Multicenter randomized phase III trial of Epirubicin plus Paclitaxel vs Epirubicin followed by Paclitaxel in metastatic breast cancer patients: focus on cardiac safety

Abstract

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.

Cardiac Complications of Cancer Treatment

“…[2,22,23] Docetaxel shows no increase in cardiac toxicity when combined with doxorubicin. This is in line with the observation that a pharmacokinetic interaction with doxorubicin as described for paclitaxel has not been observed.…”

“…This evident time relationship and the fact that most patients had no cardiac risk factors supports the assumption of causality between paclitaxel and the observed cardiac rhythm disturbances. [2,22,23] Another concern with the use of taxoids has been the development of congestive heart failure in patients treated with a combination of doxorubicin and taxoids. The cardiotoxicity associated with taxoids seems to be mild in most cases.…”

“…Cardiac risk factors included unstable angina, severe coronary artery disease, congestive heart failure and atrial fibrillation. [2,22,23] Paclitaxel is formulated in a cremophor EL vehicle to enhance the drug solubility and it is suggested that the vehicle and not the cytotoxic drug itself is responsible for the cardiac disturbances. However, the cardiac rhythm disturbances are not reported with use of other drugs containing cremophor EL such as cyclosporin.…”

“…[2,22] A similar effect has been shown for epirubicin. Baldini et al [23] evaluate cardiac safety of two different schedules of epirubicin and paclitaxel in advanced breast cancer. Patients were enrolled into a multicenter randomized phase III trial.…”

Biocatalytic Synthesis of Chiral Pharmaceutical Intermediates

“…The presence of the C-8 keto group gave an interesting intramolecular chemistry to afford a compound with a novel pleuromutilin-derived 35 ring system, which was achieved by acid-catalyzed conversion of C-8 ketopleuromutilin. the formation of the spindle during cell division (35)(36)(37)(38)(39). Paclitaxel inhibits the depolymerization process of microtubulin (39,40).…”