CIS-DIAMMINEDICHLOROPLATINUM(II) GIVEN IN LOW-DOSE CONTINUOUS-INFUSION WITH CONCURRENT RADIOTHERAPY TO PATIENTS AFFECTED BY INOPERABLE LUNG-CARCINOMA - A PHARMACOKINETIC APPROACH

The pharmacokinetics of cis-diamminedichloro platinum(II) (cisplatin), given as a continuous infusion with concurrent radiotherapy to patien ts with locally advanced inoperable non-small-cell lung carcinoma, was investigated in 16 cases. The regimen, repeated for 6 consecutive wee ks, consisted of weekly 10-Gy radiotherapy given in five fractions fro m Monday to Friday, and concurrent 100-h infusion of cisplatin deliver ed at a daily dose of 4 mg/m(2) by a central venous catheter and a por table pump. Throughout the weeks of therapy the platinum levels were d etermined in plasma and in ultrafiltered plasma by respectively induct ively coupled plasma atomic emission spectrometry and inductively coup led plasma mass spectrometry. Mean levels of platinum in plasma ([Pt]( tot)) increased from the 1st to the 6th week of infusion, while mean l evels of platinum in ultrafiltered plasma ([Pt](uf)), 110 mu g/l, show ed no marked variation throughout the therapy. [Pt](uf) ranged from 16 % to 22% of the total Pt. Mean levels of Pt in ultrafiltered plasma we re of the same order of magnitude as those found to be active invitro as radiopotentiators. Pt decay levels were measured for 24 h at the en d of the 1st and 5th weeks of infusion, allowing the calculation of th e Pt half-life and the area under the decay curves. The mean value of the area under the decay curve, plotting [Pt](tot) against time (AUG), in the range 0-24 h from the end of the 5th week of infusion, was abo ut twice that from the end of the Ist week; by contrast, the mean AUC values did not vary for the [Pt](uf) against time curves. The mean val ues of the alpha half-life of Pt in the ultrafiltered plasma were in a ccordance with those published in the literature; however, an unexpect ed very long beta half-life was found (more than 100 h). Thus it was s uggested that Pt species other than free cisplatin were present in the ultrafiltered plasma; such species probably involve metal bound to lo w-molecular-mass proteins. Throughout the therapy, the toxic effects i n all patients were negligible, and 75% of them had an objective locor egional reduction of disease. In only 2 cases was progression of disea se observed within the irradiated area. On the basis of these data, it can be concluded that cisplatin at a level of 110 mu g/l in the ultra filtered plasma, in the reported scheme of continuous intravenous infu sion, has an enhancing effect on radiation and avoids concentration pe aks of platinum not bound to protein.