Epirubicin

Abstract

Epirubicin is the 4′ epimer of the anthracycline antibiotic doxorubicin, and has been used alone or in combination with other cytotoxic agents in the treatment of a variety of malignancies. Comparative and noncomparative clinical trials have demonstrated that regimens containing conventional doses of epirubicin achieved equivalent objective response rates and overall median survival as similar doxorubicin-containing regimens in the treatment of advanced and early breast cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), non-Hodgkin’s lymphoma, ovarian cancer, gastric cancer and nonresectable primary hepatocellular carcinoma. Recently, dose-intensive regimens of epirubicin have achieved high response rates in a number of malignancies including early and advanced breast cancer and lung cancer. The major acute dose-limiting toxicity of anthracyclines is myelosuppression. In vitro and clinical studies have shown that, at equimolar doses, epirubicin is less myelotoxic than doxorubicin. The lower haematological toxicity of epirubicin, as well as the recent introduction of supportive measures such as colony-stimulating factors, has allowed dose-intensification of epirubicin-containing regimens, which is particularly significant because of the definite dose-response relationship of anthracyclines. Cardiotoxicity, which is manifested clinically as irreversible congestive heart failure and/or cardiomyopathy, is the most important chronic cumulative dose-limiting toxicity of anthracyclines. Epirubicin has a lower propensity to produce cardiotoxic effects than doxorubicin, and its recommended maximum cumulative dose is almost double that of doxorubicin, thus allowing for more treatment cycles and/or higher doses of epirubicin. In summary, dose-intensive epirubicin-containing regimens, which are feasible due to its lower myelosuppression and cardiotoxicity, have produced high response rates in early breast cancer, a potentially curable malignancy, as well as advanced breast, and lung cancers. Furthermore, there is evidence to suggest that improved response rates can improve quality of life in some clinical settings, but whether this leads to prolonged survival has not yet been determined. Recently implemented supportive measures such as colony-stimulating factors, prophylactic antimicrobials and peripheral blood stem cell support may help achieve other potential advantages of dose-intensive epirubicin-containing regimens such as reductions in morbidity and length of hospital admissions. Epirubicin is the epimer of doxorubicin, with inversion of the 4′-hydroxyl group on the sugar moiety. Epirubicin is a cell cycle phase non-specific anthracycline, with maximal cytotoxic effects in the S and G₂ phases. In vitro studies showed that epirubicin possesses cytotoxicity at least equivalent to that of doxorubicin against a variety of animal and human tumour cell lines including those derived from breast, liver, lung, gastric, colorectal, squamous cell, cervical, bladder, ovarian carcinomas, neuroblastoma and leukaemia. In an in vitro murine model, epirubicin was at least as effective as doxorubicin in inhibiting basement membrane degradation, a property deemed necessary to prevent development of metastases. Significant correlations have been detected between the in vitro activity of epirubicin and other anthracyclines against various tumour specimens, and therapeutic response. Multidrug resistance to anthracyclines, vinca alkaloids, dactinomycin and epidopodophyllotoxins has been reported in a variety of tumour cell lines. In vivo antitumour activity of epirubicin was also comparable with that of doxorubicin against a variety of human tumour xenografts in mice, including breast, lung, ovarian, prostate and testicular neoplasms. The mechanism of antitumour action for epirubicin has not been completely elucidated; however, anthracyclines appear to form a complex with DNA by intercalation between the DNA strands, thus inhibiting replication and transcription. This action may be attributed, at least in part, to interference with topoisomerase-DNA ‘cleavable complex’ and helicase activity by anthracyclines. Reduction of anthracyclines to semiquinone free radicals may cause damage to DNA, cell membrane lipids and mitochondria. Myelotoxicity, which seems to be mediated, at least in part, via chromatid breaks in bone marrow cells, was lower with epirubicin than doxorubicin in pharmacodynamic studies. Anthracyclines appear to exert their cardiotoxic effects through a variety of mechanisms including impairment of heart mitochondrial function, depressed adenosine diphosphate-stimulated respiration, and changes in membrane structure and function. In a number of acute and chronic studies which measured these effects objectively in animals, epirubicin demonstrated a significantly lower propensity to produce cardiotoxic effects than doxorubicin, possibly due to a more rapid myocardiai release of epirubicin during the post-infusion period. Following rapid intravenous administration, epirubicin undergoes triphasic plasma elimination. Epirubicin exhibits a rapid initial (α) distribution phase (t_½α = 1.8 to 4.8 minutes), followed by an intermediate (β) phase (t_½β = 0.5 to 2.6 hours) and a much slower (γ) terminal elimination phase (t_½γ = 15 to 45 hours). The t_½γ of doxorubicin was approximately 40 to 70% longer than that of epirubicin in the majority of comparative pharmacokinetic studies in cancer patients. However, peak plasma drug concentrations were similar following intravenous administration of equimolar doses. Epirubicin undergoes extensive tissue distribution; volume of distribution values were high and variable (13 to 52 L/kg), but similar to those reported for doxorubicin. Area under the plasma concentration versus time curve values adjusted for dose were 30 to 70% higher for doxorubicin than epirubicin following single-dose intravenous administration. Following intravenous administration, epirubicin is rapidly metabolised to 2 glucuronides, plus epirubicinol and 4 aglycones. Epirubicin is eliminated primarily via the hepatobiliary system, with approximately 11 to 15% of a dose eliminated in the urine as unchanged drug and metabolites. Patients with moderate to severe hepatic dysfunction exhibited reduced clearance of epirubicin and elevated plasma drug concentrations. At conventional doses, the combination of FEC (fluorouracil, epirubicin 50 mg/m² plus cyclophosphamide) versus FAC (fluorouracil, doxorubicin 50 mg/m² plus cyclophosphamide) administered every 3 weeks achieved similar objective response rates of approximately 55% and median overall survival of about 15 to 20 months in patients with advanced breast cancer in large randomised multicentre trials. Recently, dose-intensive epirubicin-containing regimens have achieved higher response rates in women with metastatic breast cancer, usually ranging from about 60 to 80%, predominantly in noncomparative studies. Dose-intensive FEC regimens often included epirubicin ⩾ 75 mg/m² in combination with 500 mg/m² of both fluorouracil and cyclophosphamide, while others combined epirubicin ⩾ 60 mg/m² with higher doses of fluorouracil and cyclophosphamide administered every 3 weeks. Other dose-intensive regimens combined epirubicin with different cytotoxic drugs, used shorter intervals between treatment cycles and/or employed granulocyte colony-stimulating factor (G-CSF). A number of studies have been, and continue to be, conducted with dose-intensive epirubicin-containing regimens, such as FEC, in the adjuvant and neoadjuvant treatment of early breast cancer. Data are generally preliminary and an advantage in favour of epirubicin dose-intensification has not yet been demonstrated in terms of survival. Interim results of a large study in premenopausal node-positive women with early stage breast cancer comparing adjuvant therapy with standard doses of FEC versus a combined regimen of cyclophosphamide, methotrexate and fluorouracil (CMF) demonstrated similar local relapse rates between treatment groups. However, a trend towards a lower rate of metastasis and fewer deaths from metastatic progression were noted among FEC recipients. In a large study evaluating neoadjuvant therapy, regimens of FEC, FAC and CMF were equally effective in producing cytoreduction sufficient to avoid radical mastectomy in patients with early breast cancer. Noncomparative studies in previously untreated patients with small cell lung cancer (SCLC) reported objective response rates of approximately 65% with epirubicin 50 to 90 mg/m² every 3 to 4 weeks in combination with cyclophosphamide and vincristine. Median survival was 10 to 14 months which was similar to that achieved with other active regimens. Epirubicin in combination with 1 of more other cytotoxic drugs such as carboplatin, etoposide, cisplatin, cyclophosphamide, ifosfamide and/or vincristine, generally demonstrated slightly higher response rates (52 to 95%), but median survival was essentially equivalent (7 to 16 months). Preliminary results of a dose-finding study showed a response rate of approximately 75% in patients with SCLC receiving epirubicin 100 to 140 mg/m² in combination with cisplatin 100 mg/m² every 3 weeks plus granulocyte-macrophage colony-stimulating factor (GM-CSF). Single-agent epirubicin 100 to 140 mg/m² every 3 to 4 weeks was apparently less effective than combination regimens. Patients with non-small cell lung cancer (NSCLC) responded poorly to single-agent epirubicin < 120 mg/m² every 3 or 4 weeks. In previously untreated patients, epirubicin monotherapy 120 to 180 mg/m² every 3 to 4 weeks achieved response rates of approximately 20 to 35%, and overall survival ranged from 6 to 10 months. Similarly, such patients with NSCLC receiving epirubicin 50 to 100 mg/m² every 3 to 4 weeks in conjunction with 1 or more other agents such as cisplatin, cyclophosphamide or etoposide, exhibited objective response rates of approximately 30 to 40%, and overall survival ranged from 5 to 11 months. High-dose epirubicin (120 mg/m²) plus cisplatin 60 mg/m² every 4 weeks achieved an objective response rate of 54% and median overall survival of 9 months among 35 previously untreated patients with NSCLC. In another study, epirubicin 135 mg/m² combined with etoposide offered no advantage over high dose epirubicin as a single agent and was apparently more toxic. Epirubicin-containing combination regimens achieved complete remission rates of approximately 45 to 65% in patients with non-Hodgkin’s lymphoma. In studies of patients with intermediate- or high-grade non-Hodgkin’s lymphoma, epirubicin 50 to 75 mg/m² was typically administered every 3 or 4 weeks in combination with cyclophosphamide, vincristine and prednisone, with or without bleomycin (CEOP or CEOP-B). Response rates and survival were equivalent between patients receiving CEOP or CEOP-B and those receiving similar regimens containing doxorubicin (CHOP or CHOP-B). Among patients with previously untreated Hodgkin’s disease, complete response was achieved in approximately 80 to 90% of adults and 62% of children receiving epirubicin-containing regimens. In previously untreated patients with gastric cancer, objective response rates generally ranged from approximately 25 to 55%, and overall median survival ranged from about 3 to 11 months following treatment with approximately 40 to 60 mg/m² of epirubicin every 3 or 4 weeks in specific combinations with other cytotoxic agents such as fluorouracil plus mitomycin, or epirubicin 50 to 120 mg/m² plus fluorouracil. The higher response rates were achieved with higher epirubicin dose-intensities. In patients with superficial bladder cancer, single or repeated intravesical administration of epirubicin 30 to 80mg following transurethral resection (TUR) achieved response rates of approximately 45 to 85% at ⩾ 1 year follow-up. Instillation of epirubicin plus TUR was more effective than surgery alone, and achieved remission rates comparable with a regimen of intravesically administered mitomycin plus TUR. Selected regimens combining epirubicin plus interferon-α2b intravesically following surgery may improve the efficacy of epirubicin in patients with superficial bladder cancer. A number of preliminary reports demonstrated promising efficacy of neoadjuvant treatment with epirubicin 30 to 60 mg/m² intravenously every 3 or 4 weeks in combination with other antineoplastic agents, such as cisplatin plus methotrexate plus vinblastine, administered to patients with locally advanced or invasive bladder cancer. Objective response rates with neoadjuvant epirubicin-containing treatment generally ranged from approximately 45 to 90%, but appeared to be related, at least in part, to the epirubicin dosage administered. Data from 2 studies demonstrated 1.5- and 2-year survival rates of 81 and 74%, respectively, with epirubicin-containing neoadjuvant therapy. First-line treatment of patients with advanced ovarian cancer using epirubicin 50 to 75 mg/m² every 3 to 4 weeks in platinum-based combination regimens achieved objective response rates ranging from approximately 40 to 90%, which were similar to those obtained using doxorubicin in platinum-based chemotherapy regimens (approximately 55 to 90%) in comparative trials. Overall median survival was 14.0 to 24.9 months among epirubicin recipients and 24.3 to 26.5 months among the doxorubicin treatment groups. In patients with advanced prostatic cancer who had relapsed after hormonal treatment, epirubicin, with or without medroxyprogesterone acetate, achieved equivalent or superior improvements in performance status and/or pain relief compared with estramustine. Furthermore, preliminary results of a large study demonstrated that patients with hormone-resistant prostatic cancer were more likely to remain progression-free following epirubicin plus medroxyprogesterone acetate than with estramustine. In noncomparative trials, patients with primary hepatocellular carcinoma (PHCC) receiving intravenous or intrahepatic arterial administration of epirubicin (approximately 40 to 90 mg/m² every 3 weeks to 3 months), with or without other antineoplastic drugs, generally exhibited objective response rates of approximately 15% and median survival of about 2 to 4 months, which were similar to those reported for doxorubicin-containing regimens. However, epirubicin plus cisplatin via intrahepatic chemoembolisation achieved objective response rates of about 50 to 60% in 2 small studies; median survival was 9 months in 1 trial and 55% of patients were alive after 1 year in the other study. In a comparative trial, median survival for patients receiving epirubicin via the hepatic artery was significantly longer than that for patients receiving doxorubicin intra-arterially (205 vs 100 days; p = 0.0036). Limited results indicate that epirubicin may also be useful as a component of chemotherapy in patients with soft tissue sarcomas, nasopharyngeal carcinoma or advanced pancreatic carcinoma. Myelosuppression is the major acute dose-limiting toxicity of epirubicin, while cardiotoxicity is the most important chronic cumulative dose-limiting toxicity. Myelosuppression consists predominantly of leucopenia, which reaches a median white blood cell (WBC) nadir of about 3 × 10⁹/L 10 to 14 days following administration of epirubicin 75 to 90 mg/m² and usually resolves within 21 days of epirubicin administration. Approximately 3% of patients exhibit prolonged moderate to severe leucopenia (WBC < 3 × 10⁹/L) at these doses. Comparative clinical trials and in vitro studies have demonstrated that the haematological toxicity of epirubicin is lower than that of equimolar doses of doxorubicin, thus allowing administration of higher epirubicin doses. Addition of G-CSF to high-dose epirubicin-containing regimens has been used to reduce the severity of leucopenia, and antimicrobial prophylaxis reduced the incidence of hospitalisation due to febrile neutropenia in patients receiving a dose-intensive FEC regimen as adjuvant treatment for breast cancer. Severe irreversible congestive heart failure and/or cardiomyopathy may develop during or after epirubicin treatment, particularly with cumulative doses approaching 1000 mg/m². However, based on in vitro studies and comparative data from clinical trials, the frequency and severity of cardiotoxicity is lower with epirubicin than doxorubicin, which is reflected in their maximum recommended cumulative doses (1000 vs 550 mg/m²). This allows for more treatment cycles and/or higher doses of epirubicin than doxorubicin. Pathological cardiac changes include myofibrillar loss, sarcoplasmic vacuolisation and fibrosis. Most patients receiving epirubicin without adequate antiemetic therapy will experience nausea and vomiting within the first 24 hours after administration. The majority of epirubicin recipients will also develop reversible alopecia. Other adverse events include fever, diarrhoea, radiation recall and local reactions such as severe cellulitis, and the development of tissue necrosis and pain if extravasation occurs. Epirubicin has been administered intravenously in various dosage regimens, alone or in combination with other antineoplastic drugs. As single-agent therapy for advanced breast cancer, epirubicin was usually administered as 75 to 90 mg/m² every 3 to 4 weeks, although doses up to 180 mg/m² have been used. Lower doses of epirubicin, such as 50 mg/m² every 3 to 4 weeks, have conventionally been used in combination regimens such as FEC, but recently higher doses of 75 to 100 mg/m² have been employed, and epirubicin 120 mg/m² as a component of FEC was administered to a small number of patients in a dose-finding study. Similarly, dose-intensive FEC regimens have recently been employed in the adjuvant treatment of early breast cancer; epirubicin 50 mg/m² has conventionally been used in FEC regimens, but doses up to 120 mg/m² every 3 to 4 weeks have been become a more aggressive treatment option for this potentially curable disease. Patients with SCLC usually received epirubicin 50 to 90 mg/m² every 3 to 4 weeks in combination with other agents such as cyclophosphamide plus vincristine or carboplatin plus etoposide, although doses as high as 120 mg/m² have been used in combination with cisplatin or cyclophosphamide. Epirubicin 50 to 120...