Radiation Cystitis

Abstract

The bladder is incidentally exposed during radiation therapy for cancer involving pelvic structures. Radiation exposure induces urothelium damage and perivascular fibrosis, as well as traumatizes the detrusor smooth muscle, resulting in a decrease in bladder compliance and capacity. The acute and subacute phases of radiation cystitis (RC) occur during or within 3–6 months after therapy. On the other hand, late RC can develop from 6 months to years after radiation treatment. Clinical symptoms may include storage and voiding symptoms, pelvic pain and hematuria. The diagnosis is focused on the exclusion of other causes. The oral therapies include analgesics, anticholinergics, alpha-blockers and 5-reductase inhibitors. Intravesical instillation (e.g., prostaglandin, formalin, hyaluronic acid) have been used for the treatment of late RC. The management of hemorrhagic cystitis is tailored according to the severity of the symptoms, involving conservative measures, hyperbaric oxygen, fulguration, selective embolization, urinary diversion or cystectomy.

1. Introduction

Radiation is the energy emitted by a source, which is transmitted through a medium and absorbed by another body. For example, high-energy gamma particles can be used for cancer treatment. This therapeutic modality aims to reach high doses of radiation to the target organs, eradicate the tumor and respect the function of the other organs, while preserving the normal tolerance of the surrounding tissues. The treatment of pelvic organ cancers, such as rectal cancer, prostate cancer, uterine cervix cancer or bladder cancer, presents external pelvic radiotherapy as an important therapeutic option [1, 2, 3].

Advances in radiation techniques, such as high-energy linear accelerators, intensity-modulated radiotherapy, stereotactic radiotherapy and image-guided brachytherapy, have enabled the administration of increasingly effective doses to the tumor, with an improvement in treatment tolerance, while sparing surrounding tissues. Improved understanding of tissue response to radiation and radiobiological principles has enabled the improvement of fractionation schemes and optimization of the therapeutic ratio between tumor cure and normal tissue damage [1, 2, 4].

Despite the advances, tissue injury still occurs in nontarget organs. The urinary bladder is a critical organ that can be sensitive to low doses of radiation and can be intentionally irradiated in patients with bladder cancer or incidentally in patients with cancer involving other pelvic structures, responsible for acute and/or late adverse events. Bladder injuries and symptoms after irradiation of the pelvic organs define radiation cystitis (RC), and its severity is related to the total dose released, the volume of radiation exposure, the administration scheme and fractionation. Due to the impact on patients' quality of life and the increase in cancer patient survival, a better understanding of the mechanisms of radiation-induced cystitis is essential [2, 4, 5].

Complications associated with radiotherapy account for up to 5–10% of emergency urology admissions. Urinary bladder response to radiation treatment can be classified into acute or subacute reactions occurring within 3–6 months of radiation treatment and late reactions occurring after 6 months to years. Lower urinary tract symptoms are present in these patients. About 5–10% of patients will develop chronic symptoms which remain mild and easily controlled. However, symptoms may persist in a small group of patients and may become debilitating and refractory to conservative treatment [1, 3, 5, 6].

2. Pathophysiology

Radio sensitivity varies in different tissues, largely depending on their proliferative rate [1, 2, 3, 4, 5]. The normal epithelium of the bladder is sensitive to radiation and the pathological mechanisms include inflammatory effects of ionizing radiation that damage the urothelium, the detrusor muscle and the vasculature [6]. The radiolysis of water results in the production of activated oxygen free radicals (hydroxyl and superoxide radicals). Cell membrane damage and cell death occur due to lipid peroxidation caused by these highly reactive radicals [1, 7].

Another effect is the genetic damage caused by the absorption of energy by the DNA directly, as well as indirectly by the reaction of the DNA with oxygen radicals. As a consequence, replication defects, mutations and delayed cell death can occur. As a last resort, DNA damage caused by radiation can lead to secondary malignancies [1, 5, 8].

Early symptoms are thought to be caused by injury of the glycosaminoglycan (GAG) layer and the uroepithelium. In general, intermediate and basal urothelial cells show nuclear irregularities and cellular edema, showing signs of damage within the first 3 months after exposure to radiation. Around 6–12 months, an increase in the proliferative activity of the urothelium is observed. The tight junctions and normal proteoglycan layer are disrupted as a result of urothelial radiation injury, which disrupts the barrier between urine and bladder tissue, allowing hypertonic urine and isotonic tissue to come into contact with each other, which results in the appearance of irritative lower urinary tract symptoms that are commonly found early [1, 2, 6].

From 6 months onwards, an increase in vascular endothelial cell proliferation is usually observed, in addition to perivascular fibrosis and vascular thrombosis, potentially resulting in focal ischemia due to vascular occlusion. The smooth muscle of the urinary bladder is also sensitive to radiation. Edema occurs early, usually followed by cell destruction. Vascular ischemia, edema and cell destruction cause the replacement of bladder smooth muscle fibers by fibroblasts, leading to increased collagen deposition (Figures 1–4). The result is decreased bladder compliance and functional changes in bladder capacity [5, 6, 8].

Figure 1.

Perivascular as well as diffuse fibrosis of the vesical mucosa. (Image courtesy of Professor Athanase Billis MD., PhD.).

Figure 2.

Dense inflammatory infiltrate with the presence of numerous eosinophils. (Image courtesy of Professor Athanase Billis MD., PhD.).

Figure 3.

Vascular thrombosis secondary to radiation lesion of the endothelial cells. (Image courtesy of Professor Athanase Billis MD., PhD.).

Figure 4.

Intense nuclear atypia in the urothelium and edema in the vesical mucosa. (Image courtesy of Professor Athanase Billis MD., PhD.).

Urothelial regeneration and capacity is impaired and results in tissue degradation. Therefore, once the irradiated tissue is injured, effective healing does not occur, making the bladder vulnerable to trauma and infection [3, 4, 7].

Vascular endothelial cells are believed to be the main target cell for bladder damage after radiation, particularly in late complications, leading to a range of symptoms including increased urinary frequency, urgency, pelvic pain and hematuria. Changes in endothelial cells are observed months to years after radiotherapy. Injury to the epithelial cell layer does not appear to play a major role in the development of late effects [1, 5, 6, 8, 9]. Endoscopic view of late radiation damage of vesical mucosa (Figures 5 and 6).

Figure 5.

Cystoscopic findings: erythema, edema, bleeding ulcers and fibrosis (with reduced bladder capacity).

Figure 6.

Cystoscopic findings: atrophic mucosa with telangiectatic blood vessels.

3. Clinical presentation

3.1 Acute radiation cystitis

The definition of acute RC is any clinical manifestation that is provoked during or up to 3 months after the end of radiotherapy. Its side effects are experienced by almost half of the patients after pelvic irradiation in full curative doses. Clinical symptoms include storage and voiding symptoms, such as increased urinary frequency, nocturia, urinary urgency, dysuria, cystalgia with bladder spasms, and (rarely) hematuria. Acute symptoms are mainly caused by injury to the bladder mucosa, which causes a lesion in the urothelial, involving an inflammatory response and tissue edema, leaving the bladder susceptible to trauma and infection. In most cases, this condition is self-limiting and the prognosis is favorable, usually disappearing spontaneously within 6 weeks after the end of radiotherapy [2, 3, 10, 11].

3.2 Chronic radiation cystitis

Late RC can develop after as little as 3 months and possibly up to several years after the end of radiotherapy. Appears on average over the next 2–3 years. Toxicities that occur between 3 and 6 months are sometimes defined as “early delay.” Late symptomatology after radiotherapy for cancers in the pelvic region has an incidence of 5–10% despite improved techniques and is more common in patients with bladder cancer treated with radiation. The clinical presentation can be variable, including lower urinary tract symptoms, but the most characteristic clinical feature is recurrent hematuria, with variable severity, which can be fatal in more severe cases [8, 10, 12, 13, 14]. The injury caused is progressive, and the compromised tissue is susceptible to secondary urinary tract infection and minor trauma, which due to poor healing, can lead to ulcers and eventual perforation of the bladder in addition to the formation of fistulas. During the investigation, these lesions may be aggravated by inappropriate bladder biopsies, and should therefore be avoided in previously irradiated areas. Pre-existing medical conditions such as diabetes, hypertension, previous unrelated abdominal surgery, and patients receiving concomitant chemotherapy are important risk factors. The most important factors are those related to radiation treatment, including the volume of tissue treated, total bladder dose and fractionation, route of delivery (external beam and/or brachytherapy), concomitant treatments and the radiosensitivity of the affected bladder tissue. After high-dose exposures (such as after brachytherapy treatment), some areas of the bladder may be at greater risk of injury, such as the bladder neck. Therefore, it is important to identify patients with risk factors for developing a severe form [1, 5, 13, 14]. Fibrosis of the bladder wall with reduced urinary capacity can occur up to 10 years after radiotherapy. These changes predispose to the appearance of neovascularization in the form of telangiectasias and bladder bleeding, in addition to lower urinary tract symptoms that are partially related to interstitial and smooth muscle fibrosis and reduced bladder capacity. Hematuria is the main presenting symptom and can range from mild hematuria to life-threatening hemorrhage. Hematuria with clot formation can lead to urinary retention [5, 10, 12].

4. Diagnosis

Diagnosis of RC is based primarily on excluding other causes of hematuria and the patient's symptoms, as the clinical features are nonspecific and may also be caused by bladder infection or malignancy. An initial evaluation involves a complete patient history and physical examination. Diagnostic evaluation for hematuria includes urinalysis, urine culture and antibiogram to exclude infection. Urine cytology is valuable for detecting high-grade malignancy, but UTI must be interpreted with caution, as changes from prior radiotherapy can be a confounding factor. Imaging evaluation by ultrasonography, excretory urography, or computed tomography (CT) can exclude an upper tract lesion as the cause of hematuria, and magnetic resonance imaging (MRI) should be considered in the presence of a previous pelvic malignancy. The most important exam in this phase is the evaluation of the lower urinary tract in the form of cystoscopy, which may reveal atrophic mucosa with telangiectatic blood vessels, erythema, edema, bleeding ulcers, fistulas or fibrosis with reduced bladder capacity (Figures 5 and 6). At the time of cystoscopy, bladder biopsy may be performed if tumor recurrence is suspected, with special attention to the potential risk of perforation of the irradiated bladder wall. The biopsy should also be interpreted with the knowledge that changes resulting from previous radiotherapy can be confused with malignancy [1, 5, 12, 13, 15].

5. Grading

The EORTC (European Organization for Research and Treatment of Cancer) and RTOG (Radiation Therapy Oncology Group) have developed uniform scales of radiation toxicity in different target organs, which are standardized and include the subjective, objective, managerial and analytical (SOMA) assessment of late effects in normal tissues (LENT). Each organ or tissue that is within the target zone of irradiation and at risk of being injured has its own LENT-SOMA scale based on the original RTOG criteria for radiation morbidity. The LENT-SUM scale is a comprehensive system scale and provides a lot of information, but it is not practical and difficult to implement routinely outside of clinical trials. Alternatively, the severity of hematuria can be graded using RTOG/EORTC9 and NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) grading systems, which are likely to be more practical to use and therefore more widely used in clinical practice [16, 17, 18, 19].

Radiation complications involving the bladder are graded on a scale devised by the RTOG. The scale is as follows:

• Grade 1—Any slight epithelial atrophy, microscopic hematuria and mild telangiectasia

• Grade 2—Any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria and intermittent incontinence

• Grade 3—Any severe frequency and urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity (<150 ml) and frequent hematuria

• Grade 4—Any necrosis, fistula and hemorrhagic cystitis, bladder capacity (<100 ml), refractory incontinence requiring catheter or surgical intervention

• Grade 5—Death.

6. Treatment

There are several treatment options for RC. However, the dearth of high-quality evidence in the form of randomized controlled trials hampers the development of treatment algorithms. Management strategies can be divided into systemic treatments, intravesical treatments, ablative, hyperbaric and interventional procedures such as definitive surgeries. The objective of the treatment and the modality chosen depend on the symptoms presented by the patient and the stage of the disease [1, 3, 5, 10].

In acute phase, the standard management is conservative, aiming at symptomatic control with the use of anticholinergic drugs with the aim of decreasing detrusor contractility and symptomatic improvement. Alpha-blockers, 5-reductase inhibitors or phosphodiesterase 5 inhibitors may be prescribed for the relief of voiding symptoms. Interruption of radiotherapy may be considered in case of severe symptoms. However, we must consider that such interruption in the treatment can influence the control of the tumor [2, 3, 10, 11].

General behavioral guidelines are part of the treatment, good hydration is recommended in order to increase diuresis, it can limit discomfort, in addition to preventing urinary obstruction resulting from blood clots. The use of analgesics and anti-inflammatories for a short period of time period of time, can be indicated. Phosphodiesterase type 5 inhibitors include tadalafil, originally prescribed for the treatment of erectile dysfunction, its mechanism of action in improving irrigation of the bladder is still not clearly elucidated, and it should be remembered that concomitant use with nitrates is formally contraindicated [10, 16, 20].

The biggest challenge in the management of a patient with RC is hematuria. There are a variety of treatment options. Initial management is continuous bladder irrigation should be started after a three-way transurethral catheter is inserted which is continued until the urine is clear. In case of severe hematuria includes patient resuscitation, and if the hemorrhagic shock is present, aggressive intravenous fluid replacement is required, and blood transfusion is indicated. In refractory cases of hematuria require alternative treatment options, which will be discussed below [1, 3, 5, 9, 10].

6.1 Systemic therapies

The aim of systemic treatments is to replace or augment the polysaccharide layer of the bladder and reduce vascular fragility. WF10 is an intravenous formulation, a chemically stabilized chlorite-matrix manufactured from the drug substance OXO K993, also known as tetrachlorodecaoxygen, which has been shown to have a positive effect on chronic inflammatory conditions. Its mechanism of action is based on the model of a postirradiated bladder in a state of chronic inflammation. It induces natural immunity and stimulates cellular defense mechanisms through its action on natural killer cells, cytotoxic T lymphocytes and modification of the monocyte-macrophage system. It reduces inflammation quickly so healing can begin. It is a promising therapy, with studies showing a response rate of up to 80%. Veerasarn et al. showed that patients treated with WF10 (n = 37) had a significantly lower rate of recurrence of recurrent hematuria after 12 months (47% vs. 77%; P = 0.01). Side effects include nausea, headache and transient anemia. Until now, the WF10 is not currently licensed for the treatment of RC [21, 22, 23].

Sodium pentosan polysulfate is a synthetic sulfated polysaccharide believed to adhere to the surface of the bladder and is used to decrease urothelial permeability by replacing defective GAGs. Sandhu et al. recommended its use as the primary method of management of pelvic radiotherapy-associated hemorrhagic cystitis based on their experience with administering oral pentosan polysulfate sodium 100 mg three times daily to control radiation-induced hemorrhagic cystitis in 60 patients. The dose was gradually reduced to a maintenance dose of 100 mg in 21 patients who had a partial response. At the end of the study, 10 patients had a complete response. One limitation was the "time to effect," as the onset of action was from 1 to 8 weeks. During this period, 15 patients required hospitalization for bladder irrigation [24].

Corticosteroids have not been widely used in the treatment of hemorrhagic RC. However, in the literature, we found reports of remission of hematuria obtained only after treatment with dexamethasone. Furthermore, a beneficial effect of glucocorticoids in the treatment of ifosfamide-induced hemorrhagic cystitis has been demonstrated. Corticosteroids can be beneficial for hemorrhagic cystitis by improving hematologic parameters by promoting erythropoiesis [25, 26].

Tranexamic acid has been used to treat hematuria and can be given in the early stages of conservative management of active bleeding in patients with prior radiotherapy, although evidence of efficacy in this group of patients is lacking.

Tranexamic acid acts by inhibiting fibrinolysis; therefore, it can lead to the formation of large clots with consequent urinary retention. Its use has been associated with an increased risk of thromboembolic events. It can be considered in bleeding; however, complications of clot retention limit its use [27].

6.2 Hyperbaric oxygenation

Hyperbaric oxygen therapy enhances oxygen delivery to tissues by increasing the amount of dissolved oxygen in plasma to induce and restore normal repair of granulocytes and fibroblasts, inducing neoangiogenesis with the restoration of ≤80% of capillary density. The usual course of treatment involves 35–40 sessions of 90–100 minutes each, 5 days a week, breathing 100% oxygen at 2 atmospheres of absolute pressure per session. Success rates range from 76% to 95% for short-term results and 72–83% for long-term results, where success is defined as symptomatic and/or cystoscopic improvement in RC [28, 29, 30].

6.3 Intravesical therapies

Response rates with intravesical therapies generally range from 60% to 90%. Formalin and alum instillations are historically evidence-based intravesical therapies for the treatment of hemorrhagic RC. Formalin precipitates cellular proteins within the epithelial layer, and this leads to fixation of friable and telangiectatic microvasculature occlusion. However, contemporary evidence is limited on the use of formalin, and devastating complications, such as patient mortality, have been described. Formalin is only recommended in cases of intractable hemorrhagic cystitis that may require urinary diversion [31]. Aluminum salts, such as potassium or ammonium aluminum sulfate, act by precipitating proteins on the surface of cells. Intravesical instillation of alum is not as effective as formalin; however, it has fewer side effects and may represent an early treatment option if more conservative initial measures are unsuccessful. Hyaluronic acid is an important mucopolysaccharide that can be instilled into the urinary bladder and is part of new intravesical therapies that aim to replace the protective layer of GAG to reduce the exposure of underlying epithelial cells to urine. It has immunomodulatory properties that improve the healing of connective tissue. Epsilon aminocaproic acid can be instilled into the bladder and inhibits fibrinolysis to neutralize urokinase in telangiectatic vessels. Several other agents, including prostaglandins, botulinum toxin, polydeoxyribonucleotides and early placental extract, have also been reported, with limited response rates [6, 10].

Tacrolimus acts as a potent immunosuppressant that improves the barrier function of the skin and mucosa, in addition to inducing local vasoconstriction. It is a calcineurin inhibitor that hinders the production and release of pro-inflammatory cytokines in T cells. Although systemic administration has a high incidence of adverse events, when used specifically locally, minimal adverse events occur. This effect led to studies investigating intravesical instillation of tacrolimus as a possible treatment for radiation hemorrhagic cystitis. The effect of liposomal tacrolimus was also observed in the model of cyclophosphamide-induced hemorrhagic cystitis [32, 33].

6.4 Ablative therapies

Ablation techniques and coagulation with laser therapy or argon-beam therapies are methods that can immediately control bleeding. Although there is a need for general or spinal anesthesia, they are associated with a complete response in 75–97% [3]. The Green Light LASER spares the surrounding tissue as it can ablate blood vessels with selective absorption of green light by intravascular oxyhemoglobin. In contrast, the YAG laser is not selective and has an increased risk of bladder perforation [34]. In the case of argon-beam coagulation, an argon probe is directed approximately 3 mm from the vessel and a monopolar current is directed through it and has a safety mechanism to prevent perforation. The depth of ablation can be changed by adjusting the settings of energy and gas flow. In addition, the current follows the path of least resistance and moves to the adjacent tissue after coagulation has been achieved [35].

6.5 Interventional radiologic

Despite limited evidence of its use in the treatment of hemorrhagic RC, arterial embolization may be a therapeutic possibility. Small series of cases describe its use, with the resolution of hematuria ranging from 90% to 100% and depending on the group of patients [36, 37]. Ischemic complications occur in 10–62.5% of patients and may include skin or bladder necrosis, gluteal paresis, Brown-Sequard syndrome and perineal or buttock pain, depending on the selectivity of embolization [3, 36].

6.6 Definitive surgical treatment

If all other less invasive treatment methods fail, urinary diversion with or without cystectomy can be performed. However, this approach has high morbidity. A series of 21 patients undergoing cystectomy and urinary diversion for intractable hemorrhagic cystitis showed that 42% of patients developed a Grade III or IV ClavienDindo complication. Furthermore, the 3-month mortality rate was 16% [38].

There are no widely adopted definitive clinical approach algorithms for managing patients with radiation-induced hematuria. The stepwise, evidence-based approach to the treatment of this patient population can be found in Figure 7.

Figure 7.

Algorithm for radiation-induced hemorrhagic cystitis illustrating the recommended practical management.

As important as management are strategies to reduce the effects on the urinary tract, such as performing radiotherapy sessions with a full bladder (except in cases of bladder cancer in which this is not possible). In addition, there has been increasing interest in the use of stereotactic body radiation therapy (SBRT). The main advantage is that the treatment, based on image-guided approaches with narrow margins, is done in five fractions (750–800 cGy per fraction), with lower doses for adjacent organs at risk. Biochemical control was comparable to standard IMRT, and treatment morbidity was low [2, 4, 39].

7. Conclusion

Currently, high-quality evidence describing the management of RC is scarce. Acute radiation injury to the bladder is usually self-limiting; however, delayed RC, although relatively rare, can lead to severe bleeding and can be difficult to treat. In the absence of robust evidence for any treatment modality, most patients are managed supportively in the first instance and most patients require multimodal treatment. Numerous treatment options have been studied over the last few decades, but many patients still require surgery to stop life-threatening hematuria. Surgery of this nature is often associated with significant morbidity, and any alternative treatment options should be further explored. In the future, large randomized trials that explore emerging management strategies are needed to strengthen evidence-based treatment strategies.