Chemotherapy-induced bladder cancer.

Abstract

The use of chemotherapy in the management of cancer started in the 1940s when the cytotoxic effect of nitrogen mustard was first explored. The therapeutic concept was based on warfare experience of the toxic effects of nitrogen mustard on the lymphatic system. A large number of chemotherapeutic drugs have been developed since then, and by the year 2000 more than 50 drugs were available for clinical use. The chemotherapy regimens usually consist of drug combinations with the aim of overcoming tumour cell resistance. Chemotherapy is now one of the cornerstones for curative and palliative treatment of malignant diseases. However, essentially all chemotherapeutic drugs also induce short-term and/or long-term side-effects. This article highlights the risk of inducing secondary bladder cancer. The main treatment focus over the years has been on cyclophosphamide and derivatives thereof. This drug belongs to the oxaphosphorin group and is chemically related to nitrogen mustard. Cyclophosphamide is a prodrug that needs bioactivation by cytochrome P450 enzymes to exert its cytotoxic effects. Of the three main DNA-binding components (phosphoramide mustard, nornitrogen mustard and acrolein) phosphoramide is the main active cytotoxic component. The presumed mechanism of action is alkylation of DNA resulting in DNA cleavage, and cross-linkage of DNA strands and DNA proteins. This, in turn, affects DNA replication and induces apoptosis. Cyclophosphamide is currently used primarily in the management of malignant diseases such as Hodgkin’s and non-Hodgkin’s lymphomas, leukaemias, breast cancer, ovarian cancer, small cell lung cancer and neuroblastomas. The drug is also used as immunosuppressive therapy in benign diseases such as Wegener’s granulomatosis, a necrotizing granulomatous vasculitis, and in Goodpasture’s syndrome. The first human case of urinary bladder cancer attributed to cyclophosphamide exposure was reported in the early 1970s [1]. Since then numerous reports have been published on this phenomenon [2 8]. Travis et al. quantified the risk of bladder cancer following cyclophosphamide therapy in a large cohort (n 6171) of 2-year survivors of non-Hodgkin’s lymphoma (NHL) [3]. Forty-eight patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy. Detailed information on chemotherapeutic drugs and cumulative dose received was collected for all subjects. Some of the patients in the cohort also received radiation therapy. Dose to the target organ was estimated from individual radiotherapy records. Evaluations of the risk of secondary cancer as a result of treatment with cyclophosphamide alone, radiation alone or both therapies were made relative to those