Phase I study of the combination of monthly carboplatin and weekly cisplatin

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Abstract
Two cycles of the combination of carboplatin (C), given every 4 weeks with weekly doses of cisplatin (P), were administered on an outpatient basis to 28 previously untreated patients. One cycle consisted of one dose of C and 4 doses of P. The toxicity of 250 mg/m2 of C, combined with escalating doses of P (20, 30, 35, 40 mg/m2) was evaluated first. Thrombocytopenia was dose-limiting and cumulative. At the dose level of 40 mg/m2 of P, the median Pt nadirs during the first and second cycles were 190 (range: 44 to 232) x 103/μL and 90 (range: 15 to 165) x 103/μL, respectively. The median delivered dose intensity (DI) of P was 40 mg/m2/wk in the first cycle and 40 mg/m2/wk in the second cycle. In the second part of the study, 40 mg/m2 of P were combined with a C dose adapted to individual renal function according to the formula dose (mg) AUC x (GFR + 25) where AUC - 4.5 mg/mL/min. The administration of doses of C ranging from 219 to 493 mg/m2 was associated with a more severe and more variable thrombocytopenia, more frequent P delays and decrease of the median delivered DI of P (first cycle: 33 mg/m2/wk; second cycle: 32 mg/m2/wk). At all dose levels, leukopenia was mild to moderate, and neurotoxicity and severe GI toxicity were absent. No significant reductions of the creatinine clearance values were observed. All patients treated at 40 mg/m2 of P suffered from cumulative subjective toxicity during the second month of therapy. A maximum of 2 monthly doses of 250 mg/m2 of C and 8 weekly doses of 40 mg/m2 of P can be safely given on an outpatient basis. This short intensive regimen can be used as induction or neoadjuvant treatment for rapidly growing platinum-sensitive tumours.