating the severity of RC has not been confirmed. RICAS, specially designed for acute RC, acquires its score by evaluating the severity of common symptoms of RC (Herst et al. 2020). PROMS have been rarely employed to guide disease management based on clinical experience. Likewise, a recent meta-analysis has suggested that it is more commonly used in palliative radiotherapy research, and it has been primarily used as a benchmarking tool (Oldenburger et al. 2020). Considering their advantages and disadvantages, PROMS can meet the needs of modern humanistic medicine to a certain extent and should be used to complement clinician scoring systems. All the measures are mentioned in supplementary data (O'Leary et al. 1997;Chong et al. 2005;Herst et al. 2020;Di et al. 2021). In brief, RTOG can be adopted to achieve a faster initial clinical evaluation of the condition, whereas CTCAE is more comprehensive and accurate in evaluating the degree of RC. LENT-SOMA is more difficult in clinical use due to the complexity of its scoring details. PROMS based on the patient's evaluation have been used in a few clinical studies. Taken together, clinicians and research staff should select the most suitable measure after considering the advantages and drawbacks of the above measures.

Prevention
The causes of a variety of side-effects from radiation damage are related to some main factors which are the total radiation dose, the volume of the irradiated tissue, and the sensitivity of the normal tissue to radiation, and sometimes with other risks or some potential positional errors during the therapy. Reducing the damage from radiotherapy or preventing it if possible is the main focus of this review. The prevention strategies in this review are divided into four parts: discovering relative risk factors, maintaining the filling situation of the bladder, using novel technologies (e.g. VMAT, IMRT, HT, and CT-ICBT), and selecting appropriate combined treatments.

Risk factors
Existing research has confirmed that the dose and volume irradiated to the bladder wall are correlated with the severity of RC, with several dose-volume parameters recognized. For instance, Gustavo et al. revealed a significant relationship between bladder dose and cystitis: Grade I cystitis ¼ 66 ± 13.18 Gy vs Grade III cystitis ¼ 68.56 ± 8.53 Gy (Montana and Fowler 1989). Moreover, grade II cystitis was reported to be associated with the volume of the bladder wall receiving 20 Gy less than 34% and 35 Gy less than 25% (Shinde et al. 2021). On the other hand, Sofia et al. found that an increase from 75 Gy to 80 Gy in bladder D2cm 3 resulted in a higher incidence of grade !2 cystitis (Spampinato et al. 2021). Likewise, higher D 5cc for the bladder was noted in patients with grade !1 cystitis (Okonogi et al. 2018). Another study indicated that Grade 2-4 bladder toxicity occurred more in patients with D2cc >95 Gy (Kim et al. 2017).

Controlling the volume of the bladder
Because of the anatomical position of the bladder, its volume change will cause the dose-volume alteration in the shape of the target area and surrounding normal tissues during radiotherapy (Nasser et al. 2021). Inokuchi et al. reviewed 309 patients with high-risk prostate cancer who received IMRT (78 Gy/39F) and suggested that V75 (bladder neck) and V70 (bladder wall) >75Gy are correlated with late severe hematuria. Even in multivariate analysis, V75 (bladder neck) was still significant (Inokuchi et al. 2017). Bladder filling before administering radiotherapy results in a lower dose of radiation exposure to the bladder. A bladder Scan, functioning as an ultrasound-based volume scanner, is beneficial to identify the bladder volume more successfully (Kuo et al. 2021). It exhibits similar efficiency to CT in estimating the bladder volume without the risk of the bladder being irradiated (Mullaney et al. 2018). An Australian prospective clinical study of 524 prostate cancer patients introducing the BladderScan group reached a lower maximum bladder V50 than the control group (46.4% of 17 vs. 50.9% of 17) (Cramp et al. 2016). Irish scientists conducted another randomized trial of 110 PC patients. They reported that the 540 ml group has a more reproducible bladder volume than the 1080 ml group (p ¼ .003) without poor QoL and radiation toxicities (Mullaney et al. 2014). Recently, a Chinese clinical study of 166 locally advanced cervical cancer (CC) patients retrospectively suggested that the bladder volume between 100 and 150 ml had a lower incidence of late RC and milder reactions (p ¼ .022) (Ma et al. 2019). In brief, during radiotherapy, the radiotherapy planner must select an appropriate reproducible bladder volume and may use ultrasound or CT to assess bladder volume for bladder irradiation dose-volume reduction.

Applying novel technologies of radiotherapy
Novel technologies like helical tomotherapy (HT), CTguided 3D intracavitary brachytherapy (CT-ICBT), volumetric modulated arc therapy (VMAT), and RapidArc have come into use. This year, Chinese research on 96 IIB-IIIB CC patients compared HT þ CT-ICBT and IMRT þ ICBT and found that the occurrence of severe radiation cystitis (evaluating according to RTOG guideline) was 2.1% (1/48) vs. 18.7% (9/48) with no statistically significant differences in both 3-year OS and PFS between the above groups (Ye et al. 2021). French research followed up 41 sacral chordoma patients and compared tomotherapy with proton-tomotherapy, which had a significantly lower occurrence of radiationinduced cystitis. The combined group had a little higher OS, but this was not statistically significant, nor was a locoregional relapse-free interval (Beddok et al. 2021). A Chinese retrospective study compared VMAT and IMRT. It concluded that only 0.9% of 331 patients with IA-IVB CC who received VMAT developed grade 3 cystitis (by RTOG/EORTC) (Lin et al. 2019). Extended-field radiotherapy has been conducted using IMRT rather than the 3dimensional conformal (3D-CRT) 4-field box technique. Canadian scientists have identified a statistically lower occurrence of radiation cystitis in the IMRT group after a long-term follow-up of 38 advanced-stage endometrial carcinoma patients (Rabinovich et al. 2015). RTOG 0126 trial on 748 prostate cancer (PC) patients drew the same conclusion, i.e. the IMRT group has much lower V65, V70, and V75 of the bladder, along with a significant decrease in acute GU toxicity (Michalski et al. 2013). Liu et al. compared three technologies (including 3D-CRT, IMRT, and RapidArc) among 30 rectal cancer patients and suggested that 3D-CRT, with a significantly higher V40 of the bladder (p < .01), is less effective in OAR protection (Liu et al. 2015). Different fractionations of radiotherapy affect PFS and the incidence of adverse events. In comparison with conventional radiotherapy (73.8 Gy/41F), hypofractionated radiotherapy (70 Gy/28F) achieves a slightly higher DFS (86.3% vs. 85.3%) at the cost of increased late G2-3 genitourinary adverse events (HR, 1.31-1.59, by CTCAE V3) (Lee et al. 2016). Thus, a better precision approach to radiotherapy delivery allows for better dose distribution to the tumor tissue, thus resulting in a lower irradiated dose volume to the bladder and a lower incidence of RC.

Select combined therapy cautiously
Different ways of combining treatments affect side effects. Noteworthily, radiotherapy combined with other treatments sometimes means more urinary symptoms (Boeve et al. 2021). Some drugs (e.g. gemcitabine) have a radiosensitizing effect and, in combination with radiotherapy, increase the incidence of radiotherapy side effects. For 2270 patients with IB2-IIB stage cervical cancer, a Chinese statistical analysis has suggested that concurrent chemoradiotherapy has fewer bladder complications (OR 0.27 of 1535patients) but lowered DFS (HR 1.47) than neoadjuvant chemotherapy plus surgery (Zou et al. 2019). Datta et al. drew a similar conclusion that concurrent chemoradiotherapy (CR 79.4% of 1169 patients) leads to increased severe acute toxicities (16.4% vs. 4.9%) than radiotherapy alone (CR 69.8% of 1173 patients) for locally advanced CC patients (Datta et al. 2017). The result of NCT00191100 conducted in Mexico suggested that adjuvant gemcitabine (1000 mg/m 2 on d1, d8) and cisplatin (50 mg/m 2 on d1) plus concurrent chemoradiotherapy (6 times cisplatin 40 mg/m 2 , gemcitabine 125 mg/m 2 weekly þ concurrent external-beam RT 50.4 Gy/28F þ following brachytherapy 30-35Gy) resulted in more grade 3/4 toxicities (86.5% vs. 46.3%) than concurrent cisplatin chemoradiotherapy for 515 patients with middle or late-stage cervical carcinoma. The PFS at the follow-up of 3 years was been better in the adjuvant chemotherapy group (74.4% vs. 65.0%) (Duenas-Gonzalez et al. 2011). Patients receiving combined treatment with radiotherapy and antiplatelet/coagulant also tended to develop RC (p ¼ .002) (Sanguedolce et al. 2021).
Nevertheless, some treatments may achieve a slightly lower rate of RC, but key survival indicators (e.g. OS and PFS) must be balanced. Take prostate cancer as an example. An English clinical trial of 415 locally advanced prostate cancer patients published in 1997 reported that combined treatment of radiation therapy and goserelin had more late grade 1-3 urinary toxicities than radiation therapy only. However, the above difference did not achieve statistical significance (Bolla et al. 1997). Another comparison drawn by Canadian scientists of concurrent and neoadjuvant (n ¼ 217, n ¼ 215) androgen-deprivation therapy (ADT) combined with radiotherapy suggested that the difference between OS and late severe genitourinary toxicity did not achieve statistical significance (Malone et al. 2020). Another American phase 3 trial containing 1292 patients achieved a similar conclusion during the comparison of four different treatments: whole pelvis RT plus neoadjuvant or adjuvant hormonal therapy, prostate only RT plus neoadjuvant or adjuvant hormonal therapy. Although there was a slight difference (p ¼ .16) in severe late genitourinary toxicity, the difference in OS achieved statistical significance (p ¼ .027) between those four groups (Lawton et al. 2007).
Considering the previous paragraphs, reducing the incidence of RC is closely correlated with the choice of treatment options for patients. First, besides the conventional bladder radiotherapy dose limits, other radiotherapy variables (including D2cm 3 , D5cc, and D2cc) can be used as a reference for the occurrence of side effects of radiotherapy. Moreover, standard concurrent radiotherapy regimens are more likely to cause RC in patients with cervical cancer. Specific chemotherapy regimens (e.g. adjuvant gemcitabine) are also more likely to trigger RC. Likewise, radiotherapy combined with goserelin treatment in prostate cancer patients increases the risk of RC to a certain extent. In contrast, ADT combined with RT does not increase the incidence of RC while improving OS. The control of disease progression is the first thing clinicians should consider when weighing up the optimal treatment modality against the associated side effects. Clinicians are strongly encouraged to control bladder volume better during radiotherapy and use precision radiotherapy techniques when the firstline treatment and underlying condition of patients make them more likely to develop severe RC.

Treatment
Thus far, progress has been made in the management of acute RT (Denton et al. 2002). Table 1 lists some of the recent clinical trials and case reports published from January 2019 to December 2021, among which intravesical instillation, surgery, and HBOT have been investigated in more trials. Other burgeoning strategies (e.g. cranberry capsules and endoscopic fibrin glue) also need consideration. Cranberry products have been extensively studied in the treatment of urinary tract disorders, particularly urinary tract infections. As a natural substance, it has fewer side effects and higher compliance than chemically synthesized drugs or other invasive treatments. However, the latest published RCT did not yield positive results for RC with cranberry capsules (Herst et al. 2020).
Given the long history of treating RC, six commonly used strategies are discussed below, and some other strategies are covered in less depth.

Symptomatic treatment
Considering RC's pathological and clinical features, most acute RC tends to be self-limiting. Even patients with mild symptoms of chronic RC may benefit from symptomatic treatment. To mitigate the symptoms of frequent micturition, urgent urination, and dysuria, several treatments (e.g. phenazopyridine, flavoxate, and some other agents) are discussed below.
Phenazopyridine, an effective anesthetic, acts directly on the mucosal layer of the urethra when being taken and is excreted in the urine, eliminating discomfort and burning sensations in RC (Smit and Heyns 2010). Shore et al. conducted a clinical study to determine the safety of long-term phenazopyridine use. After reviewing 272 patients who used it for over 14 d, 13 adverse drug reactions were reported in 90 patients in the experimental group. No difference was found in the incidence of severe side effects between the long-term drug use group and a matched comparator group (Shore et al. 2020). Flavoxate is a smooth muscle relaxant that relieves the spasm of the smooth muscle of the genitourinary system. Eliminating urinary frequency, urgency, incontinence, and abdominal pain caused by the spasm of the smooth muscle of the bladder, flavoxate can be applied as one of the symptomatic treatments of RC (Denton et al. 2002). Milani et al. completed a small study comparing the effectiveness of urodynamically treatment between 1200 mg/d (13 patients) and 600 mg/d (21 patients). Both being well-tolerated, the higher dose treatment of flavoxate got better results, though this result was not statistically significant (Milani et al. 1988). However, large double-blinded RCTs should be further conducted to confirm the above results.
Anticholinergic agents have been primarily used in the urinary system to relieve colic caused by ureteral calculi. For patients with RC, anticholinergics can be used to improve urgency incontinence (Noonan and Farrell 2016). Besides the above treatments, tolterodine and analgesics also contribute to decreasing symptom severity. Besides the symptoms mentioned above, RC is prone to bleeding and infection. Hemostatic agents like PAMBA and E-aminocaproic acid can decrease the risk of bleeding, and antibiotics can be used prophylactically to reduce the chances of urinary tract infections (Ju et al. 2021). In conclusion, for mild RC symptoms, symptomatic treatments can be first applied and other treatment measures as follows may be considered if there is no relief.

Hyaluronic acid
Hyaluronic acid is a substance that can help glycosaminoglycan (CAG) mucous layer restoration, which is beneficial to defend against urinary tract infection (Damiano and Cicione 2011). A single-centre retrospective study of 97 patients who finished brachytherapy concluded that hyaluronic acid instillation could reduce the incidence of acute radiation-induced bladder toxicity, and fewer patients developed severe vesical toxicity (Samper Ots et al. 2009). Another clinical trial validated the efficacy of intravesical instillation of sodium hyaluronate (40 mg/50 ml/week, from 8 to 24 weeks). The outcomes indicated that in 15 patients with radiationinduced cystitis, their bladder capacity rose from 85 ml to 243.3 ml, which was the statistical significance (Sommariva et al. 2010). Besides, a prospective clinical trial combined sodium hyaluronate and chondroitin sulfate, which both replenish the glycosaminoglycan. This management turned out to have a statistically significant effect on decreasing the nocturnal voiding frequency (evaluated by ICSI-Q3) of 18 patients. However, more randomized, controlled trials are needed to confirm this outcome (Gacci et al. 2015). In 2016, prospective pilot research on 80 patients treated by RT for prostate cancer was conducted by Gacci et al. who combined hyaluronic acid and chondroitin sulfate to treat post-radiation cystitis. The authors concluded that this therapy improved urinary tract symptoms (evaluated by ICSI) regardless of clinical features (Gacci et al. 2016). This method is step 2 in the five steps of sequential management, which will be discussed in detail in the Other Treatments part (Ju et al. 2021). Thus, this treatment should first be considered since it has fewer side effects than the latter two treatments, and it is primarily effective for the treatment of acute RC.

Formalin
Formalin refers to a type of aqueous solution whose solute is an aldehyde. Formalin had been initially employed to control intractable bleeding secondary to cancer, cystitis, or radiation (Kumar et al. 1975). Applications have involved intravesical instillation and topical placement. Cotton pledgets soaked in 5% formalin solution were put onto the bleeding loci of the bladder for 15 min. The symptoms of bleeding were resolved during 16 months of follow-up (Lowe and Stamey 1997). Kumar et al. used the fact that the bladder is a hollow organ by applying formalin as a bladder infusion (Kumar et al. 1975). A comparison of the above two techniques was drawn by Lojanapiwat et al. among 19 cervical cancer patients. The conclusion was that topical application (6 of 8 patients ceased bleeding) showed the same efficiency as bladder instillation (9 of 11) but fewer side effects (three minor complications vs. four major and several minor ones) (Lojanapiwat et al. 2002). Dewan et al. investigated the concentration of formalin in 35 cervical cancer patients who received a dose averaging 68 Gy and concluded that a 1% solution was more effective than a 2% or 4% solution (Dewan et al. 1993). In contrast, another review that included 235 cases suggested that a higher concentration of formalin was correlated with a lower recurrence of hematuria. A 10% formalin solution had a higher rate of complete response and a lower rate of recurrence in patients with HC due to radiotherapy for bladder tumors. However, 5% formalin was more effective and had a lower incidence of minor complications in patients with HC due to unresectable bladder tumors or cyclophosphamide cystitis (Donahue and Frank 1989). The latest clinical research on intravesical instillation of formalin for HC referred to a retrospective study conducted in 2017. All eight patients (6 prostate cancer and 2 cervical cancer) received a dose of formalin from 1% to 4%, and the therapeutic response rate reached 75.0%. However, Ziegelmann et al. indicated the risk of non-obstructive acute kidney injury or requirement of blood transfusion using formalin instillation (Ziegelmann et al. 2017). In this study, the formalin concentration was between 1% and 4%, and the exposure time was about 10-15 min. This chemical substance has side effects that cannot be ignored, i.e. its metabolic product may cause acute renal failure or even tubular necrosis (Chugh et al. 1977). Notably, bladder irrigation with formalin has a long history of use, and it is effective in hemorrhagic cystitis. Indeed, clinicians must avoid the associated side effects when using bladder irrigation with formalin.

Alum
Kennedy et al. first used a 1% alum solution in eight patients with refractory vesical bleeding. The outcome was promising, and patients were treated without anesthesia (Kennedy et al. 1984). Some researchers tried to find the safety/efficacy profile of alum instillation, and the consequence was that around 60% of 39 patients (27 prostate cancer, 2 gynecologic cancer, 2 tor non-GU/GYN cancer 3 both cyclophosphamide and pelvic radiation, 5 other HC) achieved (Westerman et al. 2016). Other researchers also find it valid, well-tolerated, and low-cost in patients with radiation-induced intractable cystitis (Ho and Md Zainuddin 2009). Considering its side effects, Goswami et al. designed a prospective study to determine the safety of alum instillation. Some of the 12 patients had suprapubic pain, lowgrade fever for a short time, and tenesmus. On the whole, alum instillation with a 1% concentration has low toxicity and is safe to alleviate hematuria (Goswami et al. 1993). Nevertheless, it is less effective when patients are undergoing a subsequent or massive hemorrhage (Takashi et al. 1988). Also, a case reported that a girl with ALL developed prominent toxicity (Bogris et al. 2009). So before choosing this management, the patient's conditions should be primarily considered. Thus, when applying this treatment, it should first be considered for patients with non-persistent non-massive hematuria.

Laser coagulation
Radiation cystitis may lead to severe hematuria, for which general oral agents or short-time instillation do not work. Ravi et al. administered a YAG laser with power 3 W and pulse duration 3 s to 42 patients with RC, 39 patients responded well after only a single application and another two patients were relieved after two treatments. The CR percentage was 0% after the whole follow-up of 14 months. In this study, 39 of 42 patients suffering from cervical cancer received an average dose of 68 Gy to point A, and 2 bladder cancer patients received about 65 Gy (Ravi 1994). Except for the YAG laser, other types of lasers like 980-nm diode, argon beam, Greenlight KTP, and Greenlight XPS are being under investigation (Wines and Lynch 2006;Kaushik et al. 2012;Zhu et al. 2013;Talab et al. 2014;Zhang et al. 2021). Three of the above studies contained no more than 10 patients, the results of which are not convictive. One retrospective study showed that hematuria in 65% of 20 patients (19 prostate cancer and 1 bladder cancer) was alleviated after only one cycle of KTP laser coagulation, and hematuria stopped in 25% of patients after several cycles (Talab et al. 2014). The latest study published reported that the median hematuria-free interval of 18 cervical cancer patients and 3 endometrial cancer patients who finished 27 fractions of diode laser treatment was 16 months (Zhang et al. 2021). This treatment is accompanied by potential intestinal perforation, as reported in a case of a Spanish woman who completed YAG laser coagulation for treating radiation cystitis (Vicente Rodriguez and Farina 1991). Furthermore, laser electrocoagulation is more effective and noninvasive for patients with bleeding cystitis who cannot tolerate local therapy.

Hyperbaric oxygen treatment (HBOT)
Research on HBOT in the treatment of RC continues to emerge as the major method of treating radiation injuries. A phase 2-3 clinical trial called RICH-ART saw a statistically significant difference between the HBOT group (n ¼ 41) and the standard group (n ¼ 38) when treating RC. Using the EPIC urinary tract score as the study indicator, the mean total EPIC urine score increased by 17Á8 points in the HBOT group compared to 7Á7 points in the standard care group at the 4th follow-up visit. (Oscarsson et al. 2019). Also, a large-scale prospective clinical trial of 411 patients has been performed by American scientists. Its outcome was that HBOT affects chronic radiation tissue injury (e.g. radiation cystitis), supported by previous small-scale trials (Hampson et al. 2012). The advantage of HBOT is that it is well-tolerated, highly efficient, and has long-term effects (Mathews et al. 1999). With the further development of HBOT, some of its drawbacks are also mentioned in the literature. For instance, when patients are suffering from necrotizing fasciitis or ischemic injury, the efficacy of HBOT is unknown (Capelli-Schellpfeffer and Gerber 1999). In a recent clinical trial, transient mild adverse events in sight and hearing were reported in 41% of 41 patients in the HBOT group (Oscarsson et al. 2019). In a study of 71 RC patients treated with HBOT, the vast majority of whom had prostate cancer, they received an average irradiation dose of 66 Gy (45-138 Gy). Several cases of barotraumatic otitis, short-term visual disorders, and finger paraesthesia were reported in this article (Mougin et al. 2016). Hyperbaric oxygen therapy is more effective for hematuria than laser electrocoagulation, has more research data, and is more widely used. This makes hyperbaric oxygen therapy the predominant treatment modality for radiation cystitis. The problem is that not every city has access to hyperbaric oxygen chambers. For some small-scale hospitals, the development of HBOT is limited by objective conditions.

Vascular interventional therapy
Nowadays, interventional therapy has become one of the most critical treatments and plays a key role in dealing with hemorrhagic disorders. French researchers applied selective vesical embolization to seven cases of radiation cystitis and stopped refractory hemorrhage (Guillou et al. 1975). More invasive and effective management is of the utmost importance when hematuria progresses to an uncontrollable situation. Selective arterial embolization is more minimally invasive than surgery because most patients are too old and weak to undergo cystectomy (Loffroy et al. 2014). The internal iliac artery is often selected to do selective transarterial embolization (TAE). After a mean follow-up of 18.1 months, Korkmaz et al. reviewed 16 patients who finished endovascular treatment. They suggested that the ratio of the bleeding stopped in all patients reached 100%, which means transarterial embolization (TAE) significantly upgraded patients' hematocrit and hemoglobin levels (Korkmaz et al. 2016). Another study embolized bilateral or unilateral arteries for controlling refractory prostate or bladder bleeding. 83.3% of 18 patients achieved symptomatic relief by finishing the first procedure (Delgal et al. 2010). Besides selective embolization, super-selective embolization and coil blockade techniques can be selected in accordance with different situations of patients. The location of the superselective embolization is usually normal vascularity, hypervascularity, or extravasation in the vesical or prostatic arteries. Whereas the location of selective embolization is the anterior division of the hypogastric arteries, the posterior division is usually preserved. Although the more specific embolization site of superselective embolization means that treatment-related complications are likely to be relatively mild. However, a major feature of radiation injury is systemic capillary dilation, and bleeding may occur at other unembolised sites following local superselective embolization. Thus, selective embolization, therefore, allows embolization to be performed on a larger scale, avoiding repeated multiple operations (Loffroy et al. 2014). Compared with laser electrocoagulation, vascular interventions are more invasive and have a better hemostatic effect.

Surgery
Cystectomy takes on a critical significance in patients with severe hemorrhage due to radiation cystitis (Venn and Mundy 2000). In 1993, a patient was reported to suffer from uncontrollable hematuria after chemotherapy with cyclophosphamide combined with radiotherapy. She tried cystectomy and achieved significant remission (Bissett et al. 1993). With the development of surgical technology, laparoscopic cystectomy which is less traumatic when treating radiationinduced HC has been more extensively used (Alkan et al. 2006). Besides, more advanced technologies (e.g. robotassisted cystectomy) are under development (Phillips et al. 2014;Al Hussein Al Awamlh et al. 2016). The latest retrospective study with 286 patients has concluded that radical surgery is required for severe uncontrollable hemorrhagic cystitis (Tachibana et al. 2021). Notably, the reconstruction of the bladder takes on a great significance in the whole cystectomy due to the need for reservation of urination function. Resecting the whole bladder can cause a wide variety of side effects (e.g. extensive injury and sexual dysfunction) though cystectomy may be the most effective treatment. Accordingly, partial cystectomy, in which the resected urothelium is replaced for refractant hemorrhagic cystitis by omentum, was developed to maintain intact sexual function (Elzevier et al. 2005). The choice of the appropriate procedure will depend on the extent of the patient's bladder damage. For patients with less severe radiation bladder damage, only symptomatic resolution of their hematuria is required, i.e. removal of the severely damaged part of the bladder wall. In this group of patients with severe bladder fibrosis, severe loss of normal bladder function and bladder contracture after irradiation, total cystectomy may be more effective. In a clinical trial published in Lancet, the results showed that patients who underwent radical cystectomy had more than a 65% probability of adverse events, such as urinary tract infections and postoperative bowel obstruction (Parekh et al. 2018). In brief, cystectomy may be the best way to treat severe hemorrhagic cystitis but comes with severe complications and high mortality evaluated.

Other treatments
In general, the therapeutic effects of the existing treatments for RC, especially severe RC, have been limited. The combination of different treatments based on the nature of individual treatment arises as a novel promising regimen. A Chinese report has suggested that the combination therapies for RC can be categorized into five sequential steps, including step 1 as symptomatic treatment, step 2 as bladder irrigation, step 3 as electrocoagulation, step 4 as interventional embolization, and step 5 as HBOT. Ju et al. reported that the cure rate with this combination therapy in both the moderate group and severe group reached 99.8% in 582 RC patients and 94.1% in 68 RC patients, respectively (Ju et al. 2021). Likewise, Claire et al. developed a practical algorithm of RC, in which active bleeding is managed with ablation, intravescical alum or formalin, arterial embolization, and cystectomy, whereas other symptoms are treated with HBOT (Pascoe et al. 2019). Future protocols should take a multitreatment approach, based on the cohort of patients that they are treating.

Conclusion
As a common complication of pelvic tumor radiotherapy, radiation cystitis is characterized by rapid onset, persistence, or recurrence. If not effectively controlled in time, it can interrupt patients' radiotherapy delivery, affect clinical efficacy, and even negatively affect patients' life expectancy.
Taking adequate measures to prevent and treat radiation cystitis induced by abdominopelvic radiotherapy is worthy of careful consideration. Although there are a series of effective treatment modalities, including hyperbaric oxygen therapy and perfusion therapy, there is a lack of large prospective randomized controlled trials and no uniform treatment standard. It is promising that several clinical trials on RC treatments are underway. Their specific information can be found in Table 2. Current clinical experience and retrospective studies tell us that most patients with mild diseases often find relief with symptomatic treatment. In contrast, patients with severe RC may require a combination of effective treatments, thus requiring clinicians to choose an individualized treatment approach based on the patient's condition.
The prevention of radiation cystitis should be considered by the designer of the radiation therapy plan. Existing research has revealed that radiation oncologists can control the irradiation dose to the bladder at a lower level by changing the bladder volume and administering radiotherapy to pelvic tumors with a full bladder, such that the associated complications can be avoided. However, further exploration is still required to investigate how to maintain the consistency of bladder filling at all stages of radiotherapy and achieve the true meaning of patient-tailored radiotherapy. Furthermore, potential positional errors can affect the efficacy and safety of radiotherapy, which should usually be controlled in a specific range. To solve the problem of positional error in radiotherapy, cone beam CT (CBCT) is recommended to correct the positional error. in accordance with the working principle of CBCT, it directly obtains a 3D image through 2D projection data reconstruction, thus increasing the accuracy and speed of imaging. Regular CBCT images are more feasible because of the shorter scan time and lower dose of CBCT. This allows the treatment beam to be directed according to tumor motion and, if necessary, to make changes to the treatment plan (Steinke and Bezak 2008). It will significantly reduce positional error, thus increasing the accuracy of radiotherapy for patients. Moreover, clinicians can protect normal tissues by developing individualized radiotherapy plans and optimizing radiotherapy techniques in clinical practice. Increasing irradiation precision and dose calculation accuracy is confirmed as the fundamental method of preventing radiotherapy complications.

Disclosure statement
No potential conflict of interest was reported by the author(s).  Change in the intensity of bladder pain (baseline to week 7, baseline to week 10)