The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.
Subgroups with different survival expectancy can be identified among patients who are eligible for phase I clinical trials. If confirmed, the proposed prognostic model may be useful for therapeutic decision making in palliative oncology.
168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)
Our study indicated that in combination with weekly administered cisplatin amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of amifostine did not compromise the antitumor effect of cisplatin.
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