Pharmacokinetic and Toxicity Evaluation of Five-Day Continuous Infusion versus Intermittent Bolus cis-Diamminedichloroplatinum(II) in Head and Neck Cancer Patients

We administered cis-diamminedichloroplatinum(II) 30 mg/m2/day for 5 days by continuous infusion to six patients with head and neck cancer, and compared the total and filterable plasma concentrations of platinum, and toxic effects, with those observed in five additional patients who received the same dose and schedule of cis-diamminedichloroplatinum(II) by intermittent bolus. In the continuous infusion group, the total 5-day exposure to filterable platinum, determined from the area under the concentration-time curve, was 1.5 to 2-fold higher (P < 0.01) than that observed in the intermittent bolus group although the maximum filterable platinum concentration achieved was 8-fold lower (P < 0.01). These differences were not reflected by total platinum levels. Subclinical nephrotoxicity, as judged by monitoring the urinary excretion of the renal enzymes N-acetyl-β-D-glucosaminidase and alanine aminopeptidase, as well as ototoxicity, and the incidence and severity of nausea and vomiting were similar in both groups. In contrast, myelosuppression, and hypomagnesemia were more frequent in the continuous-infusion patients, suggesting that the total exposure to free platinum contributes more to these toxicities than peak levels achieved. Considering the clinically acceptable toxicity observed after administration by continuous infusion, we recommend larger therapeutic trials to define the efficacy of increased tumor exposure to filterable platinum.