Epirubicin in Breast Cancer: Present and Future

S62 • Clinical Breast Cancer Supplement September 2000

Epirubicin in Breast Cancer: Present andFutureMark Levine

Epirubicin, a member of the anthracycline family of chemotherapeutic agents, has been widely used through-out the world both as adjuvant therapy in early breast cancer and in metastatic breast cancer. Clinical trialswith epirubicin have examined the importance of a dose-response relationship, therapeutic dose, and opti-mum duration of chemotherapy. In addition, pharmacokinetic studies have provided data on ideal combina-tions with other agents. Epirubicin-containing regimens are considered to be superior to those containingcyclophosphamide, methotrexate, and fluorouracil (CMF) and are also used in patients with locally advancedstage IIIA/IIIB breast cancer. Combinations with other chemotherapeutic agents (eg, epirubicin plus a taxane,sequential or combined use of these agents) are being evaluated in ongoing clinical trials. Moreover, recentstudies have suggested that biologic markers, such as tumor HER2/neu overexpression, predict responses todose-intensive anthracycline chemotherapy, and combinations with nonchemotherapeutic regimens (eg, tras-tuzumab) may provide additional benefits, but such strategies require further evaluation.

Clinical Breast Cancer, Vol. 1, Suppl. 1, S62-S67, September 2000Key words: Breast cancer, Anthracyclines, Chemotherapy, Adjuvant therapy

Abstract

IntroductionEpirubicin, a member of the anthracycline family of

chemotherapeutic agents, is the 4'-epimer of doxoru-bicin.1 It has been widely used throughout the worldsince 1985 both as adjuvant therapy in early breastcancer and in metastatic breast cancer (except in theUnited States). Recently, the Food and Drug Adminis-tration (FDA) approved it for use as a component ofadjuvant therapy in women with early-stage, node-positive breast cancer.

Epirubicin exerts its antineoplastic effect through anumber of mechanisms. First, it intercalates betweennucleotide base pairs in DNA, resulting in the inhibi-tion of DNA, RNA, and protein synthesis. Second, thisintercalation leads to topoisomerase-II – mediatedcleavage of DNA, resulting in cytocidal activity. Third,it inhibits DNA helicase, interfering with replicationand transcription.

As a result of the different spatial orientation of thehydroxyl group at the 4' position, epirubicin has dif-ferent properties than doxorubicin (eg, pKa and

terminal half-life [t1⁄2]). Because it has a lower pKathan doxorubicin, epirubicin is more lipophilic andbetter able to penetrate cells. Also, the glucronidationof epirubicin and epirubicinol to inactive metabolitesresults in a shorter t1⁄2 for epirubicin than doxorubicin(30 vs. 45 hours).

The structural differences between epirubicin anddoxorubicin may account for the different safety pro-files between the two agents; larger doses of epiru-bicin are required to produce the same degree of toxic-ity as doxorubicin. The doxorubicin:epirubicin doseratios for similar toxicities are: 1:1.2 hematologic; 1:1.5nonhematologic; and 1:1.8 for cardiac.1,2 This in-creased safety profile allows for greater dose esca-lation that can be achieved safely (ie, a greater thera-peutic window).

Enhanced Understanding of Biology ofBreast Cancer

The evaluation of epirubicin in clinical trials hascontributed to our fundamental understanding of thetherapeutics of anticancer drugs.

Therapeutic WindowThere are data from seven randomized trials com-

paring equimolar doses of epirubicin and doxorubicinin women with metastatic breast cancer (Table 1).1,3

These studies were all relatively small in sample size;no difference was detected between the two treatment

Submitted: June 30, 2000; Revised: Aug. 8, 2000; Accepted: Aug. 12, 2000

Address for correspondence: Mark Levine, MD, Clinical ResearchInstitute, Faculty of Health Sciences, 2E, McMaster University, 1200Main St. W., Hamilton, Ontario L8N 3Z5 Fax: 905-389-9288; e-mail: [email protected]

Department of Medicine, McMaster University, Hamilton, Ontario,Canada

arms in either response rates or time to progression.A meta-analysis of these individual study data demon-strated no loss of antitumor efficacy with epirubicin,but did demonstrate a statistically significant reduc-tion in cardiac toxicity and myelosuppression.3 Thedose escalation of epirubicin used in subsequent clin-ical trials was based on these findings of decreasedmyelosuppression and cardiac toxicity.

Importance of Dose and Duration ofChemotherapy

Clinical trials with epirubicin have examined theimportance of a dose-response relationship, therapeu-tic dose, and optimum duration of chemotherapy. Inaddition, pharmacokinetic studies have provided dataon ideal combinations with other agents.

Bastholt and coworkers4 conducted a randomizedtrial in which women with metastatic breast cancerwere randomized to one of four different doses of epi-rubicin administered every 3 weeks: 40 mg/m2, 60 mg/m2, 90 mg/m2, and 135 mg/m2, with corresponding re-sponse rates of 20%, 18%, 38%, and 36%. Similarly,there was a dose-dependent relationship between thetime to progression and increasing doses up to 90mg/m2. In a series of randomized trials in metastaticbreast cancer, the French Epirubicin Study Groupdemonstrated that higher doses of epirubicin weremore efficacious (ie, 100 mg/m2 > 75 mg/m2 > 50 mg/

m2), and longer duration chemotherapy lead to bettertumor control than shorter therapy.5-7 In the adju-vant setting, they reported that fluorouracil/epiru-bicin 100 mg/m2/cyclophosphamide (FEC-100) wassuperior to FEC-50.8 Fumoleau and colleagues alsodemonstrated that 6 cycles of FEC were superior to 3cycles in women with node-positive breast cancer.9

Finally, several pharmacokinetic studies combinedan anthracycline with paclitaxel. The data indicatedthat the area under the curve of doxorubicin was in-creased with paclitaxel coadministration, whereas thearea under the curve of epirubicin did not change ap-preciably when combined with paclitaxel. This sug-gests the potential for reduced cardiac toxicity withepirubicin/paclitaxel combinations.10

Current TrendsCurrently in North America and Latin America,

87% of epirubicin use is for the treatment of breastcancer. The figure is 63% in Europe and 36% for Asiaand the Pacific Rim.

Adjuvant TherapyEpirubicin-containing regimens are considered to

be superior to those containing cyclophosphamide/methotrexate/fluorouracil (CMF; Table 2). The Dan-ish Breast Cancer Study Group reported that 9 cyclesof intravenous (I.V.) fluorouracil/epirubicin 60 mg/m2/

Clinical Breast Cancer Supplement September 2000 • S63

Randomized Controlled Trials Comparing Equimolar Doses of Epirubicin and DoxorubicinTable 1

* Numbers represent doses of doxorubicin and epirubicin in mg/m2 Abbreviations: A = doxorubicin; C = cyclophosphamide; E = epirubicin; F = fluorouracil; NR = not reportedAdapted from: Findlay BP, Walker-Dilks C. Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast CancerDisease Site Group and the Provincial Systemic Treatment Disease Site Group. Cancer Prev Control 1998; 2:140-146 and Ormrod D, Holm K,Goa K, et al. Epirubicin: a review of its efficacy as adjuvant therapy and in the treatment of metastatic disease in breast cancer. Drugs Aging 1999;15:389-416.

StudyNo. of Assessable

PatientsTreatment Group*

Response Rate (%)CR + PR (CR)

Median Survival(months)

French trial (1988)28 113 FAC-50 52 (9) 18.2

117 FEC-50 50 (14) 15

Italian trial (1988)29 221 FAC-50 57 (15) 20

222 FEC-50 54 (11) 19

Lopez (1989)30 46 FAC-50 46 (16) 16

48 FEC-50 44 (12) 14

Heidemann (1990)31 51 AC-40 42 (8) NR

66 EC-40 42 (18)

Lawton (1993)32 28 A-70 36 (7) ~8

28 E-70 32 (0) ~10

Gasparini (1991)33 21 A-20 38 (5) 11

22 E-20 36 (0) 12

Castiglione (1990)34 ~50 A-20 29 15

~50 E-20 20 13

cyclophosphamide (CEF-60) was superior to 9 cycles ofI.V. CMF, both administered every 3 weeks.11 TheNational Cancer Institute of Canada Clinical TrialsGroup (NCIC-CTG) demonstrated that 6 cycles ofCEF-120 (epirubicin 60 mg/m2 days 1 and 8) wassuperior to CMF (classical oral Milan regimen) inwomen with node-positive breast cancer, for bothrelapse-free and overall survival endpoints.12

One trial from the Southeastern Oncology Groupcompared cyclophosphamide/doxorubicin/fluorouracil(CAF) with CMF in stage II breast cancer patients andfound no difference between regimens.13 The only co-operative group trial published to date by U.S. inves-tigators reporting a difference in favor of doxorubicin-based therapy (6 months of CAF) versus CMF is theIntergroup trial performed in node-negative women.14

Note that the FDA has recently approved epirubicinas a component of CEF-120 and FEC-100 for adjuvanttherapy in women with early-stage breast cancer.

The recent Early Breast Cancer Trialists’ Collabo-rative Group Overview Analysis reported that in post-menopausal women, chemotherapy plus tamoxifenresulted in improved disease-free and overall survivalcompared to tamoxifen alone.15 Data from the indi-vidual trials indicated that those studies in which ananthracycline was included in the chemotherapy regi-men suggested the superiority of chemotherapy plustamoxifen over tamoxifen alone. For example, in aNational Surgical Adjuvant Breast and Bowel Project(NSABP) trial, doxorubicin and cyclophosphamide(AC) plus tamoxifen was superior to tamoxifen alone.16

Also, in a European study, epirubicin plus tamoxifengave better results than tamoxifen alone.17

Some patients with node-negative breast cancerhave a risk of recurrence approaching that for node-

positive disease. Active research continues to identifynew prognostic factors that may differentiate womenat high risk of recurrence from those at low risk. Thisis particularly important for a large group who fallinto an "intermediate" risk, based on the traditionalfactors of tumor size and grade. Whether epirubicin-containing regimens are used in the treatment ofnode-negative, high-risk patients is determined by atrade-off between the incremental benefit over CMFand increased toxicity. (In Canada, the NCIC-CTG in-cludes high-risk, node-negative patients in anthra-cycline clinical trials.) If epirubicin-containing regi-mens are used in the node-negative situation, clini-cians should clearly explain the benefits and risks tothe patient.

Locally Advanced Breast CancerAnthracycline-containing regimens (eg, CAF and

FEC) are traditional therapy for patients with locallyadvanced breast cancer stage IIIA and IIIB. TheEuropean Organization for Research and Treatmentof Cancer (EORTC), NCIC-CTG, and the Swiss Groupfor Clinical Cancer Research conducted a trial of 6cycles of neoadjuvant FEC every 4 weeks (fluorouracil500 mg/m2 I.V. days 1 and 8, epirubicin 60 mg/m2 days1 and 8, and cyclophosphamide 75 mg/m2 orally days1-14) versus 6 cycles of epirubicin 120 mg/m2/cyclo-phosphamide (EC-120) + granulocyte colony-stimu-lating factor (G-CSF) every 2 weeks in 448 patientswith locally advanced or inflammatory breast cancer.18

No differences were detected between treatment armsin both disease-free and overall survival.

Metastatic Breast CancerThe goal of treatment in metastatic breast cancer is


Randomized Trials Comparing CMF with CAF or FEC as Adjuvant Therapy of Early Breast CancerTable 2

* Not statistically significant† High-risk patients ‡ P < 0.05§ P < 0.01Abbreviations: A = doxorubicin; C = cyclophosphamide; DFS = disease-free survival; E = epirubicin; F = fluorouracil; M = methotrexate; NR =not reported; OS = overall survival; RFS = relapse-free survival

AuthorNo. of

PatientsPatient Population

ChemotherapyRegimen

RFS Rate (%) OS Rate (%)

Carpenter et al13

Hutchins et al14

Mouridsen et al11

Levine et al12

528

2691†

1180

710

Node-positive;Pre- and post-menopausal

Node-negative;Pre- and post-menopausal

Node-positive and node-negative premenopausal;Node-positive postmenopausal

Node-positive; pre- andperi-menopausal

CAF x 6 vs. CMF x 6

CAF vs. CMF

FEC x 9 vs.CMF (I.V.) x 9

CEF-120 x 6 vs.CMF (p.o.) x 6

NR

5-year DFS: 85 vs. 82‡

6-year: 63 vs. 58§

5-year: 63 vs. 53§

5-year: 74 vs. 68*

5-year: 92 vs. 90‡

6-year: 70 vs. 65§

5-year: 77 vs. 70‡

Epirubicin in the Present and Future


to control the symptoms from the disease and maxi-mize quality of life, while hopefully improving life-span. While many clinicians believe that systemictreatment does not improve survival,19 this paradigmmay be changing. Data from recent randomized trialshave demonstrated improved survival in patients withadvanced breast cancer treated with newer agentscompared to traditional therapies.20,21 (In treatingmetastatic breast cancer patients, new regimens orchemotherapeutic agents that are found to be partic-ularly promising are rapidly moved to evaluation inthe adjuvant setting.)

A number of factors determine the particular treat-ment for metastatic breast cancer, including: 1) site ofmetastases (liver and lung versus other); 2) estrogenreceptor (ER) status; 3) and disease-free interval.Combination chemotherapy using an anthracyclinehas generally been used for aggressive or rapidly ad-vancing disease, and epirubicin- and doxorubicin-con-taining regimens are commonly used in this setting.Joensuu and collaborators reported results that chal-lenged the dogma on the use of combination chemo-therapy in advanced breast cancer.22 Women withmetastatic breast cancer were randomized to eitherfirst-line FEC followed by mitomycin and vinblastine(MV) upon disease progression, or first-line, single-agent, weekly epirubicin followed by mitomycin atprogression. No difference was detected in responserate and time to progression between treatmentgroups. The data also suggested that patients who re-

ceived single-agent therapy had an improved qualityof life.

Future DirectionsThe concept of dose intensity has been employed in

the development and testing of chemotherapy regi-mens over the years. Undoubtedly, dose and dose in-tensity play a role in anticancer effect. At one end ofthe spectrum is the use of high-dose chemotherapywith stem-cell support. Recent clinical trials in the ad-juvant high-risk setting and metastatic breast cancerhave failed to demonstrate an advantage of high-dosechemotherapy plus stem-cell support over conven-tional-dose chemotherapy regimens.23,24 It is possiblethat differences may emerge with longer study follow-up. However, such therapy has fallen out of fashion infavor of other strategies to improve outcome.

Biologic markers may be used to predict response tochemotherapy and to tailor specific regimens. Overthe years, estrogen and progesterone receptor tumorstatus have played an important role in predicting re-sponses to hormonal therapy. Recent studies have sug-gested that tumor HER2/neu overexpression predictsresponses to dose-intensive anthracycline chemo-therapy.25 Compared with women with HER2/neunonoverexpressing tumors, all patients with tumorsthat overexpressed HER2/neu were more likely tohave an improved result with dose-intensive anthra-cycline-based therapy than with lower-dose or non-anthracycline chemotherapy. However, these data

Ongoing Randomized Trials of Adjuvant Epirubicin-Based TherapyTable 3

Abbreviations: A = doxorubicin; C = cyclophosphamide; D = docetaxel; E = epirubicin; ER = estrogen receptor; F = fluorouracil; G-CSF =granulocyte colony-stimulating factor; GONO = Northwest Oncology Group; HDC = high-dose chemotherapy (melphalan, thiotepa);M = methotrexate; NCIC-CTG = National Cancer Institute of Canada Cooperative Trials Group; P = paclitaxel; PR = progesterone receptor;T = taxane

Cooperative Group Patient Population Regimens

NCIC-CTG MA.21

U.S. Community-Based

French Cooperative Group

International CollaborativeCancer Group

Italian

GONO MIG 5

GONO MIG 7

Pre- or post-menopausal womenwith operable, high-risk breast cancer

Pre- and post-menopausal women withnode-positive operable breast cancer

Pre- and post-menopausal women withnode-positive early breast cancer

Postmenopausal women with node-positive or node-negative early breast cancer

Pre- and post-menopausal; node-positive;ER or PR

Pre- and post-menopausal with node-positive,stage II breast cancer

Pre- and post-menopausal with node-positive,stage III breast cancer

FEC-120 q 4 weeks x 6EC-120 + G-CSF days 1 and 15 x 6 → P q 3 weeks x 4AC q 3 weeks x 4 → P q 3 weeks x 4

EC q 3 weeks x 4 → T q 3 weeks x 4ET q 3 weeks x 8

FEC-100 q 3 weeks x 6FEC-100 q 3 weeks x 3 → D q 3 weeks x 3

E (days 1 and 8) x 6E (days 1 and 8) x 3 → D x 3

E x 4 → CMF x 4E x 4 → T x 4 → CMF x 4

FEC q 3 weeks x 6ET q 3 weeks x 4

ET q 3 weeks x 4ET q 2 weeks x 2 → Apheresis → HDC

Mark Levine


were obtained from retrospective cohort studies, andfurther research is warranted.

Epirubicin combinations with other chemothera-peutic agents are also being evaluated in ongoing clini-cal trials. Based on the results of the Cancer and Leu-kemia Group B (CALGB) trial in which AC followedby paclitaxel was superior to AC alone, regimens arebeing developed that incorporate taxanes into epiru-bicin-containing regimens.26 Planned clinical trialsexamining these epirubicin-containing regimens in-clude the MA.21 trial conducted by the NCIC-CTGand the U.S. community-based adjuvant trial (Table3). In the Canadian trial, women with node-positive orhigh-risk node-negative breast cancer are randomizedto 6 cycles of FEC-120 or 6 cycles of EC-120 days 1 and15 + G-CSF, each followed by 4 cycles of paclitaxel or 4cycles of AC, followed by 4 cycles of paclitaxel. In theU.S. trial, node-positive women are randomized to 4cycles of EC-100 followed by 4 cycles of a taxane or 8cycles of epirubicin 90 mg/m2 and a taxane (ET-90).

Research is also focusing on epirubicin combina-tions with nonchemotherapeutic regimens. Data froma CALGB study demonstrated that the addition oftrastuzumab to chemotherapy provided additionaltherapeutic benefits, including an improvement inprogression-free and overall survival in patients whoreceived trastuzumab plus chemotherapy comparedwith those who received AC or paclitaxel alone.27

However, the potential cardiac toxicity associated withtrastuzumab and anthracycline combinations re-quires further study.

Finally, there is a plethora of ongoing investigationswith antiangiogenic agents. Should these agents proveeffective in the treatment of breast cancer, a logicalapproach would be to combine them with conven-tional chemotherapy agents. Advances in cancer treat-ment may also be combined with those in humangenome sequencing. Hopefully, in the near future, cli-nicians may identify specific molecular defects usinggene chip assays and deliver a specific therapeuticagent.

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Epirubicin in the Present and Future


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34. Castiglione M, Schatzmann E, Goldhirsch A, et al. Adriamycin (A) versusepirubicin (E): low-dose weekly schedule in metastatic breast cancer.Preliminary results of tumor response and of quality-of-life measure-ments. Proc Am Soc Clin Oncol 1990; 9:48a (Abstract #182).

Mark Levine

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Epirubicin in Breast Cancer: Present and Future