Cyclophosphamide hemorrhagic cystitis with

Cyclophosphamide Hemorrhagic cystitis due to acrolein metabolite (prevent with MESNA)... 

Levine LA, Jarrard DF. Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J Urol 1993 149(4) 719-23. 

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. 

Clinical trials showed therapeutic efficacy in a broad spectrum of tumors these include SCLC, testicular tumors, sarcomas, breast cancer, renal cell cancer, pancreatic tumors and lymphomas. Ifosfamide is less myelosuppressive than cyclophosphamide but is more toxic to the bladder. Therefore it is recommended that ifosfamide is coadministered with the thiol compound mesna to avoid hemorrhagic cystitis and to reduce the risk of developing bladder cancer. Other side effects include neurotoxicity and myelosuppression. 

The use of effective prevention strategies can decrease the incidence of hemorrhagic cystitis to less than 5% in patients receiving cyclophosphamide or ifosfamide. There are three methods to reduce the risk administration of mesna, hyperhydration, and bladder irrigation with catheterization. 

Twenty percent of patients receiving pelvic irradiation may experience hemorrhagic cystitis, especially with concurrent cyclophosphamide. Viral infections commonly associated with this condition occur most frequently in bone marrow transplant recipients who also may receive cyclophosphamide. 

Mechanism of Action An antineoplastic adjunct and cytoprotective agent that binds with and detoxifies urotoxic metabolites of ifosfamide and cyclophosphamide. Therapeutic Effect Inhibits ifosfamide- and cyclophosphamide-induced hemorrhagic cystitis. 

Mechlorethamine Forms DNA cross-links, resulting in inhibition of DNA synthesis and function Hodgkin s and non-Hodgkin s lymphoma Nausea and vomiting Moderate depression of peripheral blood count excessive doses produce severe bone marrow depression with leukopenia, thrombocytopenia, and bleeding alopecia and hemorrhagic cystitis occasionally occur with cyclophosphamide cystitis can be prevented with adequate hydration busulfan is associated with skin pigmentation, pulmonary fibrosis, and adrenal... 

Treatment with large doses of cyclophosphamide carries considerable risk of pancytopenia and hemorrhagic cystitis and therefore is generally combined with stem cell rescue (transplant) procedures. Although cyclophosphamide appears to induce tolerance for... 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

In animal studies, NAC has been shown to prevent hemorrhagic cystitis that results from administration of cyclophosphamide or its position isomer ifosfamide. Hemorrhagic cystitis results from the toxic effect of acrolein, a metabolic product of cyclophosphamide or its position isomer ifosfamide. The mechanism whereby NAC prevents this toxicity may be prevention of the intracellular depletion of antioxidants, such as GSH, by acrolein. Concomitant administration of NAC with cyclophosphamide or ifosfamide does not impair antineoplastic activity, because both anticancer drugs are inactive until they are metabolized by the liver to their phosphoramide mustard metabolites. 

Like cyclophosphamide, ifosfamide causes a hemorrhagic cystitis in a high proportion of patients, with an occasionally fatal outcome. The damage to urinary bladder epithelium is caused by acrolein, a metabolite that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk of oxazaphosphorines (12). Mesna (sodium... 

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]. 

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. ... 

Cyclophosphamide prodnces a similar response rate as chlorambucil (30% to 40%) and can be used in patients who have difficulty tolerating chlorambncU or in whom response is not optimal. Some patients refractory to chlorambucil will respond to cyclophosphamide. Cyclophosphamide is less commonly used because of its risk of hemorrhagic cystitis and bladder cancer with prolonged treatment. ... 

Answer A. The symptoms are those of a mild case of hemorrhagic cystitis. Bladder irritation with hematuria is a fairly common complaint of patients treated with cyclophosphamide, It appears to be due to acrolein, a product formed when cyclophosphamide is bioactivated by liver P450 to form cytotoxic metabolites. Urinary tract problems may also occur with methotrexate from crystalluria due to its low water solubility. 

Folinic acid (leucovorin) reduces the toxicity of methotrexate because it provides an active form of folate to normal (nonneo-plastic) cells, resulting in leucovorin rescue. Dexrazoxane is a free radical trapping agent that is thought to reduce the cardiotoxicity of anthracyclines (eg, doxorubicin). Mercaptoethanesulfonate (mesna), which inactivates acrolein, is available for protection against hemorrhagic cystitis in patients treated with cyclophosphamide and related drugs. 

Because acrolein is formed, the same precautions against hemorrhagic cystitis that were previously outlined for cyclophosphamide must be taken hydrate well, irrigate thoroughly, and administer with mesna. As previously stated, mesna will not prevent chloroacetaldehyde-induced toxicity. 

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