Ifosfamide is a parenterally administered alkylating agent similar to cyclophosphamide that is used in the treatment of several forms of cancer including lymphomas, sarcoma and advanced forms of solid organ cancer such as breast, testicular, ovarian, gastric and lung cancer. Ifosfamide therapy is associated with minor transient serum enzyme elevations and has been linked to cases of acute liver injury, including acute cholestatic hepatitis and veno-occlusive disease.
Ifosfamide (eye fos' fa mide) is an analogue of cyclophosphamide and thus a nitrogen mustard-like alkylating agent that is used in the therapy of several forms of leukemia, lymphoma and solid organ cancer. Like cyclophosphamide, ifosfamide requires activation in the liver to form its active intermediaries which act by modifying and cross linking purine bases in DNA, thus inhibiting DNA, RNA and protein synthesis and leading to programmed cell death (apoptosis) in rapidly dividing cells. Ifosfamide was approved for use in the United States in 1988 and its major indication is for germ cell testicular cancer, but it is also used in combination with other agents in the treatment of breast, lung, bladder, cervical, and ovarian cancer, Hodgkin's and non-Hodgkin’s lymphoma, and soft tissue and osteogenic sarcomas. Ifosfamide is given intravenously and is available in liquid formulations (1 and 3 gram vials), generically and under the trade name Ifex. Recommended doses vary by body weight and malignant condition. Common side effects include alopecia, nausea, vomiting, diarrhea, gastrointestinal upset, cystitis, oral ulcers and bone marrow suppression. It is commonly given with mesna to reduce the risk of hemorrhagic cystitis.
The toxicity of ifosfamide seems to be similar to that of cyclophosphamide. Mild and transient elevations in serum aminotransferase levels are found in a high proportion of patients receiving ifosfamide. Because ifosfamide is typically given in combination with other antineoplastic agents, its role in causing the serum enzyme elevations is often not clear. The abnormalities are generally transient, do not cause symptoms and do not require dose modification. Clinically apparent liver injury from ifosfamide has been limited to a small number of cases of cholestatic hepatitis arising within a few weeks of receiving ifosfamide (with other antineoplastic agents). In addition, sinusoidal obstruction syndrome has been reported after conditioning regimens that have included ifosfamide in preparation for hematopoietic cell transplantation. The onset of injury is usually within one to three weeks of the myeloablation and is characterized by a sudden onset of abdominal pain, weight gain, ascites, marked increase in serum aminotransferase levels (and lactic dehydrogenase), and subsequent jaundice and hepatic dysfunction. The severity of sinusoidal obstruction syndrome varies from a transient, self limited injury to acute liver failure. The diagnosis is usually based on clinical features of tenderness and enlargement of the liver, weight gain, ascites and jaundice. Liver biopsy is diagnostic but often contraindicated, because of severe thrombocytopenia after bone marrow transplantation.
Mechanism of Injury
The cause of idiosyncratic hepatotoxicity from ifosfamide is not known. The sinusoidal obstruction syndrome induced by ifosfamide is probably related to the direct toxic effect of ifosfamide on sinusoidal cells in the liver, causing their necrosis and release into the sinusoids, obstruction and obliteration of hepatic veins. Ifosfamide is extensively metabolized by hepatic cytochrome P450 system and more than 150 metabolites have been identified, but their pharmacokinetics and toxicities are not well defined.
Outcome and Management
The severity of liver injury ranges from mild elevations in liver enzymes to massive, fatal hepatic necrosis due to sinusoidal obstruction syndrome. There is currently no specific therapy for veno-occlusive disease other than supportive management and avoidance of further damage. Rechallenge should be avoided.
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