CUA: Radiation-induced Hemorrhagic Cystitis (2018)

See Original Report

Background

• Radiation-induced hemorrhagic cystitis is an adverse event that can occur in patients with previous radiation for malignancy
• The European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) classification of late radiation effects is a commonly used classification system for grading
  • See Table 1 from Original Report.

Diagnosis and Evaluation

• History and physical exam
  • History
    • Characterize symptoms and confirm history of a patient’s radiation therapy.
    • Identify other pathological factors that may explain or contribute to the patient’s symptoms
  • Physical exam
    • Abdominal and pelvic exam to assess for alternative causes of bleeding.
• Labs: CBC, coagulation studies, serum creatinine, urinalyses, urine culture and cytology
• Imaging: CT-urogram
  • As with any patient presenting with hematuria and a high risk of malignancy, all patients should undergo axial imaging to assess for upper tract sources of bleeding
• Cystoscopy: all patients with hematuria should undergo at least one initial cystoscopy with or without fulguration of suspect lesions and biopsy of any lesions concerning for malignancy for diagnostic and therapeutic purposes

Management

• Mild symptoms may resolve with continuous bladder irrigation with saline solution and this should be tried first in all patients with hematuria associated with clotting or retention.
• Laser therapy (Greenlight, KTP, argon beam coagulator) and endoscopic use of hemostatic agents (gelatin matrix (Floseal)), may play a role in early management, but insufficient data exists to evaluate their efficacy and safety
• Persistent or recurrent clinically significant hematuria
  • Intravesical agents (2)
    1. Alum irrigation
       • MOA: acts as an astringent agent and exerts its effect through protein precipitation causing decreased capillary permeability, contraction of intercellular space, vasoconstriction, and hardening of the capillary endothelium
       • Relatively acute onset of action, easily applied, and generally well-tolerated.
       • Typically administered as a 1% concentration of alum mixed with sterile water, irrigated through the bladder at 250‒300 ml per hour, at a duration up to the discretion of the clinician. Ideally, the bladder should be irrigated free of clots prior to initiation of therapy.
       • Common side effects are bladder spasms, suprapubic discomfort, and clotting of the catheter due to precipitant formation. Special caution should be used in patients with poor renal function due to increased risk of toxicity
       • Limited long-term durability, only a third of patients require no further treatment.
    2. Hyaluronic acid
       • MOA: repair of the normal glycosaminoglycan (GAG) layer of the bladder
       • May improve symptoms of radiation-induced hemorrhagic cystitis and may provide further benefit in those with significant LUTS
       • Slow onset of action and lack of research in severe hematuria may limit its usefulness in the acute or inpatient setting
       • An RCT found that hyaluronic acid was at least as effective as hyperbaric oxygen therapy in the treatment of radiation-induced hemorrhagic cystitis.
    3. Multiple other intravesical options have been used in limited case series
  • Systemic agents (2)
    1. Hyperbaric oxygen
       • MOA: hyperoxia induces primary neovascularization, secondary growth of healthy granulation tissue, and induces short-term vasoconstriction that may help control active bleeding
       • Safe and effective; should be considered an early treatment option for radiation-induced hemorrhagic cystitis in patients who have failed cystoscopy and fulguration.
       • Due to significant resource and expertise requirements, its use may be limited based on access and availability
       • Most common complications are related to barotrauma (barotraumatic otitis in 6%, visual field disturbances in 1%)
    2. Oral pentosan polysulfate (Elmiron)
       • MOA: serves as a synthetic GAG; adheres to the bladder mucosa, where it supplements the bladder’s own glycosaminoglycan layer (similar to intravesical hyaluronic acid).
       • May improve symptoms of radiation-induced hemorrhagic cystitis and may provide further benefit in those with significant LUTS.
       • Safe and generally well-tolerated, however, the slow onset of action (1-8 weeks) limits its usefulness in treatment of acute or severe radiation-induced hemorrhagic cystitis
    3. Multiple other systemic agents have been used in limited case series
• Refractory and life-threatening hematuria (3):
  1. Transarterial embolization
     • An option in those for whom less invasive methods have been unsuccessful.
     • Preference should be given to selective or super-selective embolization when available to lessen possible side effects
  2. Intravesical formalin
     • Rapid onset of action
     • Must administered under anesthetic (general or spinal) due to pain with administration
     • Due to significant morbidity associated with the procedure, formalin instillations should only be used in those who have failed less invasive treatments. If treatment is necessary, all attempts should be made to prevent reflux into the upper tracts, and the patient needs careful monitoring for potential side effects
     • Major complications typically associated with refluxing into the upper urinary tract and consist of ureteric stricture function, ureteropelvic junction and uretrovesical junction obstruction requiring urinary diversion, decreased bladder capacity, and vesicular fistulas.
  3. Cystectomy and urinary diversion
     • Urinary diversion with or without cystectomy should be reserved only for those who have failed previously available therapy; clinicians and patients should be aware of the high morbidity and mortality of the procedure before proceeding with surgery
     • Small case studies have evaluated the use of urinary diversion alone in those who may not tolerate a cystectomy, either through cutaneous ureterostomy or bilateral nephrostomy tubes. Caution should be advised, as long-term follow-up in urinary diversion without cystectomy for benign conditions has shown a high rate of complications in the remaining bladder.
• Treatment selection
  • Hyperbaric oxygen therapy can be offered as initial therapy but access may be limited
  • Hyperbaric oxygen, intravesical hyaluronic acid, and systemic SPP have slow onset of action.
  • If acute onset of action needed, intravesical alum can be used.
    • Formalin has rapid onset of action but has high morbidity.
  • In patients with significant LUTS, both [intravesical] hyaluronic acid and [oral] SPP (those that repair GAG layer) may be preferred as they also improve urinary symptoms associated with hemorrhagic cystitis

See Figure 1 from Original Report for summary figure