Epirubicin

Abstract

Epirubicin is a semisynthetic derivative of doxorubicin which has been extensively evaluated in patients with breast cancer. It is effective in the management of metastatic disease and as adjuvant therapy in patients with early breast cancer. In the adjuvant setting, epirubicin-based therapy appears to have efficacy at least equivalent to that of the standard therapy cyclophosphamide, methotrexate and fluorouracil (CMF), with the most recent trials, predominantly in premenopausal patients, reporting significant gains in relapse-free survival and overall survival for epirubicin-based vs CMF therapy. In a single trial, the 5-year relapse-free survival of postmenopausal patients receiving long term hormonal therapy (tamoxifen) was significantly increased when epirubicin was added as singleagent chemotherapy and compared with tamoxifen alone. In patients with metastatic disease, epirubicin- and doxorubicin-containing regimens (with cyclophosphamide and fluorouracil; FEC and FAC) are therapeutically equivalent. Increasing the dose of epirubicin appears to improve response rates in patients with either metastatic or early disease but, with the exception of 1 adjuvant study, improved overall survival has not been demonstrated. Quality of life (QOL) has yet to be adequately evaluated with epirubicin. The major adverse effects of epirubicin are acute dose-limiting haematotoxicity and cumulative dose-related cardiotoxicity. Other important adverse effects include mucositis, nausea and vomiting, reversible alopecia and local cutaneous reactions. However, the tolerability of epirubicin is better than that of doxorubicin at equimolar doses. Conclusion: Epirubicin has been extensively investigated in patients with breast cancer and has been found to be a highly effective agent, both for the treatment of patients with metastatic disease and as an adjuvant therapy. Recent trials have confirmed that, in selected patients requiring adjuvant therapy, FEC therapy is at least as effective as CMF, a standard treatment. FEC is also therapeutically equivalent to FAC in patients with metastatic breast cancer, and because the therapeutic index appears to be better the opportunity exists to increase dose intensity in an effort to improve efficacy. Such trials, and those of combinations of epirubicin with newer or alternative agents, should result in the introduction of more effective and better tolerated epirubicin-based protocols for adjuvant therapy and the management of patients with advanced breast cancer. In the meantime there is sufficient evidence to justify consideration of epirubicin for inclusion in first-line therapies for patients with early or metastatic breast cancer. The antitumour activity of epirubicin, like that of other anthracyclines, is thought to result from intercalation between DNA base pairs and stabilisation of the topoisomerase II-DNA complex, leading to irreversible DNA strand breakage. The cytotoxicity of epirubicin in a variety of human tumour cell lines in culture increases exponentially with drug concentration and duration of exposure. Epirubicin has shown equivalent cytotoxic effects to doxorubicin in human breast tissue in vitro and in various human tumour cell xenograft models in mice, including a number of human breast cancer cell lines. In addition, epirubicin and paclitaxel have demonstrated an additive effect against a breast cancer cell line in a human xenograft model. Epirubicin administered with granulocyte colony-stimulating factor (G-CSF) only, or with G-CSF plus paclitaxel, docetaxel or fluorouracil and cyclophosphamide is effective at mobilising stem cells in patients with breast cancer. The number of CD34+ cells collected per patient during leukapheresis ranged from 2.8 to 14.6 × 10⁶/kg with epirubicin 90 to 200 mg/m². The target level of CD34+ cells was generally reached after 2 apheresis procedures. Cellular resistance to epirubicin and other anthracyclines may occur via a number of proposed mechanisms including P-glycoprotein-mediated resistance, changes in topoisomerase II activity, increased levels of intracellular glutathione or glutathione-S-transferase, induction of heat shock proteins and blockade of apoptopic pathways. However, studies of methods of predicting or preventing resistance that are based on this information have had mixed results. The clinical use of anthracyclines may be limited by adverse haematological and cardiac effects, but on an equimolar basis epirubicin is less myelo- and cardiotoxic than doxorubicin. However, the drugs are administered at equimyelotoxic dosages clinically and at these dosages noncardiac-related toxicities are also equivalent. Epirubicin undergoes triphasic elimination from the plasma after intravenous administration [terminal phase of the plasma elimination half-life (t½γ)is 18 to 45 hours]. It has a large volume of distribution and high concentrations are reached in a number of tissue types as well as in red blood cells. Epirubicin is extensively and rapidly metabolised in the liver to epirubicinol and aglycone and glucuronide metabolites, all of which appear to lack cytotoxic effects at concentrations attained in vivo. The area under the plasma concentration-time curve (AUC) of epirubicin is linearily related to dose and for doses of 60 to 150 mg/m² ranged from 1600 to 4200 μg/L • h. As expected from the prominent hepatic metabolism of epirubicin, plasma clearance of the drug is reduced in patients with hepatic dysfunction. The pharmacokinetic profile of epirubicin is not affected by the presence of renal failure. After administration of epirubicin, approximately 11 to 15% of the dose is excreted unchanged or as metabolites in the urine in the urine. Around 35% of an administered dose of epirubicin undergoes biliary excretion after hepatic metabolism. Although the pharmacokinetics of epirubicin are similar to those of...