Hemorrhagic cystitis

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Daniela Bates
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1 Hemorrhagic cystitis Bradley Rosenberg, MD Assistant Professor of Urology Oakland University William Beaumont School of Medicine Comprehensive Urology

2 Hemorrhagic cystitis Definition: Sustained hematuria and lower urinary tract symptoms in the absence of active tumor or other condition, like infection Etiology: Chemotherapy/other meds Radiation Others (rare)

3 Hemorrhagic cystitis Diagnosis: Signs/symptoms: hematuria +/- clots, dysuria, urgency, frequency, suprapubic pain Urine culture, cytology Upper tract imaging (CT, U/S, IVP) Cystoscopy +/- biopsy (r/o malignancy, fistula)

5 Hemorrhagic cystitis Treatment : Prevention Supportive care Systemic agents Intravesical therapy Non-pharmacologic interventions

6 Hemorrhagic cystitis Complications : Anemia Recurrent UTI Hydronephrosis +/- renal failure Bladder perforation Death

7 Etiology Medications: Cyclophosphamide/Ifosphamide Busulfan Thiotepa Methenamine Immune agents (PCNs, danazol) Psychotropics

8 Cyclophosphamide Cytoxan Oxazaphosphorine alkylating agent used against cancer, benign conditions If no prevention, incidence up to 60% Morbidity & mortality (4%) are high Hemorrhage usually early (weeks-months) Fibrosis and malignancy are other sequelae

9 Cyclophosphamide Metabolized to toxic by-product acrolein, leading to urothelial ulceration Transmural edema, mucosal ulceration, epithelial necrosis Dose-dependent May lead to fibrosis, diminished compliance

10 Cyclophosphamide Histology: transmural edema, mucosal ulceration, epithelial necrosis Dependent on dose, rate/route of administration Healing by mucosal hyperplasia, bizarre papillary proliferation Leads to fibrosis, diminished compliance

11 Cyclophosphamide Prevention: Hyperhydration IVF hydration Diuresis Frequent urination Continuous bladder irrigation All dilute drug, and reduce amount of time drug is in contact with the urothelium

12 Cyclophosphamide Prevention : Mesna (2-mercaptoethane sulfonate) Thiol compound binds, neutralizes acrolein in the bladder Active only in the urine IV, PO forms Reduces incidence to 5-40%

13 Radiation XRT of GU system, cervix, rectum Bladder symptoms < 20%, hemorrhage 9% Months years later Promise of less morbidity with intensitymodulated photon radiotherapy (IMRT) or proton beam radiotherapy

14 Radiation cystitis

15 Radiation induced GU sequelae To ureters, bladder and urethra: Hemorrhage Fibrosis/stricture Lower urinary tract symptoms Reduced bladder compliance Fistula Development of cancer

16 Factors leading to RC Dose/fractionation of radiation Volume of tissue treated Mode of delivery (external beam/brachy) Concurrent treatments Radiosensitivity of affected bladder tissue Other factors: DM, anticoagulants, etc.

17 Late radiation morbidity scoring 17

18 Late radiation toxicity Meta-analysis (Ohri et al, Can J Urol 2012) 11,835 patients treated for PCA Reporting time 3-10 years later Median toxicity > grade 2= 17% (6-41%) Median toxicity > grade 3= 3% (0-13%)

19 Radiation cystitis pathophysiology Acute phase Lasts for up to several weeks after radiation ends Symptom-free phase Dose-dependent, lasts months-years Chronic irreversible late-response phase > 5% of patients with pelvic radiation

20 Radiation cystitis pathophysiology Radiation causes obliterative endarteritis The lumen of small vessels become narrowed or obliterated, causing ischemia Atrophy and fibrosis of mucosa, submucosa Telangiectatic blood vessels (fragile) Bladder becomes hypovascular, hypocellular, hypoxic May lead to necrosis, fistulae

21 Economic burden of RC 1,111 patients admitted over 5 yrs.(kiechle et al, Urology Practice, 2016) Mean age 74 yo Median LOS = 4 days Median cost of hospitalization =$7,151 29% required blood transfusion 34% required endourologic procedures 3% required nephrostomy tubes

22 Treatment No guidelines exist Begin with least invasive Prevention Oral agents Intravesical agents Hyperbaric oxygen Surgical intervention

23 Shown to prevent radiation cystitis Given along with radiation Weekly intravesical instillations Helps restore glycosaminoglycan (GAG) layer Sodium hyaluronate

24 Pentosan Polysulfate Sodium Elmiron 100 mg tid PO or SL Polysaccharide Coats mucosa, preventing cell injury by cytotoxins Probably best in mild, chronic cases

25 Aminocaproic acid Amicar Inhibitor of plasmin, the enzyme responsible for fibrinolysis Given PO, IV, intravesically Load with 5 gms, then 1 gm hourly until cessation of bleeding (max. 30gm/24 hrs.) Intravesical 12gm/L at 50cc/hr, or 2.5% solution 1 hr. TID

26 Intravesical agents Normal saline Alum Aminocaproic acid Silver nitrate Prostaglandin Formaldehyde

27 Saline bladder irrigation Mainstay of therapy Normal saline via large bore (> 22 French) 3 way catheter Manual clot evacuation OR cystoscopy with fulguration PRN

28 Aluminum K Sulfate Alum Intravesical agent, used as continuous irrigant Astringent activity on urothelium Hardens capillary endothelium, inhibiting mobility of proteins Does not damage epithelium 1-4% solution

29 Alum Complete response in over 50% Adverse effects spasms, fever, frequency, clotting of precipitate, pain Little systemic absorption Aluminum toxicity encephalopathy, seizures No need for anesthesia

30 Formalin Used in severe, refractory bleeding Aqueous dilute solution of formaldehyde Similar to acrolein fixes vessels in bladder mucosa Anesthesia required Avoid ureteral exposure reverse Trendelenberg, cystogram, occlusive balloons

31 Formalin 1-10% solution Instill 50cc +, dwell for minutes Up to 83% effective, dose-dependent Complication rate significant, dose-dependent Bladder contraction Ureteral obstruction

32 Hyperbaric oxygen Promotes healing in conditions of tissue hypoxia, ischemia Breathe 100% oxygen pressurized to between atm for minutes Increased oxygen diffusion gradient into tissues, interstitium Reverses radiation-induced damage by: Promoting angiogenesis, collagen formation Enhancing leukocyte function Free radical formation

34 Hyperbaric oxygen Typically used in radiation-induced cystitis sessions usually required Used for chronic, intermittent bleeding Pros: Well tolerated Effective (response rates 27-92%) No adverse effects on bladder structure, function

35 Hyperbaric oxygen Cons: Not as useful in acute hemorrhage Expensive Time consuming High recurrence rate Complications: Barotrauma (pneumothorax, tympanic membrane perforation) Oxygen toxicity - rare (seizure, lung damage) Promotion of cancer growth?

36 Hyperbaric oxygen Mougin et al, Urology patients, median age 72 (39-87) Grade > 3 in 70% Average 29 sessions (3-50) Success in 65% (52% cured), median f/u 15 months 9 barotrauma otitis, 6 minor neurologic

37 Non-pharmacologic interventions Endovascular embolization or arterial ligation Selective, using coils or other Risk claudication of gluteals, bladder necrosis Urinary diversion Percutaneous nephrostomy tubes Cutaneous ureterotomies Intestinal diversion Surgical interventions Cystectomy with diversion

38 Survivorship Distressing, under-investigated Lab at Beaumont, headed by Michael Chancellor, MD Working on mouse model Investigational treatments Tissue culture studies Looking for biomarkers Radiation cystitis foundation

39 Future directions Tacrolimus (FK506) Immunosuppressant Liposomal delivery mechanism Stem cell injection Botox Vascular endothelial growth factor (VEGF), endothelial cell injections

40 Summary Hemorrhagic cystitis is not uncommon, difficult Inflammation, bleeding, urinary bother from GU toxins, radiation Treatment includes oral & intravesical agents, hyperbaric oxygen, or non-pharmacologic interventions May need multiple modalities to achieve success

41 Thank You

EARLY HYPERBARIC OXYGEN THERAPY IMPROVES OUTCOME FOR RADIATION-INDUCED HEMORRHAGIC CYSTITIS

ADULT UROLOGY EARLY HYPERBARIC OXYGEN THERAPY IMPROVES OUTCOME FOR RADIATION-INDUCED HEMORRHAGIC CYSTITIS KIAN TAI CHONG, NEIL B. HAMPSON, AND JOHN M. CORMAN ABSTRACT Objectives. To assess the clinical