AUTHOR AND EDITOR INFORMATION

Section 1 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Tumors of the pelvic organs (ie, prostate, bladder, colon, rectum) are common in men, comprising 45% of expected new cancer diagnoses for the year 2000. In women, cancer of the uterus, ovary, bladder, rectum, and vagina/vulva were expected to make up 23% of new cancer diagnoses in 2001. 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.

History of the Procedure

Radiation morbidity is due to incidental treatment of normal 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).

Problem

Radiation therapy can be used as primary, adjuvant, or palliative treatment and often complements medical or surgical therapy for malignancies. Ideally, radiate only the tumor and exclude 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.

Frequency

The reported frequency of radiation cystitis varies. This is 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:

• Prostate - Overall, 9-21%; reported mean, 14.2%
• • 3- to 4-box small-field therapy (66 Gy)
  • • Grades 1 and 2 (Radiation Therapy Oncology Group [RTOG]/European Organization for Research and Treatment of Cancer [EORTC] scoring) - 24-64%
    • Grades 3 and 4 - 2-9%
  • Conformal beam therapy (70-78 Gy)
  • • Grades 1 and 2 - 65%
    • Grades 3 and 4 - 9%
• Cervix - Overall, 3-6.7%; reported mean, 4.9%
• • Combination 4-field external beam therapy (70-80 Gy) and Cesium implants
  • • Grade 1 - 1-3%
    • Grade 2 - 1-2%
    • Grade 3 - 2-5%
• Bladder - Overall, 2-47%; reported mean, 17.8%
• • 3- to 6-beam small-field therapy (32-57.5 Gy)
  • • Grades 1 and 2 - 19-49%
    • Grades 3 and 4 - 33-48%

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.

• Genitourinary toxicity - IMRT versus 3-dimensional conformal radiotherapy
• • IMRT
  • • Grade 2 - 17-36%
    • Grade 3 - 0.3-0.5%
  • 3-dimensional conformal radiotherapy
  • • Grade 2 - 42-60%
    • Grade 3 - 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 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. After treatment for bladder cancer, acute symptoms (ie, those observed during treatment and lasting less than 1 year) are usually self-limiting and occur in 50-80% of patients for all tumor types.

Etiology

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

• Volume and area of bladder affected (the trigone is more symptomatic if affected than the dome of the bladder)
• Dose rate (<0.8 Gy/h decreases risk of cystitis) and daily fraction size (doses >2 Gy/fraction increases risk)
• Total dose (toxicity increases when total dose received exceeds 60 Gy to the bladder): Conformal therapy allows higher doses to the target tissue while maintaining lower total dose delivered to the bladder.

Pathophysiology

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.

• Early findings (<12 mo) are submucosal inflammation and fibrosis, perineural inflammation, surface ulceration, and epithelial atypia (eg, nuclear pleomorphism, hyperchromatism, granular cytoplasm, all of which also can occur late).
• Late findings (>12 mo) 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 because of (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.

Clinical

In 1983, radiation complications were graded on a scale derived by the RTOG. They are graded 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 (<150 mL), frequent hematuria
• Grade 4 - Any necrosis, fistula, hemorrhagic cystitis, bladder capacity (<100 mL), refractory incontinence requiring catheter or surgical intervention
• Grade 5 - Death

In general, symptoms from radiation cystitis can be grouped into acute and late phases.

• Acute symptoms are caused by the inflammatory response to ionizing radiation and are similar to 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 in contracted bladders, ulcer formation, fistulas, and bladder dysfunction; therefore, clinical presentation can include frequency, urgency, dysuria, hematuria, incontinence, hydronephrosis, pneumaturia, and fecaluria.

INDICATIONS

Section 3 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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.

RELEVANT ANATOMY

Section 4 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

• Superior surface (uterus and ileum in the female; ileum and colon in the male): The dome of the bladder has a peritoneal component.
• Inferior surface (rectum, vasa deferentia, seminal vesicles, and ureters in the male; uterus and vagina in the female)
• Anterolateral: This is separated from the pubic bone by the retropubic space and contains an abundance of fat and venous plexus.
• Bladder epithelium (3-7 layers of transitional epithelium): Cells rest on a basement membrane of collagen and adhesive glycoproteins. The basal epithelium contains actively proliferating cells, and luminal cells are umbrella-type cells bound by tight junctions. The urothelial surface contains sulfated polysaccharides (glycosaminoglycans) that function as a permeability barrier to bacteria, proteins, ions, and other substances.
• Bladder (subepithelial tissues): The lamina propria lies beneath the basement membrane and consists of loose connective tissue and occasional smooth muscle fibers. The detrusor muscle is the following layer and consists of smooth muscle in 3 layers, ie, inner and outer longitudinal orientated layers and a middle circular layer. The outer muscle layer extends down the urethra in females and to the end of the prostate in males and constitutes the involuntary sphincter. The external sphincter is composed of striated muscle and is at the end of the prostate in men and surrounds the middle third of the female urethra.
• Bladder innervation: Parasympathetic innervation arises from S2-S4 nerve roots and forms the pelvic plexus. The fibers then join those from the hypogastric plexus and innervate the bladder through the vesical branches. Sympathetic innervation is derived from T11-L2, descends through the sympathetic trunk, and reaches the hypogastric plexus. These fibers join the pelvic plexus and proceed toward the bladder. The external sphincter and pelvic floor muscles are innervated with fibers from S2-S3 and travel in the pudendal nerve. The sensation of stretch and fullness is believed to run in the parasympathetic nerves, while pain, touch, and temperature are carried through the sympathetics.
• Blood supply: Arterial supply is from the superior, middle, and inferior vesical arteries, which are branches of the internal iliac artery. Venous return is through a rich venous plexus surrounding the bladder and draining into the internal iliac vein. Some venous return also travels to the plexus of Santorini in the retropubic space.

CONTRAINDICATIONS

Section 5 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Surgery is reserved for the management of severe complications that do not respond to medical management.

WORKUP

Section 6 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Lab Studies

• Urinalysis, urine culture, urine cytology
• • Radiation cystitis can mimic many different diseases. As a result, a complete evaluation of the urinary tract is required, including urinalysis to assess for hematuria, pyuria, and urine pH.
  • Perform a urine culture to confirm or rule out infection, and perform urinary cytology to screen for tumor.
  • Neoplasia, urinary tract infection, and stone disease manifest with similar findings.
• Complete blood cell count
• • If the patient is bleeding, a CBC count is required to assess hemoglobin, hematocrit, and adequate platelet count.
  • A WBC count for infection is necessary if the patient is febrile.
• Electrolytes, BUN, creatinine
• • These levels are needed to assess renal function.
  • Obstructive uropathy may be present because of stricturing of the urinary tract and poor emptying.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT): These are needed to rule out coagulopathies if the patient is bleeding.

Imaging Studies

• Intravenous pyelography
• • Intravenous pyelography (IVP) is useful to evaluate anatomic abnormalities of the GU tract (eg, stricturing, fistula formation).
  • IVP is needed to rule out other causes of hematuria, if present, such as calculus disease and neoplasia.
• Renal ultrasonography: As an option to IVP, ultrasonography can be used to assess for hydronephrosis from scarring, renal tumors (as another cause of bleeding), and calculus disease.
• CT scanning
• • CT scanning alone is not useful in the management of radiation cystitis; however, it may help in the diagnosis of bladder fistulas.
  • Findings include 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%), and extraluminal mass that often contains air (75%).

Other Tests

• Urodynamics
• • This is only needed when the diagnosis is not clear based on history and physical examination findings.
  • Urodynamics can help 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.
  • Acutely, reported findings include detrusor instability in 40-50% of patients, decreased peak flow rate, decreased bladder compliance, and decreased bladder volume (approximately 20% volume reduction).
  • After the acute phase has passed (6 mo), most bladder parameters return to normal. Some authors report a persistent loss of bladder compliance; however, it is not significantly different than in control subjects.

Diagnostic Procedures

• Cystoscopy
• •  Acute radiation injury is characterized by radiation changes such as telangiectasia, diffuse erythema, prominent submucosal vascularity, and mucosal edema visible on cystoscopy.
  • Chronic radiation injury can have similar findings with areas of extreme pallor in between erythematous areas and petechiae.
  • Cystoscopy is used to confirm the diagnosis and to rule out other conditions such as bladder cancer or other recurrent metastatic tumors. 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.
  • This can be combined with retrograde pyelography, if needed.
    

TREATMENT

Section 7 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Medical therapy

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.¹ 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.

Reported responses to treatments are as follows:

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 are alum, aminocaproic acid, and formalin.

Surgical therapy

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

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

Section 8 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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.

OUTCOME AND PROGNOSIS

Section 9 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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.

FUTURE AND CONTROVERSIES

Section 10 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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.

FURTHER READING

Section 11 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

For additional informations, see Medscape’s Bladder Cancer Resource Center, Prostate Cancer Resource Center, and Colorectal Cancer Resource Center.

MULTIMEDIA

Section 12 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Media file 1:  Cystoscopic view of a bladder showing the neovascularity and telangiectasia of radiation cystitis.
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Media file 2:  Cystoscopic view of a bladder showing the neovascularity and telangiectasia of radiation cystitis.
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Media type:  Photo

Media file 3:  Cystoscopic view of a radiated bladder showing areas of neovascularization next to an area of pallor due to increased collagen deposition. The collagen prevents new vessels from forming in injured areas and contributes to ischemia.
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Media type:  Photo

REFERENCES

Section 13 of 13

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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Article Last Updated: Feb 7, 2008