Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma.

AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma.

Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours.

A pharmacokinetic-pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration-time curve (AUC) values of 21 or 20 mg ml(-1).min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum-DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80-126% of target AUC values, as compared to estimated exposures of 65-213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum-DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug-target interaction.

Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma - a study of the United Kingdom Children's Cancer Study Group.

The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m(-2) b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h(-1), apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (P<0.02), with 2.44- and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (mean+/-s.d. 4.67+/-3.17 microM) higher than those of 13-cisRA (2.83+/-1.44 microM) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA.