High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m−2 day−1), thiotepa (80 or 120 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) (CTC) for 4 consecutive days. The area under the plasma concentration–time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity

High-dose chemotherapy with peripheral blood progenitor cell transplantation in the adjuvant treatment of breast cancer

High-dose chemotherapy as adjuvant treatment for high-risk breast cancer has been and is being investigated in a series of randomized trials. The preliminary information from 5 studies is difficult to interpret. The data are consistent with a modest benefit of high-dose therapy, but strong evidence for this is lacking. Additional follow-up and the results of several large trials outside the United States are awaited. Hitherto unrecognized pharmacologic interactions between high-dose agents and long-term to toxicities sub as cognitive function impairment complicate the issue considerably

High-dose chemotherapy with peripheral blood progenitor cell transplantation in the adjuvant treatment of breast cancer

High-dose chemotherapy as adjuvant treatment for high-risk breast cancer has been and is being investigated in a series of randomized trials. The preliminary information from 5 studies is difficult to interpret. The data are consistent with a modest benefit of high-dose therapy, but strong evidence for this is lacking. Additional follow-up and the results of several large trials outside the United States are awaited. Hitherto unrecognized pharmacologic interactions between high-dose agents and long-term to toxicities sub as cognitive function impairment complicate the issue considerably