No abstract

Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m(2), thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m(2) is reached, concomitantly with the presence of an additional cardiac risk factor.

BACKGROUND The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression‐free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7–12.3) and 20.0 months (95% CI, 17.2–22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9–13.6) and 26 months (95% CI, 18.1–33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade ≥ 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options. Cancer 2004. © 2004 American Cancer Society.

Aims To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism. Methods Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m x2 i. . Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (E max ) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined. Results An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 mmol l ) of epirubicin followed by paclitaxel 30 h later. An E max relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 mmol l x1 (tC 0.1 ). The tC 0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood. Conclusions Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the E max relationship between neutropenia and tC 0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.

No abstract

The results of the present study indicate that the addition of G to E plus T as front line treatment for advanced breast cancer is well tolerated with an ORR of 92%. On the basis of the high activity and interesting progression free and overall survival rates, the GET combination deserves further evaluation in randomized trials.

The aim of the study was to evaluate cardiac safety of two different schedules of Epirubicin and Paclitaxel in advanced breast cancer patients enrolled into a multicenter randomized phase III trial. Patients received Epirubicin 90 mg m À2 plus Paclitaxel 200 mg m À2 (3-h infusion) on day 1 every 3 weeks for eight courses (arm A), or Epirubicin 120 mg m À2 on day 1 every 3 weeks for four courses followed by four courses of Paclitaxel 250 mg m À2 on day 1 every 3 weeks (arm B). Left ventricular ejection fraction was evaluated by bidimesional echocardiography at baseline, after four and eight courses of chemotherapy and every 4 months during follow-up. Baseline median left ventricular ejection fraction was 60% in arm A and 65% in arm B; after four courses, figures were 57 and 60%, respectively. After eight courses, the median left ventricular ejection fraction in arm A declined to 50% while no further reduction was detected in arm B by adding four courses of high-dose Paclitaxel. Seven episodes of congestive heart failure were observed during treatment in arm A. Present monitoring demonstrated that the risk of congestive heart failure or impairment in the cardiac function correlated only with the cumulative dose of Epirubicin; no impact on cardiotoxicity can be attributed to high-dose Paclitaxel.