Dr. med. Dirk Manski



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Radiation Cystitis

Definition of Radiation Cystitis

Radiation cystitis is damage to the urinary bladder as a complication from 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 of prostate cancer is the most common reason for radiation cystitis, followed by cervical cancer and bladder cancer. Up to 9% of patients develop a 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 much later compared to the intestinal epithelium, since the regeneration time of the urothelium is slower. The acute reaction is followed either by healing or is proceeded by the second (ischemic) phase of tissue reaction.

Ischemic response:

The second phase of the radiation injury leads to an 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. Symptoms of the ischemia are recurrent hematuria and there is an increased risk for bladder fistulas.

Fibrotic reaction:

In the course of recurrent ischemia, the bladder walls reacts with progressive fibrosis and shrinkage. The fibrotic shrinkage may occur up to 10 years after radiation therapy.

Signs and Symptoms


RTOG Classification of long-term complications and toxicity after radiation therapy. RTOG=Radiation Therapy Oncology Group.
Gastrointestinal Urogenital
Grade 1 Increased frequency or change in quality of bowel habits not requiring medication Frequency, dysuria, urgency not requiring medication
Grade 2 Diarrhea requiring drugs, mucous discharge not necessitating sanitary pads, pain requiring analgesics Moderate urinary frequency (less than hourly), occasional hematuria, numerous telangiectasias
Grade 3 Diarrhea requiring parenteral support, severe mucous or blood discharge necessitating sanitary pads, requiring surgery for stenosis, bleeding requiring transfusion severe urinary frequency (<1/h), severe dysuria, frequent hematuria, bladder capacity below 150 ml
Grade 4 perforations, fistulas, life-threatening hemorrhage, necrosis perforations, fistulas, severe hemorrhagic cystitis, bladder capacity below 100 ml
Grade 5 any fatal complication any fatal complication

Diagnosis of Radiation Cystitis

Treatment of Radiation Cystitis

Acute cystitis after irradiation:

Frequent (taken into account) side effect in up to 60% of pelvic radiation treatments for prostate cancer. Symptomatic treatment with anticholinergics, NSAID and/or intravesical instillations to regenerate the GAG ​​layer with e.g. chondroitin sulfate (Madersbacher et al, 2012). If hematuria is present, increasing diuresis might prevent bladder irrigation.

Endoscopic therapy (TURB):

TURB / Coagulation of the bladder is indicated for persisting hematuria, or unexplained hematuria to confirm the diagnosis and mandatory for bladder tamponade.

Oral therapy:

ε-aminocaproic acid, an inhibitor of fibrinolysis (antagonist for urokinase) which 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:

Following substances can be instilled in cases with refractory hematuria despite of endoscopic trials for hemostasis:

ε-aminocaproic acid:

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

Alum:

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

Formalin:

Formalin may be used in a 1% solution. Instillation must be done under anesthesia for 10 min. Formalin leads to denaturation of superficial urothelium layers which creates hemostasis and causes severe pain.

High rate of side effects: ureteral stricture, bladder perforation, fistula, contracted bladder, acute tubular necrosis, anuria. Before therapy, cystography must rule out vesicoureteral reflux. Positioning of the patient with elevated upper body. The urinary bladder is filled by gravitiy (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 only 30%. Hardly any side effects.

Palliative cystectomy:

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







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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