Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Paclitaxel (Taxol) efficacy in patients with advanced breast cancer resistant to anthracyclines.

We assessed the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered by 3-hour intravenous infusion in 15 patients with advanced breast cancer resistant to anthracyclines. Paclitaxel was administered at 175 mg/m2. In the event of severe toxicity, dose reductions to 150 or 125 mg/m2 could be made; otherwise, the dose was subsequently increased to 200 mg/m2. Patients received a median of five cycles of treatment (range, one to nine cycles). Paclitaxel induced three complete responses and four partial responses, for an overall response rate of 47%. The most frequently observed toxicities associated with paclitaxel administration were neutropenia and alopecia, which occurred in all patients. The frequency and severity of the observed toxicities were never of clinical concern. We conclude that paclitaxel is active in breast cancer patients clinically resistant to anthracyclines and that it can be safely administered by 3-hour infusion with standard premedication. Considering the good tolerability, higher doses of paclitaxel in advanced breast cancer should be explored.

New active drugs in the treatment of lymphomas.

Lymphomas include a vast number of pathologic conditions in which the search for new active drugs follows different routes. Hodgkin's disease and high-grade non-Hodgkin's lymphoma are very sensitive to chemotherapy, responding well to existing regimens; the inability to cure seems to be caused by acquired drug resistance. Newer strategies using classic chemotherapeutic agents and the use of modulators of resistance are the main focus of research in these malignancies. For indolent lymphomas, the inability to cure may be caused by the difficulty in eradicating completely an apparently sensitive disease. The search for new drugs in this field has focused on chemotherapeutic agents with new mechanisms of action, among which the purine analogues are the most important novelty, and on biologic therapy. There is evidence of activity of drug targeting, using monoclonal antibodies, immunotoxins, and radioimmunotherapy. Their role in the treatment of these malignancies will probably be different from that of traditional drugs, perhaps in the context of eradication of minimal residual disease after effective conventional therapy.