Radiation Cystitis

Radiation cystitis is inflammation and damage of the bladder wall due to ionising radiation to the pelvis. It most commonly follows treatment of prostate, cervical, endometrial, bladder, rectal and other pelvic cancers, with external beam radiotherapy or brachytherapy.

Acute radiation cystitis occurs during or within 3 months of treatment, with urothelial inflammation, oedema and denudation, and usually resolves.

Chronic (late) radiation cystitis appears months to years later (median 2 to 3 years, but up to 10 to 20 years). It is caused by obliterative endarteritis, progressive ischaemia, fibrosis and urothelial atrophy. The result is a friable, telangiectatic bladder mucosa with chronic haematuria, small capacity and poor compliance.

Incidence of late haemorrhagic cystitis is 5 to 10 percent. It rises to up to 20 percent with:

• Doses above 65 to 70 Gy to the bladder
• Concurrent chemotherapy such as cyclophosphamide
• Prior transurethral surgery
• Diabetes and vascular disease

Complications:

• Haemorrhage with clots and retention, severe anaemia
• Bladder contracture, vesicoureteral reflux and hydronephrosis
• Fistulas (vesicovaginal, vesicorectal, enterovesical)
• Infection
• Secondary urothelial carcinoma (increased relative risk, long latency)

• Acute: dysuria, frequency, urgency, suprapubic pain, nocturia, and microscopic haematuria during or shortly after radiotherapy.
• Chronic: painless or painful gross haematuria (intermittent or persistent), clot retention, frequency, urgency, urge incontinence, bladder spasms and suprapubic pain.
• Reduced bladder capacity and incontinence due to a fibrotic bladder.
• Anaemia and fatigue from chronic blood loss.
• Pneumaturia, faecaluria and recurrent infection when there is a fistula.
• Flank pain with ureteric stricture.
• Often accompanied by radiation proctitis, urethral stricture or erectile dysfunction.

• History of pelvic radiotherapy (dose and field, timing), and exclusion of other causes of haematuria (a delay in diagnosis of malignancy is dangerous): urine culture, urine cytology, blood tests (haemoglobin, clotting, creatinine).
• Imaging: renal and bladder ultrasound (hydronephrosis, bladder wall thickening, clots) and CT urography to exclude upper tract tumours, stones and fistulas.
• Flexible or rigid cystoscopy: pale, thin mucosa with telangiectasia, mucosal erythema, ulceration and active bleeding sites, in a bladder with reduced capacity; biopsy of suspicious areas (to exclude recurrence of cancer or secondary carcinoma), though biopsy of irradiated mucosa can cause non-healing ulcers and bleeding, so take it only when needed.
• Urodynamics for incontinence and low compliance in chronic cases.
• Rule out BK virus and adenovirus infection in transplant or immunosuppressed patients.

Therapy escalates according to severity. Treat bleeding first with resuscitation, bladder irrigation and clot removal.

• Initial: hydration, transfusion for anaemia (target haemoglobin above 7 to 8 g/dL), correction of coagulopathy, and discontinuation of anticoagulants and antiplatelets if feasible.
• Insert a three way large calibre urethral catheter (20 to 24 Fr) with continuous saline irrigation. Perform manual clot evacuation with irrigation, or cystoscopic clot evacuation under anaesthesia with fulguration of bleeding sites using diathermy or laser (holmium or neodymium:YAG).
• Antifibrinolytics: tranexamic acid 1 g orally or intravenously three times daily for 5 to 7 days, or aminocaproic acid 1 g every 4 to 6 hours (caution with upper tract clots and thrombotic risk).
• Pain and symptoms: antimuscarinics (oxybutynin 5 mg two to three times daily, solifenacin 5 to 10 mg daily), phenazopyridine, analgesics, and treatment of infection with culture directed antibiotics.
• Hyperbaric oxygen therapy: 2.0 to 2.5 atmospheres absolute for 90 to 120 minutes, once daily, 5 days per week, for 30 to 40 sessions. It stimulates angiogenesis in irradiated tissue, with resolution of haematuria in 60 to 90 percent. It is the best supported therapy for persistent haematuria after first line treatment.
• Contraindications to hyperbaric oxygen: untreated pneumothorax, certain chemotherapeutic agents (doxorubicin, cisplatin, bleomycin), and uncontrolled seizures. Side effects are barotrauma of the ear, myopia and claustrophobia.
• Intravesical agents are used for refractory haematuria:
  • Instillation of 1 percent alum (aluminium potassium sulphate) solution by continuous irrigation (200 to 300 mL/hour) for several hours to a few days (monitor serum aluminium in renal impairment, and avoid with renal failure).
  • Hyaluronic acid 40 mg in 50 mL weekly for 4 to 6 weeks (then monthly).
  • Chondroitin sulphate.
  • Sodium pentosan polysulfate (oral 100 mg three times a day, or intravesical).
  • Formalin 1 to 4 percent instillation under anaesthesia (last resort). A cystogram is required to exclude reflux and perforation, as formalin causes ureteral fibrosis, bladder contraction and fistulas.
  • Silver nitrate.
• Selective arterial embolisation of the internal iliac, vesical or uterine arteries (by interventional radiology) for refractory, severe haemorrhage. Risks are gluteal claudication and ischaemic complications.
• Surgical options for intractable haemorrhage, intractable pain or a contracted bladder: urinary diversion (ileal conduit or percutaneous nephrostomies), with or without cystectomy (simple or radical cystectomy), or bladder augmentation in select patients. Ureteric stents or nephrostomy for obstruction.
• Fistulas: surgical repair with an interposition graft (omentum or Martius flap), or diversion.
• Prevention: bladder sparing radiotherapy techniques (intensity modulated radiotherapy, image guidance, bladder filling protocols, dose constraints), hydration during treatment, avoid bladder toxic drugs, and early referral. Mesna 20 percent of ifosfamide dose before and after (at 0, 4 and 8 hours) and hydration prevent chemotherapy induced cystitis.
• Follow up: surveillance cystoscopy every 1 to 2 years for secondary malignancy in long term survivors with persistent haematuria.