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Symptoms, Diagnosis, and Treatment of Radiation Cystitis

Definition of Radiation Cystitis

Radiation cystitis is damage to the urinary bladder as a complication of pelvic radiation therapy of malignant tumors (Crew et al., 2001).

Epidemiology

5–21% of patients treated with radiation therapy in the pelvic region develop lower urinary tract symptoms. Radiation therapy for prostate cancer is the most common reason for radiation cystitis, followed by cervical cancer and bladder carcinoma. Up to 9% of patients develop moderate to severe radiation-induced cystitis with recurrent hematuria after conformal beam therapy (70–78 Gy) for prostate cancer.

Etiology of Radiation Cystitis

The severity of the disease depends on the radiation dose to the urinary bladder. Three phases of tissue response to irradiation can be distinguished:

Acute reaction:

An inflammatory response with tissue edema and hyperemia develops within 4–6 weeks; this is later compared to the intestinal epithelium since the regeneration time of the urothelium is slower. The acute reaction is followed either by healing or the second (ischemic) phase of tissue reaction.

Ischemic response:

The second phase of the radiation injury leads to ischemic tissue damage due to necrosis of the vascular endothelium and perivascular fibrosis. Histology reveals the picture of obliterative endarteritis. The ischemic bladder wall becomes more sensitive to external factors like bacterial infection, and the ability to heal is reduced significantly. Other symptoms of ischemia are recurrent hematuria and an increased risk of bladder fistulas.

Fibrotic reaction:

Recurrent ischemia of the bladder walls leads to progressive fibrosis and shrinkage. The fibrotic shrinkage may occur up to 10 years after radiation therapy.

Signs and Symptoms

• Dysuria, frequency, nocturia.
• Recurrent hematuria, recurrent urinary tract infections
• Signs of the bladder fistula are persisting urinary tract infections, urinary incontinence, and pneumaturia.
• See table classification of long-term complications after radiation therapy

Diagnosis of Radiation Cystitis

• History: Hematuria? Dose, radiation fields, type of radiation?
• Cystoscopy (with biopsy if necessary)
• Voiding cystourethrography: if fistula is suspected

Treatment of Radiation Cystitis

Acute cystitis after irradiation:

Acute cystitis after irradiation is a frequent and expected side effect in up to 60% after radiation therapy for prostate cancer. Symptomatic treatment includes anticholinergics, NSAIDs, and intravesical instillations to regenerate the GAG layer with, e.g., chondroitin sulfate (Madersbacher et al., 2012). Increasing diuresis might prevent the need for bladder irrigation if hematuria is present.

Endoscopic therapy (TURB):

TURB and coagulation of the bladder is indicated for persisting or unexplained hematuria to confirm the diagnosis and to treat bladder tamponade.

Oral therapy:

ε-aminocaproic acid is an inhibitor of fibrinolysis (antagonist for urokinase) and is eliminated via the urine. Dosage: 35 mg 1-1-1-1 for up to four weeks. Indication: persisting hematuria after endoscopic hemostasis.

Intravesical therapy for refractory hematuria:

The following substances are options for instillation therapy in patients with refractory hematuria after unsuccessful endoscopic trials for hemostasis (off-label treatment):

ε-aminocaproic acid:

0.02% solution as a continuous bladder irrigation over 1–2 days.

Alum:

Alum is potassium aluminum sulfate, used in a 1% solution for bladder irrigation with 100–600 ml/h. Aluminum toxicity is possible if used for several days, and renal function is impaired.

Formalin:

Formalin may be used in a 1% solution; it leads to the denaturation of superficial urothelium layers, which creates hemostasis and causes severe pain. Anesthesia is necessary for formalin instillations.

High rate of side effects: ureteral stricture, bladder perforation, fistula, contracted bladder, acute tubular necrosis, anuria. Before therapy, cystography must rule out vesicoureteral reflux, and the patient is positioned with an elevated upper body. The urinary bladder is filled by gravity (15 cm H2O); after 10 min, the formalin is drained, and the bladder is rinsed with distilled water.

Silver nitrate:

Silver nitrate is used in a 0.25–1% solution. Application see formalin.

Additional therapeutic options:

Hyperbaric oxygen therapy:

Hyperbaric oxygen therapy aims at reducing the ischemic tissue reaction and may lead to a long-term improvement of hematuria. Treatment regimens are very different: 10–60 treatments, 2–3 atm of oxygen, 75–120 min duration. Response rates in the long term are only 30%, but there are hardly any side effects.

Palliative cystectomy:

Indications are recurrent hematuria despite endoscopic interventions, bladder fistula, bladder capacity below 200 ml with unbearable frequency, and severe bladder pain. The morbidity and mortality are higher than in the cystectomy series without prior pelvic radiation therapy. Urinary diversion is possible using colon (conduit) or ureterocutaneostomy. Usage of the small intestine after pelvic radiation therapy may not be possible.

References

Crew u.a. 2001 CREW, J. P. ; JEPHCOTT, C. R. ; REYNARD, J. M.: Radiation-induced haemorrhagic cystitis.
In: Eur Urol
40 (2001), Nr. 2, S. 111–23

Madersbacher, H.; van Ophoven, A. & van Kerrebroeck, P. E. V. A. GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycans-A review.
Neurourol Urodyn, 2012.

  Deutsche Version: Strahlenzystitis