Epirubicin

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Abstract
Epirubicin, an anthracycline antitumour antibiotic which is structurally related to doxorubicin, is among the most active single agents used in the management of patients with breast cancer. The drug may be administered alone or in combination with other agents both to patients with early breast cancer and to those with metastatic disease. There is a clear relationship between epirubicin dose and tumour response. Dose intensified regimens have produced improved response rates in patients with advanced breast cancer compared with standard dose therapy; however, improved overall survival has not yet been demonstrated. The combination of epirubicin with newer agents such as vinorelbine or paclitaxel shows considerable promise, as does the use of epirubicin in high dose regimens with peripheral blood progenitor cell support. The major adverse effects of epirubicin are acute dose-limiting haematological toxicity and cumulative dose-related cardiac toxicity. These effects are less severe after epirubicin administration than after equimolar doses of doxorubicin. Other major adverse effects of epirubicin administration include mucositis, nausea and vomiting, reversible alopecia and local cutaneous and vesicant reactions. In summary, epirubicin has an established role in the treatment of both early and advanced breast cancer. In combination with other highly active agents or in dose intensified regimens administered with haemopoietic growth factor and/or peripheral blood progenitor cell support, epirubicin may play a significant role in emerging breast cancer treatment strategies. The pharmacodynamic properties of epirubicin are similar to those of other anthracycline antitumour antibiotics. Epirubicin is most active in S and G2 phases of the cell cycle, although the drug exhibits activity in all phases of the cell cycle. After intercalation between DNA base pairs, epirubicin stabilises the topoisomerase II-DNA complex, resulting in irreversible DNA strand breakage. Epirubicin is cytotoxic in vitro and in vivo to breast cancer and other human tumour cells, and cell kill increases with increasing drug concentration. Tumour resistance to epirubicin and cross-resistance between epirubicin and other antineoplastic agents may occur as a result of several mechanisms, particularly P-glycoprotein—mediated multidrug resistance. A number of drugs, including lonidamine, verapamil, quinidine and tamoxifen attenuate in vitro epirubicin resistance. In clinical studies, lonidamine administered with epirubicin improved response rates, but not survival; the addition of verapamil or quinidine did not improve outcomes. Epirubicin is toxic to mammalian haemopoietic cells and cardiac tissue. In vitro, epirubicin causes less haematological and cardiac toxicity than equimolar doses of doxorubicin. The iron chelator dexrazoxane reduced epirubicin-induced cardiac damage in rats. After bolus intravenous administration, epirubicin undergoes triphasic elimination from the plasma. Its terminal plasma elimination half-life in patients with cancer is 18 to 45 hours. The drug has a large volume of distribution and is concentrated in a variety of normal and cancerous tissues. Epirubicin undergoes extensive hepatic metabolism to epirubicinol and aglycone and glucuronide metabolites. Predictably, plasma clearance is reduced in patients with hepatic dysfunction. Six to 7% of epirubicin is eliminated renally as unchanged drug, and approximately 35% of an administered dose undergoes biliary excretion. The pharmacokinetics of epirubicin and doxorubicin are similar, although epirubicin is metabolised by different pathways and has a shorter terminal plasma elimination half-life than doxorubicin. Mean area under the plasma concentration-time curve (AUC) values for doxorubicin are higher by a factor of 1.3 to 1.7 than AUC values for equimolar doses of epirubicin. Objective response rates to standard doses of epirubicin monotherapy (≤90 mg/m2 every 3 weeks) in previously treated patients with advanced breast cancer ranged from 16 to 50%. The combination of epirubicin with newer antineoplastics such as paclitaxel or vinorelbine in small, noncomparative studies in patients with advanced breast cancer has produced promising preliminary results (response rates 44 to 83%). A clear relationship exists between epirubicin dose and response rate; however, improved survival as a result of dose intensification [with or without haemopoietic growth factor (HGF) support] has not yet been demonstrated in patients with early breast cancer. Few comparative studies with epirubicin or other agents in patients with advanced breast cancer have demonstrated significant survival differences between treatment groups; median survival in these patients is generally less than 2 years. Epirubicin 50 to 75 mg/m2 plus cyclophosphamide and fluorouracil (FEC) administered as single doses every 3 weeks is an active and well-studied regimen in patients with advanced breast cancer. FEC is at least as active as the combination of cyclophosphamide, methotrexate and fluorouracil (CMF); it has produced better objective response rates in some studies and superior relapse-free survival in subgroups of patients in other studies. FEC and CMF have similar effects on quality of life. Patients with metastatic breast cancer who have received prior adjuvant chemotherapy respond less well to chemotherapy for metastatic disease, although the type of regimen (FEC or CMF) administered in the adjuvant setting does not seem to affect response rates. In equimolar or equimyelosuppressive doses, alone or in combination with other agents, epirubicin and doxorubicin produced similar response rates and survival in patients with advanced breast cancer. Patients who fail to respond to first-line chemotherapy for advanced breast cancer may respond to salvage therapy, but response rates are generally below 10%. In noncomparative...