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Biomedical subjects

B Greifenberg

Publications and source records attributed to B Greifenberg.

6 recordsLinked to original sources
PubMed1995

Pharmacokinetics of 4'-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer.

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4'-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m2 THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t1/2 alpha), 3.15 min; terminal elimination half-life (t1/2 gamma), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml-1mg-1 m-2, resulting in a mean plasma clearance of 86.9 1h-1 m-2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4'-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadriamycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r = 0.800, P < 0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.

Adult↗
PubMed1991

Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group.

Doxorubicin and ifosfamide are the two most active agents used in the treatment of advanced inoperable soft-tissue sarcoma, but their use in combination produces dose-limiting myelosuppression. To explore the feasibility of combining optimal doses of both drugs, doxorubicin (75 mg/m2) and ifosfamide (5 g/m2) were given every 3 weeks with recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF; 250 micrograms m-2 day-1) by subcutaneous injection for up to 14 days after each course. A total of 52 patients with progressive metastatic soft-tissue sarcoma were entered, none having received prior chemotherapy. One patient was ineligible and received no treatment after registration. Preliminary analysis of six cycles of chemotherapy revealed that the full protocol dose intensity had been administered to the majority of patients. Although the median leucocyte and neutrophil counts did not fall with subsequent courses of chemotherapy, the duration of neutropenia increased with each course delivered. Cumulative thrombocytopenia was a major dose-limiting toxicity and was the main reason for any dose modifications that occurred. Although 26 patients experienced infections after one or more courses of treatment, in only 7 was admission required for parenteral antibiotics. One patient died as a result of septicaemia after the first cycle of treatment. To date, there have been 22 responses (43%) with 8% complete remissions. It appears that the administration of rhGM-CSF allows this high-dose regime of chemotherapy to be given safely and the early encouraging response rate adds support to the concept that increasing the dose of doxorubicin improves the outlook for patients with advanced soft-tissue sarcomas.

Adult↗
PubMed1991

New therapeutic modalities for the clinical use of rhGM-CSF in patients with malignancies.

Data from several clinical trials in patients with solid tumors clearly demonstrate that recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) is able to shorten the time period of neutropenia after chemotherapy and to reduce neutropenia-related morbidity such as infections, time in hospital, etc. A placebo-controlled, double-blind multicenter trial including 81 patients with acute lymphoblastic leukemia and non-Hodgkin's lymphoma demonstrates the efficacy of rhGM-CSF to enhance engraftment (neutrophils greater than 0.5 x 10(3)/mm3) after autologous bone marrow transplantation (p less than 0.001) and to reduce the frequency of bacterial infections (34% vs. 56%). In addition, GM-CSF is able to shift the cell cycle of myeloid leukemic cells from the G0 to S phase in vitro and in vivo, which results in an increased sensitivity to cell-cycling-dependent cytostatic agents. Dose intensification of chemotherapy in patients with soft tissue sarcoma and metastatic breast cancer is possible due to adjuvant treatment with GM-CSF and results in a higher frequency of remissions. Further controlled clinical studies are warranted to support these results.

Animals↗
PubMed1990

Phase I study with combination therapy of pirarubicin, etoposide, and vincristine in small-cell lung cancer.

The toxicity and efficacy of the combination of pirarubicin (THP), etoposide, and vincristine were investigated in a phase I trial. The dose of THP was modified in steps of 10 mg/m2 or 5 mg/m2 differences, starting with 40 mg/m2 i.v. on day 1. Doses of etoposide (100 mg/m2 i.v. days 1-3) and vincristin 2 mg i.v. day 1) remained constant. The schedule was repeated every 3 weeks. A minimum of four patients were recruited at each dose level. The maximum tolerated dose (MTD) was defined as follows: toxicity WHO grade 3 and 4 in five of eight patients of one dose step (exception: leukocytopenia at the time of nadir WHO grade 4 is relevant for the MTD). Currently, 20 patients have been treated. The administered dose levels of THP were (mg/m2); 40 (5 patients), 50 (4 patients), 55 (6 patients), and 60 (5 patients). Screening of cardiac function (ECG, ultrasound cardiography) was performed at the start of the treatment and before each course. There were no signs of cardiotoxicity up to a cumulative dose of 360 mg/m2. Leukocytopenia WHO grade 3 was observed in seven courses (12%), and grade 4 was observed in two courses (3%) as main side effects. The subjective tolerability (nausea, vomiting, and alopecia) was mild to moderate. We decided upon 55 mg/m2 MTD because WHO grade 4 leukocytopenia developed in one patient after the first course and two not conclusively clarified early deaths occurred at the 60 mg/m2 pirarubicin dose level. Eighteen patients were evaluable for response: one CR (6%), eight PR (44%), four NC (22%), one EP (6%), and four ED (22%). This means a response rate of 50% and a median survival time of 10 months. We have initiated a phase II study with the elaborated schedule.

Adult↗
PubMed1990

Phase II study of pirarubicin in metastatic breast cancer.

Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

Adult↗