Cystitis hemorrhagic, cyclophosphamide

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. 

Few side effects can be alleviated by the use of antidotes. An example is the prevention of hemorrhagic cystitis caused by cyclophosphamide by the concomitant infusion of mesna. 

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

Alkylating agents Cyclophosphamide Myelosuppression, hemorrhagic cystitis Alopecia, stomatitis, amenorrhea, aspermia, secondary leukemias... 

CHOP Cyclophosphamide Alkylating agent Prodrug CYP 3A4/5, 2D6 Hemorrhagic cystitis... 

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. 

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. 

A toxicity that is unique to cyclophosphamide and ifosfamide is cystitis. Dysuria and decreased urinary frequency are the most common symptoms. Rarely, fibrosis and a permanently decreased bladder capacity may ensue. The risk of development of carcinoma of the bladder also is increased. Large intravenous doses have resulted in impairment of renal water excretion, hyponatremia, and increased urine osmolarity and have been associated with hemorrhagic subendocardial necrosis, arrhythmias, and congestive heart failure. Interstitial pulmonary fibrosis may also result from chronic treatment. Other effects of chronic drug treatment include infertility, amenorrhea, and possible mutagenesis and carcinogenesis. 

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. 

Hemorrhagic cystitis (chronic low-dose cyclophosphamide) PO 20 mg/kg q3-4h Hemorrhagic cystitis (high-dose cyclophosphamide) IV 40% of cyclophosphamide dose at 0, 3,6, 9 hr and IV fluids. 

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... 

Massive diffuse hemorrhage due to cyclophosphamide-induced or radiation cystitis has been treated successfully with intravesicular PGE1 PGEj, and carboprost. Febrile reactions and severe bladder spasm are dose-dependent (63-65). 

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

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. 

Cyclophosphamide causes significant dose-related infertility in both men and women as well as bone marrow suppression, alopecia, hemorrhagic cystitis, and, rarely, bladder carcinoma (see Chapter 55 Cancer Chemotherapy). 

In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase the risk of cyclophosphamide-induced damage (38). 

Hemorrhagic cystitis and bladder cancer are well-known complications of cyclophosphamide. The damage to the urinary bladder epithelium is caused by acrolein, a metabolite of cyclophosphamide that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk (23). Mesna (2-mercaptoethane sodium sulfonate) is used to prevent this adverse effect. It is excreted by the kidney, and it binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. Intravesical prostaglandin E2 has been suggested as an alternative treatment (23). 

Mesna is used to prevent or ameliorate hemorrhagic cystitis produced by the anticancer drugs cyclophosphamide and ifosfamide. It is excreted by the kidney and binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. It is also used as a mucolytic. 

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]. 

Droller MJ, Sral Rand Santos G. Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology, 20 256-258,1982... 

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