Iron chelation with deferoxamine: comparing the results of a critical pathway to a national survey.

PURPOSE: The clinical outcomes of an institution's critical pathway that uses a comprehensive approach to serum ferritin management are reported. The results of this center are compared with the results of a national survey of deferoxamine (DFO) use and serum ferritin level outcomes. METHODS: Current DFO dosing and serum ferritin levels of 38 patients at this center were summarized. A questionnaire was then sent to 98 centers throughout the United States requesting information on criteria for beginning treatment with DFO, administration methods, dose modifications, and serum ferritin levels. RESULTS: The application of a critical pathway in this program resulted in 29 of 38 patients maintaining serum ferritin levels <2,000 ng/mL. Of the 42 institutions that responded to the survey, 10 attained this ferritin level in > or =50% of their patients. Ferritin levels ranged from 500 ng/mL to >20,000 ng/mL, and wide variations were reported in all study parameters. CONCLUSIONS: Iron overload can be effectively managed with alteration of DFO doses and routes using a consistent approach. Modification of administration methods, including administration of DFO during red blood cell transfusions, are indicated to attain ferritin levels of <2,000 ng/mL.

Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group.

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.

Murine neuroblastoma: further evaluation of the C1300 model with single antitumor agents.

The murine C1300 neuroblastoma model has been evaluated as a possible model for children with widespread metastatic disease. Drug toxicity studies were conducted in adult A/J mice with various doses of antitumor agents. Adriamycin, BCNU, bleomycin, guanazole, acronycine, isophosphamide, DTIC, ICRF-159, cyclophosphamide, vincristine, and vinblastine were adminstered intraperitoneally to random groups of normal mice. After identification of appropriate doses, chemotherapy studies were conducted with varius regimens of drugs. Chemotherapy was administered to adult A/J mice when their subcutaneously implanted tumors measured 1.0-1.7 cm in diameter. Antitumor drugs can be classified into three groups according to drug efficacy. BCNU, cyclophosphamide, and isophosphamide were extremely active. Cytosine arabinoside was reported to be active against this murine tumor in a previous publication. Drugs with minimal activiyt which deserve further evaluation included adriamycin, guanazole, ICRF-159, DTIC, and vinblastine. Inactive drugs were acronycine, bleomycin, 5-fluorouracil, and vincristine. These experiments suggest that children with metastatic neuroblastoma may respond to cyclophosphamide, isophosphamide, and BCNU, while DTIC, adriamycin, ICRF-159, guanazole, and the vinca alkaloids may also be effective. The results suggest that agents selected by the C1300 model should be given adequate clinical trials.