In several cohort studies of germ-cell tumours in men, treatment with etoposide, cisplatin and bleomycin was associated with an increased risk for acute myeloid leukaemia. A strongly increased risk for acute myeloid leukaemia was also found in one cohort study of lung cancer patients treated with etoposide, cisplatin and vindesine. The possibility cannot be excluded that etoposide exerts its effects only in the presence of other cytotoxic agents. In these studies, the possibility cannot be excluded that the excess leukaemia risk was partly or wholly due to the other agents. No increase in the incidence of leukaemia was observed.
Preliminary studies suggest that the remainder of the dose is excreted in the faeces.
Biphasic elimination is seen in a number of animal species. Glucuronide metabolites have been reported in the urine of rabbits and rats. Oxidation of etoposide to quinone species and a catechol metabolite have been reported in cell systems, occurring either by peroxidase oxidation or cytochrome P450-mediated demethylation involving CYP3A4. These oxidation products have cytotoxic activity, but it is unclear how much they contribute to the activity of etoposide. The major dose-limiting toxic effect of etoposide in humans is myelosuppression, manifest principally as leukopenia.