Cyclophosphamide Induced Hemorrhagic Cystitis: The Role of Protein Deficiency in its Occurrence

Abstract

Cyclophosphamide (CPM) is an alkylating agent that has proved an effective anti-metabolite in the treatment of many tumors. One of its adverse effects is the development of severe hemorrhagic cystitis often requiring cessation of treatment. This report evaluates the influence of a protein deficient diet on the incidence of this severe complication in an animal model with a tumor burden. Seventy-two ACI Rats (200 g) were implanted with Morris Hepatoma. Following two weeks of tumor growth, animals were divided into four groups. Group I ( n =18) and Group III ( n =18) rats were fed a regular diet and a protein free diet respectively but received no chemotherapy. Animals in Group II ( n =18) and Group IV ( n =18), each received CPM 100 mg/kg IP once weekly for two weeks while being maintained respectively on a regular diet or protein free diet. The animals were evaluated for nutritional intake, serum protein, hematuria, weight change, tumor size, morbidity and mortality. Animals were sacrificed at 2 wk and evaluated for gross and microscopic bladder and renal pathology. Hemorrhagic cystitis was noted in 7/18 (38.9%) Group IV rats. No other treatment group experienced this complication. Hydroureter and renal cystic degeneration was noted in three (16.7%) animals in Group IV and once each in Groups II and III. All groups had equivalent caloric intake but a deficient protein intake occurred in Groups III and IV characterized by decreased serum albumin. Weight loss, morbidity and mortality was greatest in Group IV. These data suggest that the development of CPM induced hemorrhagic cystitis is related to the state of nutrition. Protein deficiency significantly increases the risk of this complication. Careful nutritional assessment prior to therapy and nutritional support of cancer patients receiving CPM might prove beneficial.