Tumors of the pelvic organs (ie, prostate, bladder, colon, rectum) are common in men, comprising 35% of expected new cancer diagnoses for the year 2009. In women, cancer of the uterus, ovary, bladder, rectum, and vagina/vulva were expected to make up 14% of new cancer diagnoses in 2009. Radiation therapy is an important management tool for the treatment of these malignancies, creating significant potential for the development of radiation injury to the bladder.
Radiation morbidity is due to incidental treatment of healthy organs. Efforts to reduce the complications of radiation have led to improvements in delivery mechanisms of radiation to the target organ.
Wide-field treatment was the standard of care for years, but it is associated with high morbidity. Cobalt therapy had high complication rates because of its low energy and resulting higher doses to healthy structures near the target. This was required to achieve an adequate dose to the tumor. Newer techniques and energy sources focus therapy on the target, minimizing collateral radiation to healthy structures. These techniques and energy sources include conformal beam therapy, CT- or ultrasound-guided brachytherapy, diversity of energies presently available (higher energies produce better tissue penetration, resulting in smaller doses to surrounding normal tissues), and more beams used (allows lower dose per beam, thus reducing the maximum dose to normal structures beyond the target tissues).
Radiation therapy can be used as primary, adjuvant, or palliative treatment and often complements medical or surgical therapy for malignancies. Ideally, only the tumor receives radiation, excluding nontarget organs. Conformal beam therapy and brachytherapy attempt to do this. However, incidental irradiation of nearby tissues is unavoidable either because of invasion of surrounding organs by tumors or because of proximity of cancers to neighboring pelvic structures. Radiation cystitis is one complication of radiation therapy to pelvic tumors and manifests primarily as an alteration of the voiding pattern.
The urinary bladder can be irradiated intentionally for the treatment of bladder cancer or incidentally for the treatment of other pelvic malignancies. The sequelae of radiation injury to the bladder can range from minor temporary irritative voiding symptoms and asymptomatic hematuria to more severe complications such as gross hematuria, contracted nonfunctional bladder, persistent incontinence, fistula formation, necrosis, and death.
This article reviews the process of radiation injury and discusses the current standard for treatment of this condition.
The reported frequency of radiation cystitis varies because of difficulties in data collection (usually performed as a 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.
Frequency of radiation cystitis (>1 y posttreatment) based on common tumor sites (any symptom) is as follows:
Intensity-modulated radiotherapy (IMRT) has recently been shown to deliver higher doses to the target area while minimizing complications. Increasingly used for the treatment of prostate cancer, doses of 81 Gy have been delivered. The complication rate is lower compared with 3-dimensional conformal therapy, although not all studies show a significant difference.
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 3-dimensional conformal radiation therapy. Fewer grade 2 bladder complications occur with IMRT, but the rate of grade 3 complications is similar with both modalities. GI symptoms can be further reduced by using fiducial marker-based position verification in patients with prostate cancer. After treatment for bladder cancer, acute symptoms (ie, those observed during treatment and lasting < 1 y) are usually self-limiting and occur in 50%-80% of patients, regardless of tumor type.
Rate of long-term complications depends on the following 3 major factors:
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. Injury within radiated tissue results from the energy transferred by ionizing radiation to other molecules. 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 radiosensitivity to radiation is at the M and G2 phase of the cell reproductive cycle. Radiation may also directly cause rapid cell death from mitotic arrest, point mutations in 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. This, in turn, may cause further submucosal fibrosis as the subepithelial tissues become exposed to the caustic effects of urine. This may manifest as pain in the clinical setting resulting from any of the above-mentioned mechanisms. 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.
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 bladder.
In 1983, radiation complications were graded on a scale derived by the RTOG. They are graded as follows:
In general, symptoms from radiation cystitis can be grouped into acute and late phases.
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 the symptoms. 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 (see Treatment). Urodynamics may be required if a patient presents with more complicated symptoms. Most symptoms can be evaluated by a thorough history and physical examination. Gross hematuria is an indication to evaluate volume status, coagulation status, and the need for RBC transfusion. Cystoscopy and renal imaging are also indicated to rule out other possible causes of genitourinary (GU) bleeding. 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.
Surgery is reserved for the management of severe complications that do not respond to medical management.
Cystoscopic view of a bladder showing the neovascularity and telangiectasia of radiation cystitis.
Cystoscopic view of a bladder showing the neovascularity and telangiectasia of radiation cystitis.
Cystoscopic view of a radiated bladder showing areas of neovascularization next to an area of pallor due to increased collagen deposition. The collage....
Therapy is primarily aimed at relief of symptoms. The exception is hyperbaric oxygen (HBO) therapy. Treatment with HBO can potentially reverse the changes caused by radiation. HBO therapy stimulates angiogenesis, which reverses the vascular changes induced by ionizing radiation. Preservation of bladder function and the noninvasive nature of treatment (30 sessions total) favor its use. Some reports claim 70% response with HBO. However, if significant fibrosis and ischemia have already occurred, HBO therapy does not reverse the changes and only prevents further injury.
Symptomatic frequency and urgency are best treated with anticholinergic agents.
Once all other causes of dysuria have been ruled out, phenazopyridine hydrochloride can be used to provide symptomatic relief.
Hemorrhagic cystitis is a more serious complication of radiation cystitis. Once all clots have been evacuated and adequate drainage achieved, medical options to control the bleeding include continuous bladder irrigation alone, a 1% alum bladder installation, a 1%-10% formalin bladder installation, aminocaproic acid (Amicar) bladder installation, sodium pentosanpolysulphate, HBO therapy, and oral estrogens.
Prophylaxis against the development of radiation cystitis has been reported with the use of the antioxidant orgotein prior to receiving radiation. Dimethyl sulfoxide (DMSO) has also been described to have a radioprotective effect. However, few studies have evaluated its use in human bladders.
The concept of using antioxidant therapy involves the theory that healthy tissues are damaged by free radicals produced within the target cell and then released into the extracellular space. The free radical is then allowed to travel to normal cells, where it then causes damage and clinically produces toxicity. Free-radical scavengers normally exist intracellularly and thus are not found in the extracellular space. By administering exogenous free radical scavengers, the intent is to decrease collateral damage to cells by picking up the extracellular free radicals.
Note that these agents may also prevent collateral cell damage within tumors themselves. This could potentially decrease the effectiveness of anticancer therapy. Although reports exist of decreased toxicity with these agents, few report on overall disease control with antioxidant therapy compared to controls. One study looking at antioxidant therapy for oral tumors does show decreased toxicity with comparable tumor control rates. However, the study was small and involved a multimodality therapy, which may have contributed to their good results. Antioxidants require further study before they are put into widespread use.
Medications and other medical treatments are listed below.
If the symptoms of radiation cystitis are not severe but significant enough for a patient to seek help, sodium pentosanpolysulphate with or without pentoxifylline for pain is a reasonable first step. If symptoms become more severe or oral therapy is not satisfactory, HBO therapy, based on the available literature, appears to yield the most consistent results.
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 the next least toxic agent. In order, these agents include alum, aminocaproic acid, and formalin.
HBO therapy has a reported response rate of 27%-92%, and the recurrence rate is 8%-63%. In adults, administer as 100% oxygen at 2-2.5 atm; each lasts from 90-120 min administered 5 d/wk for a total of 40-60 sessions. HBO therapy is pregnancy category A.
Sodium pentosanpolysulphate (Elmiron) has a response rate of 71%-100%, and the recurrence rate is 23%. It protects transitional epithelium by restoring the bladder glycosaminoglycan layer. Adult dosing is 100 mg PO tid until symptoms resolve, for a minimum of 4 wk. Sodium pentosanpolysulphate is a pregnancy category B drug.
Formalin is a 37% solution of formaldehyde and water. The response rate is 52%-89%, and the recurrence rate is 20%-25%. Its mechanism of action is as a tissue fixative. Adult dosing depends on method of administration. Dosing for local therapy consists of 5% formalin pledgets placed endoscopically on bleeding points for 15 min, then removed. For bladder irrigation, 1%-10% solution (4% preferred) is used; manually fill the bladder to capacity under gravity (catheter < 15 cm above symphysis pubis); contact time ranges from 14 min for 10% solution to 23 min for 5% solution; this is a painful procedure and requires a general anesthetic. Formalin is a pregnancy category C drug.
Alum has a response rate of 50-80%, and the recurrence rate is 10%. Alum causes protein precipitation in the interstitial spaces and cell membranes, causing contraction of 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 5 L of distilled water; run intravesically at a rate of 3-5 mL/min and increase to a maximum of 10 mL/min if returns are not clear; continue for 6 h after bleeding stops. Alum is a pregnancy category C drug.
Aminocaproic acid (Amicar) has a response rate of 91%, and recurrences are not reported. It is an antifibrinolytic agent that inhibits plasminogen activation, thus decreasing plasmin. Adult dosing is 200 mg of aminocaproic acid in 1 L of isotonic sodium chloride solution. Run intravesically according to severity of bleeding and continue for 24 h after bleeding stops. Aminocaproic acid is a pregnancy category C drug.
Conjugated estrogens (Premarin) have a response rate of 100%, and the recurrence rate is 20% (1 report of 5 patients only). Its mechanism of action 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 5 mg/d PO for 4-7 d. Conjugated estrogen is a pregnancy category X drug.
Pentoxifylline (Trental) has been shown to relive 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 400 mg PO tid for 6 wk. Pentoxifylline is a pregnancy category C drug.
Cystoscopy is useful in the initial management of radiation cystitis, 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. However, if symptoms persist, cystoscopic intervention is rarely successful.
Surgery is reserved for the management of severe complications that do not respond to medical management. Indications for surgery include ongoing gross hematuria that does not respond to bladder irrigations or that require numerous transfusions, small contracted bladder with incontinence or severe frequency, and specific complications of radiation (eg, fistulas, hydronephrosis, strictures).
Surgical options for hemorrhagic cystitis include cystoscopy and fulguration, percutaneous nephrostomy tube insertions, internal iliac artery embolization, surgical diversion, and cystectomy.
Surgical options for small-volume bladder include bladder augmentation, urinary diversion, and cystectomy.
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.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Bladder Cancer and Blood in the Urine.
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.
Symptoms of radiation cystitis are chronic in nature. If therapy is required for symptomatic disease, it tends to be permanent. 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 recurrent and occasionally refractory to therapy. Few follow-up studies and the small number of patients reported in these studies limit proper interpretation of treatment outcome.
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.
The use of endoscopic injection sclerotherapy has been reported with good results in a limited number of patients with intractable hemorrhagic cystitis. 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 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.