Hemorrhagic cystitis cyclophosphamide therapy

The answer is c. (Hardman, pp 1238-1239.) Remission maintenance can be carried out by combination therapy, which includes cyclophosphamide. Cyclophosphamide causes hemorrhagic cystitis. Doxorubicin and carmustine are useful in the treatment of acute lymphatic leukemia, but neither is known to cause hemorrhagic cystitis. 

Direct contact of the bladder epithelium with the catabolites acrolein and 4-hydroxy-cyclophosphamide is responsible for the hemorrhagic cystitis that can be a consequence of therapy with cyclophosphamide [78]. Aggressive hydration provides prophylaxis against this toxicity to the efferent urinary tract [79]. The sulfhydryl compound mesna has also demonstrated uroprotec-tive ability during therapy with cyclophosphamide [80]. Although hemorrhagic cystitis is a dose-related toxicity, chronic low doses of orally administered cyclophosphamide are also associated with development of this adverse event [81]. 

Treatment is largely supportive. Cyclophosphamide is adsorbed to activated charcoal and charcoal should be used for substantial, recent ingestions. Patients may require aggressive fluid support. Standard supportive therapies, such as vasopressors, should be utilized as clinically indicated. Patients may require prolonged observation due to the delay in the development of adverse effects. Antibiotics may be needed due to development of immunosuppression. MESNA has been used for management of cyclophosphamide-induced hemorrhagic cystitis. 

Drug therapy may also cause renal insufficiency due to lower urinary tract obstruction. Ureteral obstruction can be caused by calculi or retroperitoneal fibrosis. Bladder dysfunction with urinary outflow obstruction can result, particularly in males with prostatic hypertrophy, from anticholinergic drugs including tricyclic antidepressants and disopyramide. Bladder outlet and ureteral obstruction may result from bladder fibrosis following hemorrhagic cystitis with cyclophosphamide or ifosfamide therapy. Concurrent treatment with mesna can prevent cystitis and this complication. 

The immunosuppressive effect of cytotoxic agents, with or without the concurrent use of steroids, can result in serious infections, which are the primary cause of death in patients with minimal-change nephropathy. Other toxicities associated with cyclophosphamide include gonadal fibrosis, which results in sterility, hemorrhagic cystitis, alopecia, and a potential to develop malignancy in those on long-term treatment. Patients on chronic steroid therapy often develop growth retardation, osteoporosis, obesity, and cataracts. ... 

When used in combination with corticosteroids, cyclophosphamide is dosed at 1-3 mg/kg for oral therapy and 0.5-1.0 g/m of body surface area for intravenous therapy. The most common route of cyclophosphamide administration is intravenous, although there is little evidence that this is better than oral administration. Likewise, there is no evidence to suggest the optimal duration of treatment. Based on empirical experience, cyclophosphamide generally is dosed monthly for 6 months and then every 3 months for a period of either 2 years or for 1 year after the nephritis is in remission." " Of course, cyclophosphamide therapy is not without risk. Serious toxic effects include suppression of hematopoiesis, opportunistic infections, bladder complications (e.g., hemorrhagic cystitis and cancer), sterility, and teratogenesis. White blood cell counts must be monitored during cyclophosphamide therapy, and if the nadir is less than 1500/mm, the dose must be adjusted to keep the white cell count above 1500/mm. Nausea and vomiting associated with cyclophosphamide can be controlled with oral ondansetron plus dexamethasone. ... 

Observational studies In a retrospective study in 215 patients with non-infectious ocular inflammation treated with cyclophosphamide with or without glucocorticoids, low white cell counts and hemorrhagic cystitis were the most common adverse reactions, leading to drug withdrawal in 38 patients (18%) and 14 patients (6.5%) respectively during the first year of therapy [24]. Opportunistic infections led to withdrawal in six patients (3.0%), including Pneumocystis jiro-vecii pneumonia, which was fatal in one patient, who had not taken prophylaxis. 

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