Hemorrhagic Cystitis

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Hemorrhagic cystitis is defined as gross hematuria secondary to diffuse inflammation of the bladder. Viral infection, radiation-induced inflammation, and chemotherapy-induced inflammation account for the majority of cases among cancer patients. While relatively un-

common in patients with genitourinary malignancies, viral-mediated hemorrhagic cystitis occurs in as many as 50 % of patients undergoing bone marrow transplantation (Bedi et al. 1995). The principle etiologic factor involved is the BK polyomavirus. Viral-mediated hemorrhagic cystitis often occurs several weeks after transplantation and is usually self-limited. The role of antiviral therapy is unclear at present; therefore, no specific treatment recommendations beyond standard hematu-ria management can be made for viral hemorrhagic cystitis.

The association between hemorrhagic cystitis and the oxazaphosphorine alkylating agents, cyclophos-phamide and ifosfamide, has been well documented (Philips et al. 1961; Burkert 1983; Klastersky 2003). These chemotherapeutic drugs are used frequently in the treatment of breast cancer, lymphoma, and sarcoma but also have application in poor-risk and chemotherapy-resistant germ cell tumors. Cyclophosphamide is associated with a 24% incidence of irritative voiding symptoms, 7%-53% incidence of microscopic hematuria, and 1 %-15% incidence of gross hematuria (Ta-lar-Williams et al. 1996). Older series report hemor-rhagic cystitis in as many as 68 % of patients treated with cyclophosphamide (Burkert 1983). The causative agent of urothelial toxicity is acrolein, a hepatic metabolite eliminated primarily through urinary excretion (Cox 1979). Peak urine levels occur approximately 5 h after the start of chemotherapy infusion (Takamoto et al. 2004). Early pathologic changes include transmural edema, mucosal ulceration, and urothelial necrosis all of which may occur within 24 h of a single dose (DeV-ries and Freiha 1990). With repeated exposure, urothelial damage is progressive and may become irreversible (Forni et al. 1964; Koss 1967). The entire urothelium is at risk; however, the bladder is most frequently affected as it receives the longest exposure. In the acute setting, cystoscopy reveals diffuse inflammatory changes, while in the delayed setting chronic changes such as edema, pale mucosa, telangiectasia, and patchy inflammation are prominent (Coleman and Walther 2005).

Contemporary studies report a lower incidence of hemorrhagic cystitis secondary to cyclophosphamide than do historical series. This is due in large part to the development and routine application of preventative measures such as hydration and prophylactic mesna (sodium 2-mercaptoethane sulfonate). Intravenous normal saline is given concurrently with cyclophos-phamide infusion to reduce the urinary concentration of acrolein through an increase in urine output (Philips et al. 1961). Unfortunately, the prevention of clinically significant urothelial damage is inconsistent with hydration; therefore, hydration therapy alone cannot be recommended as adequate prophylaxis. Mesna, a non-toxic thiol compound, was specifically developed to bind and inactivate acrolein without interfering with tumor control (Brock et al. 1981). Numerous randomized trials have demonstrated the superiority of mesna relative to placebo and hydration in the prevention of gross hematuria (Araujo and Tessler 1983; Fukuoka et al. 1991; Shepherd et al. 1991). With the routine incorporation of mesna into cyclophosphamide or ifosfami-de-containing chemotherapy regimens, modern rates of severe hematuria range from 0 % -13 %. Mesna must be administered before cyclophosphamide to ensure adequate urinary levels are available when acrolein reaches peak urinary concentration. For this reason, mesna has no place in the treatment of established cy-clophosphamide-induced hemorrhagic cystitis. Based on simplicity, convenience, and proven efficacy, a two-dose mesna regimen (15 min before and 4 h after cyclo-phosphamide) is recommended (Katz et al. 1995). There is suggestion that the addition of dexamethasone may improve the prophylactic efficacy of mesna (Vieira et al. 2003). Prior episodes of hemorrhagic cystitis do not absolutely contraindicate the repeat administration of cyclophosphamide or ifosfamide provided that mesna is given prophylactically (Andriole et al. 1987).

The management of cyclophosphamide-induced hemorrhagic cystitis can be difficult. At the present time, there is no specific therapeutic option that can be recommended ahead of standard management strategies. Intravesical prostaglandin (PGE1, PGE2, and PGF2a) therapy is one option that may hold future promise. Initial interest in the use of prostaglandins was generated by case reports of demonstrated success in cases of otherwise intractable bladder hemorrhage secondary to cyclophosphamide (Miller et al. 1994; Trigg et al. 1990; Shurafa et al. 1987). Subsequent series report 50 % complete resolution of hematuria after the administration of carboprost tromethamine (PGF2 ) for a median treatment period of 6 days (Levine and Jarrard 1993). Although the exact mechanism of action is unknown, prostaglandin may improve hematuria through platelet aggregation and vasoconstriction. Bladder spasms (78%) are a frequent occurrence with intravesical prostaglandin therapy; however, adverse effects on renal or bladder function are negligible as are systemic complications. Prostaglandins have since found application in the management of other forms of severe hemorrhagic cystitis. Hyperbaric oxygen treatment (HBO), typically reserved for cases of refractory radiation cystitis, has also been used to treat hemor-rhagic cystitis resulting from cyclophosphamide. Animal models suggest that HBO may be of value as prophylaxis or treatment in this setting (Hader et al. 1993).

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