Clinical and pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients.

A phase I and a pharmacokinetic study of 96-h infusions of doxorubicin were performed in order to evaluate the maximum tolerated dose with this schedule of administration. Seventeen patients suffering from a digestive carcinoma were included in the study and a total of 71 courses of treatment were performed. The starting dose was 15 mg/m2/day and was increased in 2.5 mg/m2/day increments. The main toxicities observed were neutropenia and mucositis, which became limiting from 22.5 mg/m2/day (90 mg/m2 over a 96-h period); this dose was therefore defined as the maximal tolerated dose. No objective response to treatment was observed. For further studies, the recommended dose should not exceed 20 mg/m2/day. A plasma plateau concentration of doxorubicin was reached within 24 h. Despite a constant infusion rate, the plasma concentration of doxorubicin showed transient variations in several patients. However, an average plasma concentration could be evaluated for 33 courses of treatment, and this was linearly related to the dose. Doxorubicinol was the only detected metabolite of doxorubicin and its plasma concentration progressively increased throughout infusion. A detailed pharmacokinetic study was performed in 13 courses of treatment. The mean plasma clearance of doxorubicin was 25.2 l/h/m2 and the mean terminal half-lives of doxorubicin and doxorubicinol were respectively 43.6 and 66.2 h. Urinary excretion of doxorubicin plus metabolite was regular from the 24th to the 96th hour of infusion; however, the proportion of doxorubicinol progressively increased in urine. The protracted half-life of this metabolite probably explains its accumulation during infusion.

[Results of a sequential polychemotherapy (adriamycin, vincristine, cyclophosphamide, methotrexate) in small-cell and undifferentiated bronchial cancer]. / Résultats d'une polychimiothérapie séquentielle (adriamycine, vincristine, cyclophosphamide, méthotrexate) à petites cellules et indifférenciés.

40 patients suffering from inoperable bronchial cancer (25 anaplastic cancers, 15 undifferentiated cancers) were treated by a sequential association (Adriamycinee, Vincristine, Cyclophosphamide, Méthotrexate), repeated every 5 weeks. 28 patients already had metastatic cancer. A partial objective response (regression greater than 50%) was observed in 7 undifferentiated cancers and 14 anaplastic cancers. The treatment was interrupted 3 times for digestive and/or hematological toxicity; however, no deaths due to toxicity were reported. The mean survival is 8 months and 5 patients live for more than 18 months. The immediate effectiveness and mean survival place this protocol among polychemotherapies presently considered for this type of cancer. The number of evolutive recoveries observed during the maintenance stage settles the problem of the use of an efficient, slightly toxic and durable chemotherapy.