Orally active antitumour agents, patient compliance and clinical trials

Abstract

The first part of this project is concerned with non-compliance with drug therapy in breast cancer patients. It is assumed that cancer patients are highly motivated by fear of their disease and by the associated symptoms. This work attempted to evaluate the level of non compliance in breast cancer patients taking tamoxifen and to determine the factors pre-disposing some patients to non-compliant behaviour. A structured questionnaire was developed and used to interview 151 patients in three different types of outpatient clinic. Nineteen (13%)patients were found to have stopped therapy at some stage. The reasons for non-compliance included side effects, having no faith in therapy,lack of comprehension and memory problems. These results suggest patients suffering from breast cancer are not fully compliant. The second part of the project continued previous work on the pharmacokinetics of mitozolomide, an imidazo (5, 1-d}-1,2,3,5, tetragin-4(3H)one undergoing a phase I/II clinical trial. Mitozolomide was administered orally to eighteen patients at a dose of 90 mg/m? to determine the activity of the drug at this dose, to extend the knowledge on the toxicity profile of the drug and to confirm the essential pharmacokinetic parameters, established in the phase I trial. A reversed phase high performance liquid chromatography method was used to assay drug levels in patients' plasma. Results indicated that the oral dose of the drug given bore no relation to the amount of drug absorbed nor to the peak plasma level attained. The bioavailability of the drug was found to vary between 25% and 100% and absorption could be delayed up to 1.8hours. 22% of patients experienced a severe thrombocytopaenia; this toxicity could not be related to the pharmacokinetics of the drug. The lack of correlation between toxicity and the pharmacokinetics of the drug could limit the clinical usefulness of mitozolomide.