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Epirubicin

A Review of its Efficacy as Adjuvant Therapy and in the Treatment of Metastatic Disease in Breast Cancer

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Summary

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.

Pharmacodynamic Properties

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.

Pharmacokinetic Properties

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 doxorubicin the differences are important. Epirubiamericancin has a shorter t½γ than doxorubicin and the clearance of is slightly more rapid. In addition, mean AUC values for doxorubicin are 1.3- to 1.7-fold greater than those for epirubicin when values are adjusted for dose.

Various pharmacokinetic parameters of epirubicin were not altered versus when the drug was given with verapamil or dexrazoxane. Cimetidine increased the AUC of coadministered epirubicin. Preliminary data suggests that the pharmacokinetic profile of epirubicin may be affected when paclitaxel is given immediately before epirubicin, but not when the drugs are given in the reverse sequence. The AUCs of epirubicin metabolites were significantly increased when epirubicin and paclitaxel were coadministered, regardless of the sequence of administration. The pharmacokinetic profiles of paclitaxel or docetaxel were not affected by the addition of epirubicin.

Therapeutic Efficacy in Breast Cancer

Adjuvant therapy in early breast cancer. Adjuvant chemotherapy significantly improves survival in patients with early, operable breast cancer. The combination of epirubicin plus cyclophosphamide and fluorouracil (FEC) has been compared with standard cyclophosphamide/methotrexate/fluorouracil (CMF) therapy in several large trials. Results of these trials are not definitive but suggest that in comparison with CMF regimens using equivalent dosages of cyclophosphamide and fluorouracil, FEC is at least as effective as the standard treatment in premenopausal women with node-positive or -negative breast cancer. Indeed, significant advantages for FEC were observed in the majority of trials including women with node-positive breast cancer and in the 1 trial that included women with node-negative disease. In the trial with the largest patient numbers per group, 63% of patients in the FEC group versus 53% in the CMF group were relapse-free at 5 years, and overall 5-year survival rates were 77 and 70% for FEC and CMF, respectively. In postmenopausal women with node-positive disease, no significant difference was observed between FEC and CMF.

It has been difficult to establish a clear dose/response effect for epirubicin. One trial has reported a clear benefit (improved relapse-free and overall survival rates at 5 years) for epirubicin 100mg over epirubicin 50mg (in a FEC regimen) in patients with node positive early breast cancer. However, results of another trial suggested no change in overall survival when the epirubicin dose was increased from 50 to 75 mg/m2 or the number of treatment cycles was increased from 3 to 6.

Adding epirubicin to tamoxifen therapy reduced the risk of relapse but did not improve overall survival over tamoxifen alone in postmenopausal patients with node-positive early breast cancer.

QOL with epirubicin has not been well investigated. In 1 large trial, QOL deteriorated in both FEC and CMF groups early in treatment, but to a greater extent with FEC. However, at 6 months QOL was similar in both groups and the improvements noted at this time continued so that at 15 months QOL was significantly above pretherapy levels.

Metastatic breast cancer. Epirubicin-containing therapy has similar efficacy to commonly used regimens containing doxorubicin or mitoxantrone for the firstline treatment of patients with metastatic breast cancer. Objective response rates are40 to 54% and median overall survival is ≈15 to 20 months.

Epirubicin in combination with various other agents (most promisingly ifosfamide) as second-line therapy has produced median objective response rates of 32 to 67.5% and median survival durations of 6.9 to 19.2 months. The administration of more dose-intensive epirubicin regimens has generally improved response rates, but not survival.

Tolerability

Bone marrow suppression is the major acute dose-limiting epirubicin toxicity. Neutropenia occurs most frequently, and thrombocytopenia and anaemia less often. However, at equimolar doses epirubicin is associated with less myelotoxicity than doxorubicin. Compared with CMF therapy, FEC causes more grade 3 to 4 neutropenia (98 vs 78% in 1 trial without G-CSF support) and significantly more hospitalisations because of neutropenic fever. However, no deaths were associated with neutropenic fever.

Epirubicin, like doxorubicin, can cause chronic irreversible cardiomyopathy leading to congestive heart failure. The risk is directly related to lifetime cumulative dose, and the risk increases exponentially above the maximum recommended cumulative epirubicin dose of 900 mg/m2. This is almost twice the recommended cumulative dose for doxorubicin. In comparative trials of FEC versus FAC, cardiotoxicity occurred more frequently with the doxorubicin-containing regimen.

Other important effects of epirubicin include mucositis, nausea and vomiting, reversible alopecia and local cutaneous reactions. Mucositis is dose related and can be dose limiting in high-dose regimens. This event occurred more frequently with a FEC regimen than with CMF in 1 trial. Nausea and vomiting are generally well controlled with antiemetic drugs, but FEC regimens appear to be less emetogenic than FAC therapy, but more emetogenic than CMF.

Secondary leukaemias have occurred in epirubicin-treated breast cancer patients who also received concomitant alkylating therapy. In 1 trial 5 of 351 patients contracted leukaemia and 2 other large trials have each reported 2 instances of leukaemia, a higher than expected incidence. Other trials have not reported any instances of leukaemia and the overall risk of developing leukaemia has been estimated to be 0.2 and 0.8% at 3 and 5 years, respectively.

Dosage and Administration

As a single agent epirubicin has been used at dosages of 50 to 135 mg/m2 administered intravenously over 3 to 5 minutes and repeated every 21 days. As a component of multidrug therapy the recommended starting dose (approved by the FDA and many European agencies) is 100 to 120 mg/m2.As part of a FEC regimen, epirubicin 60 mg/m2 given on days 1 and 8 of a 4 week cycle is an effective adjuvant therapy.

Higher doses (up to 180 mg/m2 repeated every 3 weeks) have been given without growth factor support in noncomparative studies; however, the usual maximum tolerated single-agent dose is approximately 135 mg/m2 every 21 days. To reduce the risk of cardiotoxicity the cumulative lifetime dose should not exceed 900 mg/m2. Dosage should be reduced in patients with moderate to severe hepatic dysfunction. Dose adjustment in patients with renal impairment is not necessary.

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Ormrod, D., Holm, K., Goa, K. et al. Epirubicin. Drugs Aging 15, 389–416 (1999). https://doi.org/10.2165/00002512-199915050-00006

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