Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality pf the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment

LONG-TERM FOLLOW-UP OF NONSEMINOTAMOUS TESTICULAR CANCER-PATIENTS WITH MATURE TERATOMA OR CARCINOMA AT POSTCHEMOTHERAPY SURGERY

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.</p