Radiation Cystitis

Therapeutic radiation may be delivered via various external sources. It may be applied directly to the tumor, such as in interstitial or intracavitary therapy (brachytherapy), or it can be delivered by external beam therapy. Radiation therapy works through the transfer of energy from ionizing radiation to molecules within tumor cells and related tissues. Radiation interacts with intracellular water and produces free radicals that interfere with DNA synthesis, resulting in cell death. Cells that divide rapidly are most susceptible to radiation injury. Peak sensitivity to radiation is at the M and G2 phases of the cell reproductive cycle.

Radiation may also directly cause rapid cell death from mitotic arrest, point mutations in deoxyribonucleic acid (DNA), and cell membrane damage. Concomitant use of chemotherapeutic agents may work synergistically to increase the risk of developing bladder injury from radiation. Radiation can also cause vascular changes. Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to the irradiated tissue. Collagen deposition may also cause severe scarring and further blood-vessel obliteration, resulting in tissue hypoxia and necrosis. The fibrotic barriers left behind can also impair revascularization.

These events lead to mucosal ischemia and epithelial damage. In the bladder, this in turn may cause further submucosal fibrosis as the subepithelial tissues become exposed to the caustic effects of urine. Ulcer formation, radiation neuritis, and postradiation fibrosis may cause the clinical findings of pain and discomfort.

Pathologic findings in radiated bladders include early and late findings. Early findings are defined as those occurring within 12 months after treatment, whereas late findings occur more than 12 months after treatment.

Early findings include submucosal inflammation and fibrosis, perineural inflammation, surface ulceration, and epithelial atypia (eg, nuclear pleomorphism, hyperchromatism, granular cytoplasm); epithelial atypia may also be a late finding.

Late findings include changes that are mainly fibrovascular and demonstrated by luminal occlusion, vascular ectasia, and necrosis of vessel walls. Cells with epithelial damage show cytoplasmic vacuolization and epithelial proliferation. Physiologically, these changes may produce clinical symptoms resulting from (1) ischemia and fibrosis leading to loss of bladder muscle fibers and thus to dysfunctional voiding and (2) denervation supersensitivity from ischemia causing abnormal neural stimulation of the bladder.

The rate of long-term complications depends on the following 3 major factors:

• Volume and area of bladder affected - If affected, the trigone is more symptomatic than is the dome of the bladder

• Dose rate (< 0.8Gy/h decreases risk of cystitis) and daily fraction size (doses >2Gy/fraction increase risk)

• Total dose - Toxicity increases when the total dose received exceeds 60Gy to the bladder; conformal beam therapy allows higher doses to the target tissue while maintaining lower total dose delivered to the bladder

The reported frequency of radiation cystitis varies because of difficulties in data collection (usually performed by questionnaire), differences in dosimetry and field size used, and the fact that various tumors are treated with different fields and include varying amounts of bladder exposure. The incidence of acute radiation cystitis (adverse events up to 3 months following radiation treatment) is estimated to be 50% in patients receiving pelvic radiation therapy for prostate or locally advanced cervical cancer.[5]

Prostate cancer

The overall frequency of radiation cystitis 1 year after treatment of bladder cancer is 9-21%; the reported mean is 14.2%.[6]  The incidence of hemorrhagic cystitis is approximately 11%.[7]

For 3- to 4-box, small-field therapy (66 Gy), the frequency, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring, is as follows:

• Grades 1 and 2: 24-64%
• Grades 3 and 4: 2-9%

For conformal beam therapy (70-78 Gy), the frequency is as follows:

• Grades 1 and 2: 65%
• Grades 3 and 4: 9%

Cervical cancer

The overall frequency of radiation cystitis 1 year after treatment of cervical cancer is 3-6.7%; the reported mean is 4.9%.[8]

The frequency associated with combination 4-field external beam therapy (70-80 Gy) and cesium implants is as follows:

• Grade 1: 1-3%
• Grade 2: 1-2%
• Grade 3: 2-5%

Bladder cancer

The overall frequency of radiation cystitis 1 year after treatment of bladder cancer is 2-47%; the reported mean is 17.8%.

The frequency associated with 3- to 6-beam, small-field therapy (32-57.5 Gy) is as follows:

• Grades 1 and 2: 19-49%
• Grades 3 and 4: 33-48%

Genitourinary toxicity with intensity-modulated radiotherapy

Intensity-modulated radiotherapy (IMRT) has been shown to deliver higher doses to the target area while minimizing complications. IMRT is increasingly used for the treatment of prostate cancer; doses of 81 Gy have been delivered. The complication rate with IMRT is lower than that with 3-dimensional (3D) conformal beam therapy, although not all studies show a significant difference.

The frequency of toxicity with IMRT versus the frequency with 3D conformal radiotherapy is as follows.

• Grade 2: IMRT, 17-36%; 3D conformal radiotherapy, 42-60%
• Grade 3: IMRT, 0.3-0.5%; 3D conformal radiotherapy, 1-2%

After treatment for prostate cancer, rectal complications are much lower with conformal beam therapy than with 4-box, small-field therapy (19% vs 32%, grade 2 toxicity); however, the incidence of bladder complications is unchanged, probably because of the proximity of the bladder neck and unavoidable exposure to the urethra.

IMRT has also demonstrated a significant improvement in rectal complications compared with 3D conformal radiation therapy. Fewer grade 2 bladder complications occur with IMRT, but the rates of grade 3 complications are similar. GI symptoms can be further reduced by using fiducial marker–based position verification in patients with prostate cancer.[9]

A multicenter, phase II study conducted by Kim et al found that in patients with rectal cancer, preoperative chemoradiation with cetuximab, irinotecan, and capecitabine was active and well tolerated.[10]

After treatment for bladder cancer, acute symptoms (ie, those observed during treatment and lasting < 1y) are usually self-limiting and occur in 50-80% of patients, regardless of tumor type.

Acute symptoms of radiation injury to the bladder are self-limiting and generally respond to symptomatic therapy, such as anticholinergic medications and analgesics. Severe complications of radiation injuries are difficult to manage because they tend to be chronic or recurrent and are occasionally refractory to therapy. Proper interpretation of treatment outcome is limited by few follow-up studies and the small number of patients reported in these studies.

The available follow-up studies performed with various treatment regimens demonstrate that although all have some effectiveness, no single modality is superior. They also show the recurrent nature of radiation complications of the bladder. Complications of radiation cystitis include hemorrhagic cystitis (3%-5%), vesical fistula (2%), and bladder neck contracture (3%-5%). Neoplasia and contracted bladder can also occur but are rare.

In general, symptoms associated with radiation cystitis can be grouped into acute and late-phase, or chronic, symptoms. Acute symptoms are caused by the inflammatory response to ionizing radiation and are similar to those for any inflammatory process of the bladder. They consist of urgency, frequency, dysuria, and hematuria.

Late-phase, or chronic, symptoms are the end result of the inflammatory process caused by radiation. Ischemia and fibrosis are the main factors responsible for symptoms. As a result, new symptoms can occur years after initial therapy, resulting from bladder contraction, ulcer formation, fistulas, and bladder dysfunction. Therefore, clinical presentation can include any of the following urinary symptoms:

• Frequency
• Urgency
• Dysuria
• Hematuria
• Incontinence
• Hydronephrosis
• Pneumaturia
• Fecaluria

Radiation complications involving the bladder are graded on a scale devised by the Radiation Therapy Oncology Group (RTOG). The scale is as follows:

• Grade 1 - Any slight epithelial atrophy, microscopic hematuria, mild telangiectasia
• Grade 2 - Any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria, intermittent incontinence
• Grade 3 - Any severe frequency and urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity (< 150mL), frequent hematuria
• Grade 4 - Any necrosis, fistula, hemorrhagic cystitis, bladder capacity (< 100mL), refractory incontinence requiring catheter or surgical intervention
• Grade 5 - Death

Radiation cystitis can mimic many different diseases. Neoplasia, urinary tract infection, and stone disease produce similar findings. Consequently, a complete evaluation of the urinary tract is required. The initial evaluation should include the following:

• Urinalysis to assess for hematuria and pyuria and to measure urine pH

• Urine culture to confirm or rule out infection

• Urinary cytology to screen for tumor

If the patient has hematuria, a complete blood count (CBC) is required to assess hemoglobin, hematocrit, and adequate platelet count. Gross hematuria is an indication to evaluate volume status, coagulation status, and the need for red blood cell (RBC) transfusion. Cystoscopy and renal imaging are also indicated to rule out other possible causes of genitourinary (GU) bleeding. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are needed to rule out coagulopathies if the patient is bleeding.

A white blood cell (WBC) count is necessary to assess for infection if the patient is febrile. Electrolytes, blood urea nitrogen (BUN), and creatinine levels are needed to assess renal function; obstructive uropathy may result from stricturing of the urinary tract and poor emptying. Urodynamics may be required if a patient presents with more complicated symptoms, but most symptoms can be evaluated by a thorough history and physical examination.

Biopsy

Avoid bladder biopsy because it may cause persistent bleeding or even fistula formation. However, judicious use of bladder biopsies may be indicated if a suspicious lesion or recurrent tumor is suggested.

Urodynamic studies are needed only when the diagnosis remains unclear after the history and physical examination. Urodynamics can help to assess for decreased bladder volume, postvoid residual urine, and detrusor instability. All are potentially present in radiation cystitis but are not specific for the disease.

Reported findings in acute cases include the following:

• Detrusor instability (40-50% of patients)
• Decreased peak flow rate
• Decreased bladder compliance
• Decreased bladder volume (approximately 20% volume reduction)

After the acute phase has passed (6mo), most bladder parameters return to normal. Some authors report a persistent loss of bladder compliance; however, it is not significantly different from that in control subjects.

Cystoscopy is used to confirm the diagnosis and to rule out other conditions, such as bladder cancer or other recurrent metastatic tumors. Cystoscopy can be combined with retrograde pyelography, if needed.

On cystoscopy (see the images below), acute radiation injury is characterized by changes such as the following:

• Telangiectasia
• Diffuse erythema
• Prominent submucosal vascularity
• Mucosal edema

Cystoscopic findings in chronic radiation injury can be similar to those in acute injury, with areas of extreme pallor between erythematous areas and petechiae (see the image below).

Imaging studies may consist of intravenous pyelography (IVP), CT urography, or renal ultrasonography. IVP is useful to evaluate anatomic abnormalities of the GU tract (eg, stricturing, fistula formation). If hematuria is present, IVP or CT urography is needed to rule out other causes of bleeding, such as calculus disease and neoplasia. As an alternative, ultrasonography can be used to assess for hydronephrosis due to scarring, renal tumors (as another cause of bleeding), and calculus disease.

CT scanning may also help in the diagnosis of bladder fistulas. Findings in patients with fistulas include the following[11] :

• Intravesical air (90%)

• Passage of orally or rectally administered contrast medium into the bladder (20%)

• Focal bladder-wall thickening (90%)

• Thickening of adjacent bowel wall (85%)

• Extraluminal mass that often contains air (75%)

Indications for treatment depend on the degree of symptoms present and the patient's sense of need to be treated. Grade 1 and 2 symptoms need treatment only if the patient is bothered by them. These can be managed medically. Observation is acceptable. Management of grade 3 and higher clinical presentations depends on the type of symptom. Voiding dysfunction can be managed medically if the patient desires.

Fistula formation usually requires surgical intervention. Contracted bladder and incontinence require evaluation to determine the degree of disability, bladder compromise, and potential need for surgery.

The use of endoscopic injection sclerotherapy has been reported with good results in a limited number of patients with intractable hemorrhagic cystitis.[12] This treatment involves the injection of a sclerosing agent (eg, 1% ethoxysclerol) into the bleeding areas to control the severe hematuria in patients with otherwise intractable bleeding that is not responding to simpler methods. Further studies are necessary to determine the exact role of this novel type of therapy in selected patients with radiation cystitis.

If symptoms become more severe or oral therapy is not satisfactory, the available literature suggests that hyperbaric oxygen (HBO) therapy yields the most consistent results.[13]

Follow-up

Follow-up care for radiation cystitis is generally supportive. Symptoms can be recurrent or even persistent, as in the case of dysfunctional voiding. Because symptomatic manifestations of radiation cystitis can occur many years after primary radiation therapy, regular clinical follow-up care and good communication with patients are essential.

Symptomatic frequency and urgency are best treated with anticholinergic agents. Once all other causes of dysuria have been ruled out, phenazopyridine can be used to provide symptomatic relief.

If the symptoms of radiation cystitis are not severe but are significant enough for a patient to seek help, pentosan polysulfate sodium (Elmiron), with or without pentoxifylline for pain, is a reasonable first step.[14, 15]

A randomized, double-blind, placebo-controlled pilot study in 41 men receiving external beam radiation therapy for prostate cancer found that ingestion of cranberry capsules may help prevent or reduce the severity of radiation cystitis, particularly in patients those on low-hydration regimens or with baseline urinary symptoms. The capsules were standardized to contain 72 mg proanthocyanidins. Study patients took one capsule a day at breakfast during treatment and for 2 weeks after treatment completion.[16]

Gacci et al reported that instillation of the combination of hyaluronic acid (HA) and chondroitin sulfate (CS) was effective in reducing nocturnal voiding frequency in men with bladder pain following radiation therapy for prostate cancer. Study patients underwent bladder instillation therapy with HA and CS weekly for the first month and, afterwards, on week 6, 8 and 12.[17]

Therapy for radiation cystitis is primarily aimed at relief of symptoms. The exception is HBO therapy, which can potentially reverse the changes caused by radiation. HBO therapy stimulates angiogenesis, which reverses the vascular changes induced by ionizing radiation.[18] The ability of HBO to preserve bladder function and the noninvasive nature of this treatment are features that favor its use. However, if significant fibrosis and ischemia have already occurred, HBO therapy does not reverse the changes and only prevents further injury.[19, 20]

HBO therapy has a reported response rate of 27-92%, and the recurrence rate is 8-63%.[21, 22] In adults, HBO is administered as 100% oxygen at 2-2.5 atm. Each session lasts from 90-120 minutes, and patients receive HBO sessions 5 days weekly for a total of 40-60 sessions. HBO therapy is a pregnancy category A treatment.

Nakada and colleagues reported good long-term outcomes with HBO treatment in 38 patients with radiation cystitis following irradiation of prostate cancer. At 7-year follow-up, objective and subjective improvements in symptoms were seen in 72-83% of patients. No recurrence was seen in 28 patients (74%); these patients had received an 18% lower radiation dose than patients who did experience recurrence.[23]

Surgery is reserved for the management of severe complications that do not respond to medical management. Indications for surgery include the following:

• Ongoing gross hematuria that does not respond to bladder irrigations or that requires numerous transfusions
• Small, contracted bladder with incontinence or severe frequency
• Specific complications of radiation (eg, fistulas, hydronephrosis, strictures)

Surgical options for small-volume bladder include bladder augmentation, urinary diversion, and cystectomy.

Hemorrhagic cystitis is a more serious complication of radiation cystitis. Cystoscopy is useful in the initial management, both diagnostically to rule out other pathology and for clot evacuation if bleeding is heavy. This can resolve symptoms in up to 61% of patients at initial presentation.

If bleeding is severe, bladder irrigation may be started either alone or in conjunction with hyperbaric therapy. Start continuous bladder irrigation alone first. If this is not successful, try bladder instillation. In order of increasing toxicity, these agents include 1% alum, aminocaproic acid (Amicar), and 1-10% formalin.[24, 25, 26, 27, 28, 29, 30] Other options are oral pentosan polysulfate sodium, HBO therapy, and oral estrogens.[31] If symptoms persist, however, cystoscopic intervention is rarely successful.[32]

Surgical options for hemorrhagic cystitis include the following:

• Cystoscopy and fulguration
• Percutaneous nephrostomy tube insertions
• Internal iliac artery embolization
• Surgical diversion
• Cystectomy

Cystectomy for hemorrhagic cystitis is associated with high rates of perioperative complications and mortality. It should be used only after more conservative approaches have been attempted.[33]

Pharmacologic therapy for radiation cystitis is primarily aimed at relief of symptoms. Symptomatic frequency and urgency are best treated with anticholinergic agents. Once all other causes of dysuria have been ruled out, phenazopyridine can be used to provide symptomatic relief. If the symptoms of radiation cystitis are not severe but are significant enough for a patient to seek help, pentosan polysulfate sodium (Elmiron), with or without pentoxifylline for pain, is a reasonable first step. For severe hematuria, instillation of a variety of agents into the bladder may be tried.

Formalin, a 37% solution of formaldehyde and water compounded at the pharmacy, is a tissue fixative. Adult dosing depends on the method of administration. Dosing for local therapy consists of 5% formalin pledgets placed endoscopically on bleeding points for 15 minutes and then removed. For bladder irrigation, a 1-10% solution (4% preferred) is used; manually fill the bladder to capacity under gravity (catheter < 15cm above the symphysis pubis); contact time ranges from 14 minutes for a 10% solution to 23 minutes for a 5% solution. This is a painful procedure and requires a general anesthetic. The response rate is 52-89%, and the recurrence rate is 20-25%.

Alum, which is also compounded at the pharmacy, causes protein precipitation in the interstitial spaces and cell membranes, causing contraction of the extracellular matrix and tamponade of bleeding vessels. Exposed capillary epithelium is also sclerosed. In adults, a 1% solution is prepared by mixing 50 g of potassium aluminum sulfate in 5L of distilled water; it is run intravesically at a rate of 3-5 mL/min and increased to a maximum of 10 mL/min if returns are not clear; it is continued for 6 hours after bleeding stops. Alum has a response rate of 50-80%, and the recurrence rate is 10%.

Class Summary

Urinary analgesics provide relief of bladder pain due to interstitial cystitis.

Phenazopyridine (Pyridium, ReAzo, Baridium)

Phenazopyridine is an azo dye that has local anesthetic or analgesic action. It acts directly on urinary tract mucosa when excreted.

Pentosan polysulfate sodium (Elmiron)

Pentosan polysulfate sodium protects transitional epithelium by restoring the bladder glycosaminoglycan layer. Adult dosing is 100mg orally 3 times daily until symptoms resolve, for a minimum of 4 weeks. The response rate in radiation cystitis is 71-100%, and the recurrence rate is 23%.[29] Sodium pentosan polysulfate is a pregnancy category B drug.

Class Summary

Hemostatic agents are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

Aminocaproic acid (Amicar)

Aminocaproic acid is an antifibrinolytic agent that inhibits plasminogen activation, thus decreasing plasmin. Adult dosing is 200mg of aminocaproic acid in 1L of isotonic sodium chloride solution. It is run intravesically according to the severity of bleeding and continued for 24 hours after bleeding stops.

Aminocaproic acid has a response rate of 91%, and recurrences have not been reported. This agent is a pregnancy category C drug.

Class Summary

Estrogen derivatives have been used to correct prolonged bleeding time.

Conjugated estrogens (Premarin)

The mechanism of action of conjugated estrogens in radiation cystitis is unknown. In patients with renal failure, estrogen has been reported to correct prolonged bleeding time. However, in radiation cystitis complications, bleeding time is usually normal. Adult dosing is 5mg/day orally for 4-7 days.

Conjugated estrogens have a response rate of 100%, and the recurrence rate is 20% (1 report of 5 patients only). Conjugated estrogen is a pregnancy category X drug.

Class Summary

Hemorheologic agents enhance blood flow by reducing components responsible for blood viscosity.

Pentoxifylline (Trental)

Pentoxifylline has been shown to relieve pain due to radiation fibrosis. Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity. This increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement remain undefined. Adult dosing is 400mg orally 3 times daily for 6 weeks. Pentoxifylline is a pregnancy category C drug.