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  • 1
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A 5-day continuous infusion of vincristine (VCR; total dose 4 mg/m2) has been given as part of a high-dose chemoradiotherapy regimen with bone marrow transplantation. Evidence of neurotoxicity, such as weakness, paraesthesia and intestinal hypomotility, was evaluated prospectively in nine patients. Five patients had advanced neuroblastoma and four, relapsed sarcomas, and all had responded to initial conventional-dose therapy. VCR was combined with high-dose melphalan (180 mg/m2) and fractionated total-body irradiation. Plasma concentrations of VCR were measured by radioimmunoassay during and up to 24 h after the infusion. Serum and urine electrolytes and liver function tests were measured during VCR treatment and at regular intervals thereafter. VCR concentration at 1 h ranged from 1.8 to 10.9 (median 6.6) ng/ml, and a steady state was achieved by 13–30 h (median 16 h). Levels above 1 ng/ml were maintained throughout the 5-day period with a mean steady-state concentration of 1.7 ng/ml (range 1.3–2.15). After cessation of the infusion, serum concentrations fell to below 0.25 ng/ml within 24 h. Abdominal pain occurred in one patient, but neither constipation nor ileus was seen. In two patients severe muscle pain occurred in the lower limbs towards the end of the infusion. Significant electrolyte problems did not occur and, in particular, there was no evidence of inappropriate ADH secretion. Transient increases in liver enzymes were common but bilirubin was not elevated during the period of monitoring. This regimen allows a two-fold escalation in the dose of VCR to be administered, producing sustained high serum drug levels without major toxicity.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I–II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III–IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2×300 to 2×500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination halflives of 4.15±2.57 and 28.8±12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96±2.89 to 12.22±3.95 mg l−1h. Drug clearance was independent of the dose given and equal to 109±65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r=0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1569-8041
    Keywords: palliative care ; phase I clinical trial ; retrospective study ; survival ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Patients with advanced solid tumors may be includedin phase I clinical trials. In such studies, the benefit expected is generallylower than the likelihood of toxicity and may even be non-existent if thepatient's life expectancy is too short. This study was performed to identifyprognostic variables for toxicity and survival in patients who participate inphase I clinical trials. Patients and methods:One hundred fifty-four patients treated ona phase I clinical trial in our institute were evaluated retrospectively.Univariable and multivariable analyses of patients' characteristics wereundertaken to determine their effects on the probability of grade 3 and 4toxicity and on survival. Results:Grade 3 or 4 toxicity was experienced by 56 patients(36%): dosage level at entry (P 〈 0.001) and age over 65years (P = 0.03) were independently associated with the risk oftoxicity. Median overall survival was 5 months. The multivariable analysisidentified performance status 2 or 3 (P 〈 0.001) and lactatedehydrogenase levels greater than 600 UI (P 〈 0.001) asindependent adverse prognostic variables for overall survival. Using these twoparameters, we determined a prognostic index which allowed us to discriminatethree risk groups of patients with an observed median survival of 8.5, 4.5 and1.5 months, respectively. Conclusions:Subgroups with different survival expectancy can beidentified among patients who are eligible for phase I clinical trials. Ifconfirmed, the proposed prognostic model may be useful for therapeuticdecision making in palliative oncology.
    Type of Medium: Electronic Resource
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