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Breast Cancer
Adjuvant Chemotherapy for Early Breast Cancer:
Optimal Use of Epirubicin
Stefan Glck
Miller School of Medicine, University of Miami, Miami, Florida, USA; Braman Family Breast Cancer Institute,
University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA
Key Words. Anthracyclines Adjuvant treatment Neoadjuvant treatment Doxorubicin Epirubicin

Learning Objectives
After completing this course, the reader will be able to:
1. Discuss the value of adjuvant chemotherapy in early breast cancer.
2. Critically assess the use of anthracyclines as part of adjuvant chemotherapy.
3. Describe the delivery of anthracyclines regarding dose, dose intensity, and dose density.
4. Evaluate the use of trastuzumab in the adjuvant setting.
CME

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Abstract
Anthracyclines are central components of adjuvant
combination chemotherapy regimens for early breast
cancer. Epirubicin is underutilized for this indication in the United States, where it was approved by the
Food and Drug Administration in 1999, compared
to Europe and Canada, where it gained approval in
1980. Use of epirubicin offers advantages in specific
treatment settings and patient subsets, including situations where use of dose-dense and/or dose-intense
protocols may provide additional benefits and where

combinations including taxanes and/or trastuzumab

may provide increased efficacy. Epirubicin also has a
distinct safety profile compared to doxorubicin with
regard to cardiotoxicity. In order to optimize treatment
benefits and safety concerns for node-positive, nodenegative and HER-2positive patients as well as patients
receiving neoadjuvant therapy and elderly patients it is
worthwhile to consider the potential benefits of epirubicin. The Oncologist 2005;10:780791

Introduction

dards. These agents interact directly with DNA, inhibiting

tumor cell proliferation and gene expression, and also lead
to production of free radicals that may destroy tumor cells.
Anthracyclines are important factors in optimizing adjuvant and neoadjuvant treatment and are indicated for adjuvant therapy regardless of the extent of nodal involvement,

The armamentarium of chemotherapeutic agents available

for the treatment of breast cancer has expanded greatly over
the past several decades, and complex regimens are nearly
universal today. Anthracyclines, as integral components of
most regimens, are central to the accepted treatment stan-

Correspondence: Stefan Glck, M.D., Ph.D., Professor of Medicine, Miller School of Medicine, University of Miami; Clinical Director,
Braman Family Breast Cancer Institute, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave., Suite 3510,
Miami, FL 33136, USA. Telephone: 305-243-4909; Fax: 305-243-4975; e-mail: SGluck@med.miami.edu Received March 14, 2005;
accepted for publication September 9, 2005. AlphaMed Press 1083-7159/2005/$12.00/0

The Oncologist 2005;10:780791 www.TheOncologist.com

Glck

hormone receptor status, or human epidermal growth factor receptor 2 (HER-2) expression level of the tumor.
The most commonly used anthracyclines in breast cancer treatment are doxorubicin (Adriamycin; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) and
epirubicin (Ellence; Pfizer Pharmaceuticals, New York,
http://www.pfizer.com). The choice of which anthracycline
to use is often a function of prior experience with the agent.
Epirubicin has been used to treat breast cancer in Europe
and Canada since 1980; experience with this agent in the
U.S. oncology community was delayed until the U.S. Food
and Drug Administration approval in 1999 of epirubicin for
the adjuvant treatment of breast cancer. To optimize combination chemotherapy for early breast cancer, it is important
to identify those patients who are most likely to benefit from
adjuvant treatment and to understand the advantages of epirubicin over doxorubicin in specific treatment settings. Currently, the inclusion of a taxane in the regimen and the use of
dose-dense schedules of chemotherapy are also important
considerations in optimizing treatment benefits.

A Brief History of Adjuvant Chemotherapy

Tables 1 4 summarize the major chemotherapeutic
advances in clinical research on early breast cancer in the
past 30 years. Chemotherapy with the alkylating agent
cyclophosphamide in combination with two antimetabolites, methotrexate and fluorouracil (CMF), was established as the gold standard for adjuvant therapy of early
stage breast cancer in the mid-1970s [1]. During the next
20 years, the use of cyclophosphamide in combination with
doxorubicin, the first anthracycline available for chemotherapy for early breast cancer, proved to have equivalent
efficacy to, as well as substantial advantages over, CMF
in terms of tolerability. The National Surgical Adjuvant
Breast and Bowel Project (NSABP) studies B-15 and B-23
(Table 1) found that a regimen of four cycles of doxorubicin
and cyclophosphamide (AC) was equivalent to six cycles
of CMF with respect to event-free survival, relapse-free
survival (RFS), and overall survival (OS) in breast cancer
patients regardless of nodal status, age, or estrogen-receptor
(ER) status, but that AC offered the advantages of a shorter
treatment course with fewer side effects [2]. A 5-year follow-up by the Southeastern Cancer Study Group (SECSG)
(Table 2) established that OS for node-positive patients on
a six-cycle cyclophosphamide, doxorubicin, fluorouracil (CAF) regimen was similar to OS for patients receiving six cycles of CMF [3]. Similar results were obtained
recently in a study by the Spanish breast cancer research
group GEICAM after 4 years of follow-up [4]. In the latter study, 985 patients with lymph nodepositive or highrisk lymph nodenegative breast cancer received either six

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781

cycles of CMF (600/60/600 mg/m 2) or six cycles of FAC

(500/50/500 mg/m2). Although a small benefit in diseasefree survival (DFS) was identified in patients receiving
FAC, OS was similar in both the CMF and FAC treatment
arms. However, the subgroup of high-risk lymph nodenegative patients receiving FAC had significantly longer DFS
(p = .046) and OS (p = .038), while node-positive patients in
both arms had similar rates of DFS and OS [4].
The Early Breast Cancer Trialists Collaborative Group
(EBCTCG) performed an extended 15-year follow-up
meta-analysis that included more than 14,000 patients in
trials that directly compared anthracycline-containing regimens with CMF [5]. That study found that anthracyclinecontaining regimens were significantly more effective at
preventing recurrence (hazard ratio, 0.89; p = .001, twotailed test) and increasing survival (risk of breast cancer
death rate ratio, 0.84; p < .00001, two-tailed test) than were
CMF regimens. The trend toward the superiority of anthracycline-based chemotherapy regimens over those containing CMF extends to the major subsets of early breast cancer
patients: premenopausal (age <50) and postmenopausal
(age, 5069) patients, ER-poor and ER-positive patients,
and both node-negative and node-positive patients.
Although the EBCTCG meta-analysis included both
doxorubicin-treated (60%) and epirubicin-treated (40%)
patients, since the 1990s, the four-cycle doxorubicin-based
regimen has been established in the U.S. as the standard
adjuvant treatment of early breast cancer. In Europe, the
second-generation anthracycline epirubicin (the 4'-epimer
of doxorubicin) has been used in several countries preferentially as a component of chemotherapy regimens for the
adjuvant treatment of early breast cancer. This trend was
driven by a series of large phase III clinical trials comparing
various anthracycline-containing regimens as well as CMF
regimens in both node-positive and node-negative patients.
For example, the International Collaborative Cancer Group
(ICCG) (Table 1) conducted a large randomized trial comparing two different fluorouracilepirubicincyclophosphamide (FEC) dosing regimens with two different CMF
dosing regimens in node-positive premenopausal patients.
That study found some evidence of longer OS (log-rank
test, 5.66; p = .02) and RFS (log-rank test, 4.55; p = .03)
with a six-cycle FEC regimen with a 50-mg/m2 epirubicin
dose compared with a six-cycle CMF regimen [6].
French oncologists formed the French Adjuvant Study
Group (FASG), which beginning in the 1990s conducted a
series of clinical trials, each building on the results of previous trials. The FASG 05 trial (Table 2) of combination chemotherapy in node-positive breast cancer patients with hormone receptornegative status compared epirubicin doses
of 50 mg/m 2 (FEC50) and 100 mg/m 2 (FEC100). Both the

Adjuvant Chemotherapy for Early Breast Cancer

782

Table 1. Summary of early benchmark adjuvant chemotherapy trials

Study

No. of patients

End
points

Treatment

Results

Conclusions

FASG 05
[7,8]

537 (node-positive, operable,

poor prognosis)

DFS,
OS

FEC50 versus FEC100

DFS 54.8% versus

66.3% (p = .03);
OS 65.3% versus
77.4% (p = .007)

~30% RR in DFS. Confirms

dose-response relationship.

10-year update:
DFS 45.3% versus
50.7% (p=.03);
OS 50% versus
54.8% (p=.03)

10-year update: ~24% RR DFS;

~29% RR OS. Significant OS,
DFS benefits confirmed.
Subset anal: OS better in pts
>3 versus 13 positive nodes
(personal communication, H.
Roch)

INT [1]

386
(node-positive)

DFS

CMF

Progression in
24% of controls
versus 5.3%
receiving CMF

Improved DFS with CMF adjuvant treatment

NSABP B15
[56]

2,194
(node-positive)

OS

AC 4, CMF 6; AC
4 6 months of rest
CMF 3

62.3 % DFS, 83%

OS (3-year)

AC 4 not superior to CMF 6

but less toxic, less costly

NSABP B23
[2]

2,008
(node-negative/
ER-negative)

RFS,
EFS, S

AC 4, AC 4 + tam
(5 years);
CMF 6; CMF 6 +
tam (5 years)

RFS: 87% in AC
and CMF groups
(p = .6); OS: 90%
for AC, 89% for
CMF (5-year)

No significant difference in all

four groups for RFS (p = .96),
EFS (p = .8), S (p = .8)

SECSG [3]

528
(node-positive)

OS

CAF 6 versus CMF

6 (starting dose: CAF
= 500/50/500; CMF =
600/40/600)

OS (5-year): 74%
versus 68% (p =
.41)

No significant difference in
survival, similar toxicity

ICCG [6]

759
(node-positive)

RFS,
OS

CMF1 versus FEC1;

CMF2 versus FEC2

CMF1 versus
FEC1: similar
RFS, OS. CMF2
versus FEC2:
OS, 73.8% versus
86.6% (p = .02)

RFS and OS same with CMF1

and FEC1 (p =. 03); OS and
RFS improved with FEC2 versus CMF2

Abbreviations: A, doxorubicin; C, cyclophosphamide; CAF, cyclophosphamide, adriamycin, 5-fluorouracil; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; CMF1, F + C (C, 100 mg/m 2; F, 600 mg/m 2) days 1 and 8, M (40 mg/m 2) days 1 and 8
every 4 weeks 6; CMF2, F + C (600 mg/m2 each) days 1 and 8, methotrexate (40 mg/m 2) days 1 and 8 every 4 weeks 6; DFS,
disease-free survival; E, epirubicin; EFS, event-free survival; ER, estrogen receptor; F, fluorouracil; FASG, French Adjuvant
Study Group; FEC, fluorouracil, epirubicin, cyclophophamide; FEC2, F + C (600 mg/m2 each) days 1 and 8, E (50 mg/m2) day 1
every 4 weeks 6; FEC 50, fluorouracil, epirubicin(50 mg/m2), cyclophosphamide; FEC100, fluorouracil, epirubicin(1000 mg/
m2), cyclophosphamide; ICCG, International Collaborative Cancer Group; INT, Istituto Nazionale Tumori; M, methotrexate;
NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival; pts, patients; RFS, relapse-free survival;
RR, risk ratio; S, survival; SECSG, Southeastern Cancer Study Group; tam, tamoxifen.

5- and 10-year follow-up analyses have shown significant

advantages for the FEC100 regimen in DFS (66.3% versus
54.8%; p = .03) and OS (77.4% versus 65.3%; p = .007) [7].
A 10-year follow-up revealed the superiority of six cycles
of FEC100 in terms of DFS (45.3% in the FEC50 arm and
50.7% in the FEC100 arm), with a relative risk reduction of
24% (Wilcoxon p = .03), and in terms of OS, which similarly favored FEC100 [8]. The FASG 05 trial demonstrated
a dose-response effect of epirubicin, as increasing the dose
from 50 mg/m 2 to 100 mg/m 2 in the FEC regimen resulted
in longer DFS and OS. In contrast, the Cancer and Leukemia Group B (CALGB) study (Table 2) of doxorubicin
dosing of 60 mg/m2, 75 mg/m2, and 90 mg/m2 did not show
better therapeutic efficacy with increasing doses of doxo-

rubicin. In that randomized trial of 3,121 patients, increasing doxorubicin doses produced no significant reduction
in the hazard of either cancer recurrence or death [9]. The
National Cancer Institute of Canada (NCIC) also evaluated
both moderate-risk (13 positive nodes) and high-risk (>4
positive nodes) premenopausal women receiving either
cyclophosphamide, epirubicin, 5-fluorouracil (CEF) or
CMF. Patients fared better on the CEF regimen than on
CMF; 63% of the CEF group remained relapse-free after
5 years, compared with 53% of the CMF group (p = .009),
and OS rates for CEF and CMF were 77% and 70%, respectively (p = .03) [10]. Both the FASG 05 and the NCIC MA.5
trials showed the therapeutic benefit of optimal dosing of
epirubicin as part of a combination chemotherapy regimen

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Table 2. Summary of second-generation adjuvant chemotherapy trials

Study
NCIC
MA.05
[10]

No. of patients
710
(node-positive)

End
points Treatment
RFS,
CEF 120 versus CMF
OS
epirubicin 120 days 1, 8

CALGB
9344 [57]

996
(node-positive)

LR

BCIRG
001 [22]

1,491
(node-positive and
node-negative)

TAC versus FAC

CALGB
9741 [58]

2,005
(node-positive)

A 4T 4C 4 every Dose-dense DFS,

82% versus 75%
3 weeks; A 4T 4
for other groups
C 4 every 2 weeks with
filgrastim; AC 4T 4
every 3 weeks; AC 4
T 4 every 2 weeks with
filgrastim

Results
DFS (5 years),
63% versus 53%
(p = .009); OS (5
years), 77% versus
70% (p = .03)

AC versus ACT

DFS, 75% versus

68%; OS, 87%
versus 81%

Conclusions
~19% RR for death; ~29% RR
for relapse. Moderate dose density is reasonable approach
T improved local control in
patients receiving breast-conserving surgery, despite longer
delay from surgery to RT. No
apparent benefit in patients
treated with mastectomy
DFS hazard ratio, 0.72 (p =
.001); OS, 0.70 (p = .008).
TAC/FAC hazard ratio, 0.61
(HER-2 positive), 0.76 (HER2negative)
Dose-dense DFS RR, 0.74 (p =
.010); OS RR, 0.69 (p = .013).
Dose-dense superior to conventional 3-week treatment

Abbreviations: A, doxorubicin; BCIRG, Breast Cancer International Research Group; C, cyclophosphamide; CALGB, Cancer
and Leukemia Group B; CEF120, epirubicin 120 mg/m2 every 28 days; CMF, cyclophosphamide, methotrexate, 5-fluorouracil;
DFS, disease-free survival; FAC, 5-fluorouracil, adriamycin, cyclophophamide; HER, human epidermal growth factor receptor; LR, local recurrence; NCIC, National Cancer Institute of Canada; OS, overall survival; RFS, relapse-free survival; RR, risk
ratio; RT, radiation treatment; T, paclitaxel; TAC, Taxotere, adriamycin, cyclophosphamide.

to achieve superior long-term 10-year survival in node-positive breast cancer patients at high risk for relapse [8, 11, 12].
Therapeutic benefit from epirubicin-containing chemotherapy has also been demonstrated in the setting of
node-negative disease. In a planned pooled efficacy analysis of the National Epirubicin Adjuvant Trial and the Scottish Cancer Trials Breast Group BR9601 trials, 28% of the
2,391 patients enrolled in the two studies were node-negative. The trials compared the classic CMF regimen with 100
mg/m2 epirubicin followed by CMF (ECMF) and found that
ECMF produced significantly better RFS (hazard ratio,
0.70; 95% confidence interval [CI], 0.580.85; p = .0003)
and OS (hazard ratio, 0.64; 95% CI, 0.510.81; p = .0001),
irrespective of nodal status [13]. Those trials demonstrated
that optimal dosing of epirubicin (100 mg/m2), when added
to CMF combination chemotherapy in the adjuvant breast
cancer setting, is required to achieve superior DFS and OS.
The Danish Breast Cancer Group earlier obtained similar
results. In their trial, 93% of the node-negative patients
who received CEF (with 60 mg/m2 epirubicin) survived for
6 years, compared with 83% of those who received CMF
(p < .01) [14]. Thus, extended follow-up has confirmed that
higher-dose combination chemotherapy regimens containing epirubicin improve therapeutic efficacy for both nodepositive and node-negative early breast cancer patients.

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Epirubicin in Dose-Dense and Dose-Intense

Adjuvant Chemotherapy
There is a positive correlation between delivery of the
intended doses of chemotherapy on schedule and better treatment outcomes in breast cancer [1517]. Optimal
dose intensity in combination chemotherapy is a function
of both the dose level and schedule. Dose-dense schedules
are achieved by minimizing the interval between cycles.
The concept of dose-dense scheduling stemmed from the
observation that breast cancer growth follows Gompertzian
kinetics and that shorter intervals between chemotherapy
treatments might result in a higher log-kill, thus leading
to lower relapse rates and longer survival times [18, 19].
While hematologic toxicities have historically limited dose
intensity and dose density, the availability of biotechnology
derived drugs has enabled further increases in dose intensity and dose density of established anthracycline-based
adjuvant regimens, both in terms of improved supportive
care and efficacy.
One such strategy uses the cytokine G-CSF to treat chemotherapy induced neutropenia and thereby allow for dosing to be scheduled every 2 weeks instead of every 3 weeks.
The CALGB trial 9741 (Table 2) compared dose-dense fourcycle AC chemotherapy followed by four cycles of paclitaxel
(Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.

784

bms.com) in dose-dense intervals with conventional 3-week

intervals in 1,973 node-positive patients and found that the
dose-dense regimen produced significantly better DFS
(hazard ratio, 0.74; p = .010) and OS (hazard ratio, 0.69; p =
.013) [19]. Severe neutropenia was observed less frequently
in patients receiving G-CSF support with the dose-dense
chemotherapy schedule, and the regimen was otherwise
well tolerated [19]. This finding was recently challenged
by an extensive retrospective analysis of this and two other
CALGB trials, in which patients who were ER- or progesterone-receptorpositive and received tamoxifen (Nolvadex ; AstraZeneca Pharmaceuticals, Wilmington, DE,
http://www.astrazeneca-us.com) after chemotherapy experienced a markedly smaller effect of dose-dense delivery of
chemotherapy, with a minimal reduction in the relative risk
for recurrence and no reduction in the risk for death [20]. An
updated 5-year follow-up analysis of these trials, including
CALGB 9741, is expected. The German Arbeitsgemeinschaft Gastrointestinal Onkologie (AGO) trial (Table 3)
examined 1,284 patients with more than four positive lymph
nodes using treatment with a dose-dense, dose-intense regimen of epirubicin, paclitaxel, and cyclophosphamide (ETC)
administered sequentially on a 2-week schedule with GCSF support [21]. These very high risk patients achieved 2year RFS rates of 85%, versus 82% for conventionally dosed
EC + T (p = .046, two-tailed test). Survival benefits were
observed irrespective of hormone receptor status or HER2 expression, but were particularly impressive in women
with 10 or more positive lymph nodes [21]. That trial used
epirubicin doses of 150 mg/m 2 every 2 weeks for a cumulative epirubicin dose of 450 mg/m2 in the dose-dense arm
[21]. In a smaller trial of 173 high-risk patients (10+ positive
nodes or extracapsular involvement), there was no difference in toxicity between a standard EC regimen (epirubicin
dose, 90 mg/m2) and a dose-intense and dose-dense regimen
(epirubicin dose, 120 mg/m2); 5-year OS and DFS were significantly better with the dose-intense, dose-dense regimen
[22]. Thus, several clinical trials have now confirmed the
importance of dose density and dose intensity in the adjuvant treatment of early breast cancer, especially in women
with positive nodal status.

Role of Taxanes in Epirubicin-Based

Chemotherapy Regimens
The introduction of the taxanes (paclitaxel and docetaxel
[Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ,
http://www.aventispharma-us.com]) afforded oncologists
the possibility of adding further survival benefit in the adjuvant treatment of early breast cancer. The Breast Cancer
International Research Group (BCIRG) 001 trial (Table 2)
evaluated a regimen consisting of docetaxel, doxorubicin,

Adjuvant Chemotherapy for Early Breast Cancer

and cyclophosphamide (TAC) versus conventional fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 1,491
women with lymph nodepositive breast cancer. A second
analysis at a 55-month median observation time identified a
hazard ratio for TAC over FAC of 0.72 (p = .001) in terms of
DFS and 0.70 (p = .008) in terms of OS, significantly favoring TAC [23]. Using a sequential schedule in the PACS 01
study of 1,999 women, French and Belgian oncologists
evaluated the use of docetaxel at a dose of 100 mg/m2 every
3 weeks for three cycles following three cycles of standard
FEC100 in women up to the age of 65 years (median age, 50
years) with node-positive breast cancer [24]. The sequential use of FEC100 followed by docetaxel produced significantly better DFS and OS [24]. In a planned subset analysis,
women under the age of 50 years receiving FEC100 and
docetaxel did not gain a survival benefit but experienced
fewer side effects (e.g., less neutropenia, less use of G-CSF,
and less cardiotoxicity) than those receiving six cycles of
FEC100 [24]. Women 5065 years of age experienced benefits both in longer survival and fewer adverse events, thus
making the FEC100docetaxel regimen the most effective
and least toxic among all regimens containing anthracycline and taxane components.
Several additional studies have demonstrated survival
benefits [20, 21] and good tolerability [25] in higher-risk
patients receiving dose-dense and dose-intense epirubicin, either with or without a taxane. Thus, it appears that
epirubicin may become the anthracycline of choice for use
in combination therapy with taxanes as well as in intensive
chemotherapy regimens.

Other Patient Subsets

In addition to node-positive and node-negative patients,
other subgroups, including HER-2positive patients,
patients receiving neoadjuvant treatment, and elderly
patients, have also been shown to benefit from epirubicincontaining chemotherapy. Retrospective analyses of the
CALGB 8869, NSABP B11, Southwest Oncology Group
(SWOG) 8814, and FASG 05 adjuvant trials have suggested
that overexpression of HER-2 may correlate with greater
anthracycline sensitivity [2628]. For patients whose breast
tumors overexpress the HER-2 receptor protein, treatment
with the monoclonal antibody trastuzumab (Herceptin;
Genentech, Inc., South San Francisco, CA, http://www.
gene.com), which inhibits signaling by the HER-2 receptor,
in addition to an anthracycline-containing regimen may provide additional benefits. A phase II study of the neoadjuvant
treatment of advanced breast cancer patients who received
epirubicin and cyclophosphamide followed by paclitaxel,
gemcitabine (Gemzar ; Eli Lilly and Company, Indianapolis, http://www.lilly.com), and (for those with HER-

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Table 3. Summary of recent and ongoing adjuvant chemotherapy trials

Study

No. of patients

End points

Treatment

Results

Conclusions

NCIC
MA.21

~1,500 node-positive or
high-risk node-negative;
postsurgery

DFS, OS,
toxicities,
QoL

CEF (75/60 mg/m2 [day 1, day

8]/500 mg/m2 6) every 4 wks
6; EC (120/830 mg/m2) + GCSF + EPO every 2 weeks 6
T (175 mg/m2) every 3 weeks
4; AC (60/600 mg/m2) 4T
(175 mg/m2) every 3 weeks 4

Ongoing

NSABP
B38

Goal: 4,800
(node-positive)

DD TAC (docetaxel/doxorubicin/ cyclophosphamide); DD

ACT; DD ACT +
gemcitabine

Ongoing

AGO [20]

1,018 evaluable
(4+ nodes)

ETC (E, 150 mg/m2; T, 225

mg/m2; C, 2,500 mg/m2 every
2 weeks), with G-CSF, with or
without EPO-; EC (90/600
mg/m2)T (175 mg/m2) 4,
every 3 weeks; ETC, DD and DI

DD DFS ETC, 85% versus

EC 82% (p = .046)

DD adjuvant ETC
significantly
improves DFS

ICCG
[59]

604 (node-positive)

RFS, OS

tam (20/mg po) versus tam +

E50 4 yrs

DFS, RR 27.9% with E plus

tam (p = .023)

Superior RFS with

E added to tam; no
difference in OS

DBCG
[60]

1,175 (premenopausal
node-negative; premenopausal node-positive,
ER-negative/PR-negative
or unknown; postmenopausal/PR-negative or
unknown; postmenopausal node-positive, ERnegative/PR-negative)

RFS, OS

CEF (600/60/600 mg/m2)

every 3 weeks 9; CEF +
pamidronate 4 years; aCMF
(600/40/600) q3 every 9 weeks
+ pamidronate 4 years

6-yr RFS: CEF 63%, CMF

58% (p = .003), OS: CEF
70%, CMF 65% (p = .009)

RFS RR ~27%.
Superior RFS for
CEF for premenopausal patients

PACS 01
[24]

1,999
(node-positive, <65 yrs)

DFS, OS,
safety,
cost, QoL,
predictive
factors

FEC100 6 (A); FEC100 3

docetaxel (100 mg/m2) 3 (B)

DFS at 5 years: 78.3% versus 73.2% in favor of FEC

D: log-rank unadjusted
p = .012, adjusted
p = .014; HR, 0.83 (95% CI,
0.690.99), p = .041. 5-year
OS, 90.7% versus 86.7% in
favor of FEC100
followed by docetaxel;
% log-rank unadjusted
p = .013; adjusted p = 0.017;
HR, 0.77 (0.591.0), p = .05

Addition of a taxane to FEC100 is

feasible; no unexpected toxicities

NEAT
[13]

2,021 (NEAT); 370

(SCTBG)

NEAT: E (100 mg/m2) 4

cCMF 4 versus cCMF
6; SCTBG BR9601: E (100
mg/m2) 4 CMF 4 versus
CMF 8

ECMF: RFS HR, 0.70 (p

= .003); OS HR, 0.64 (p =
.0001).

ECMF advantage
regardless of node
status, age, ER
status.

Abbreviations: A, doxorubicin; AGO, Arbeitsgemeinschaft Gastrointestinal Onkologie; C, cyclophosphamide; CMF, cyclophosphamide, methotrexate, 5-fluorouacil; cCMF, classical CMF; CI, confidence interval; DBCG, Danish Breast Cancer Cooperative Group; DD, dose dense; DFS, disease-free survival; DI, dose intense; E, epirubicin; EPO, erythropoietin; ER, estrogen
receptor; F, fluorouracil; FEC100, fluoronacil, epirubicin (100mg/m 2), cyclophosphamide; HR, hazard ratio; ICCG, International Collaborative Cancer Group; LR, local recurrence; M, methotrexate; NCIC, National Cancer Institute of Canada; NEAT,
National Epirubicin Adjuvant Trial; NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival; PACS,
picture archiving and communications system; PR, progesterone receptor; QoL, quality of life; RFS, relapse-free survival; RR,
risk ratio; SCTBG, Scottish Cancer Trials Breast Group; T, paclitaxel; tam, tamoxifen.
a
Treatment protocol not used in North America.

2positive tumors) trastuzumab found pathologic complete

responses (pCRs) in 6 of 21 patients and low cardiac toxicity
[29]. In an effort to assess toxicity in more detail, an analysis
of 10 patients who received trastuzumab plus conventional
AC revealed no significant cardiac biopsy findings [30].

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Taken together, these results suggest that the addition of

trastuzumab to epirubicin-containing chemotherapy may
be both relatively safe and effective, in contrast to the initial
observation that the combination of doxorubicin and trastuzumab induced up to a 29% rate of cardiotoxicity [31].

786

Use of neoadjuvant chemotherapy prior to definitive

surgical resection of a primary breast tumor has gained
increased acceptance, especially when patients present with
a large tumor. The rationale is that downsizing a large T2
or T3 lesion to achieve a pCR may result in better long-term
survival, while it also affords the opportunity to evaluate
the chemoresponsiveness of the patient to a specific regimen. HER-2positive patients who received neoadjuvant
therapy consisting of sequential epirubicin-based chemotherapy (FEC90) with paclitaxel followed by trastuzumab
had significantly higher rates of pathologic complete remission than patients who did not receive trastuzumab (67%
versus 25%; p = .02) [32]. Larger numbers of patients are
being enrolled in neoadjuvant clinical trials based on these
early but promising results.
A benefit of epirubicin in elderly patients was shown in
the 338-patient FASG-08 trial, which assessed the impact
of epirubicin as part of a weekly regimen in women over 65
years of age. Those who received weekly tamoxifen alone
were more likely to relapse than those who received weekly
epirubicin plus tamoxifen (hazard ratio, 1.85; p = .02) [33].

HER-2Targeted Therapy
Trastuzumab, a humanized hybrid monoclonal antibody
that selectively binds to the extracellular domain of HER-2,
has become an important component of breast cancer therapy regimens in metastatic breast cancer and more recently
in preoperative therapy [32]. Trastuzumab also produced
better survival in patients who had metastatic breast cancer
overexpressing HER-2 when it was administered in combination with paclitaxel or docetaxel, or combinations of
doxorubicin and cyclophosphamide and other cytotoxic
drugs [34, 35].
Recently, several large randomized clinical trials of
high-risk patients with HER-2positive early breast cancer
have demonstrated that trastuzumab provides additional
beneficial effects when used subsequent to anthracyclinebased chemotherapy and a taxane (Table 4). Specifically,
the NSABP B31 and North Central Cancer Treatment
Group (NCCTG) N9831 adjuvant trials were designed to
compare doxorubicin-based chemotherapy followed by
paclitaxel (ACT) with ACT plus trastuzumab either in
sequence or concurrent with paclitaxel. Preliminary efficacy findings from a combined analysis of those trials after
a mean follow-up of 2 years showed a 56% relative reduction in the risk for recurrence [36], with significant reductions in risk both in terms of DFS (hazard ratio, 0.48; p = 3.0
1012, two-tailed test) and OS (hazard ratio, 0.67; p = .015,
two-tailed test) with ACT plus trastuzumab (n = 1,672;
134 events) compared with ACT (n = 1,679; 621 events);
this is the greatest reduction in risk seen since the introduc-

Adjuvant Chemotherapy for Early Breast Cancer

tion of adjuvant chemotherapy and tamoxifen. This landmark analysis was performed before either trial completed
accrual, resulting in premature trial closure and a short
median follow-up; if the trials were analyzed individually,
results would only trend toward significance.
The ongoing Herceptin Adjuvant (HERA) trial [37]
randomly assigned patients with HER-2positive invasive
breast cancer to receive either trastuzumab for 1 or 2 years
or observation, with a primary end point of DFS; patients
were previously treated with surgery and adjuvant or neoadjuvant chemotherapy. Unlike the B31 and N9831 trials, most
patients in the HERA trial did not receive a taxane, and about
30% of patients were node-negative. An early interim analysis of the HERA trial performed at a median follow-up 1 year
after randomization demonstrated a 46%47% reduction
in the risk for recurrence in trastuzumab-treated patients,
compared with observation. Analyses of 1,694 patients
treated with trastuzumab (127 events) versus 1,693 untreated
patients (220 events) revealed a significantly longer DFS
(hazard ratio, 0.54; p < .0001). Although the short follow-up
in the HERA trial did not demonstrate a significant difference in OS, there was a trend toward superiority in the trastuzumab-treated patients (hazard ratio, 0.76; p < .26).
The findings of the NSABP B31, NCCTG N9831, and
HERA trials are indeed remarkable in that they suggest
that the addition of trastuzumab to anthracycline-based
chemotherapy, either with or without a taxane, may reduce
the recurrence rate by approximately 50%. The magnitude
of this benefit is such that the use of trastuzumab reduces
the risk for tumor recurrence in women with HER-2positive, high-risk breast cancer to rates of recurrence typical
of patients with HER-2negative cancers. Further followup of these patients is of course necessary to confirm these
findings. Nevertheless, in most instances, particularly in
North America, medical oncologists agree that the addition
of trastuzumab to chemotherapy in HER-2overexpressing
breast cancer is becoming standard therapy.

Epirubicins Safety Profile

As with any chemotherapeutic agent, toxicity is a significant
concern with anthracyclines, including long-term hematologic and cardiac toxicities. A meta-analysis of 8,563 NSABP
adjuvant breast cancer patients found that 43 patients (0.50%)
receiving cumulative doxorubicin doses of 240 mg/m 2 in
combination with cyclophosphamide (mean cumulative dose
of cyclophosphamide, 4,500 mg/m2) developed either acute
myeloid leukemia (AML) or myelodysplastic syndrome
(MDS) [38]. Additional studies of adjuvant treatment with
AC regimens suggest that rates of secondary leukemia range
from 0.5% (95% CI, 0.1%2.4%, p = .01) [39] to 0.8% [40].
Fumoleau et al. also reviewed all FASG studies for leukemia

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Table 4. Summary of adjuvant trastuzumab chemotherapy trials

Study

No. of patients

NSABP
B-31 and
NCCTG
N9831 [36]

3,351
(HER-2positive,
node-positive/
high-risk,
node-negative)

HERA [37]

BCIRG
006 [51]

End
points

Treatment

Results

Conclusions

DFS,
OS

N9831: arm A, AC 4 every

3 weeks T (80 mg/week)
12; arm B, AC 4 T (80
mg/week) 12 H (1 year);
arm C, AC 4 T (80 mg/
week) 12 + H (1 year).
B31: arm 1, AC every 3
weeks 4 T (175 mg)
every 3 weeks 4; arm 2,
AC every 3 weeks 4 T
(175 mg) every 3 weeks 4 +
H (1 year)

Pooled analysis (full

analysis not yet complete): DFS at 3 years,
ACT + H versus AC
T: 87% versus 75%;
RR, 56%. OS at 3 years,
ACTH versus AC
T: RR, 33%

At median 2-year
follow-up, H + T following AC confers
survival advantage in
all patient subsets (RR,
33%), longer DDFS.
Cardiac tolerability
acceptable.

5,090
(HER-2 positive,
node-negative/
positive, stage T1c,
LVEF 55%)

DFS,
RFS,
DDFS,
OS

H, 8 mg 6 mg every 3
weeks (2 years); H, 8 mg
6 mg every 3 weeks (1 year);
No T

T (1 year) versus no
T: 2-year DFS, 85.8%
versus 77.4% (p <
.0001); 2-year RFS,
87.2% versus 78.6% (p
= .0001); 2-year DDFS,
81.8% versus 89.7% (p
= .0001); 2-year OS,
95.0% versus 96.0% (p
= .26)

At 1-year follow-up, T
is an effective adjuvant
treatment for patients
with HER-2positive
early breast cancer;
benefits independent
of nodal status, HR
status, and type of
chemotherapy, with
manageable cardiac
toxicity

3,200
(node-positive or
high-risk
node-negative,
HER-2positive,
normal LVEF)

DFS,
OS

Arm 1, AC 4 docetaxel
4; arm 2, AC 4
docetaxel 4 + H every
week 12 H every week
40; arm 3, docetaxel + C
6 + H every week 18 H
every week 34 (no anthracycline)

Abbreviations: AC, doxorubicin and cyclophosphamide; BCIRG, Breast Cancer International Research Group; C, cisplatin or
carboplatin; CHF, congestive heart failure; DDFS, distant disease-free survival; DFS, disease-free survival; H, trastuzumab;
HERA, Herceptin Adjuvant; HR, Hormone receptor; LVEF, left ventricular ejection fraction; NCCTG, North Central Cancer
Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival; RFS, relapse-free survival; RR, risk ratio; T, paclitaxel.

safety and found a 0.28% (95% CI, 0.17%0.43%) cumulative risk for acute leukemia in 2,553 patients receiving epirubicin after 7 years of follow-up [41].
A large-scale meta-analysis of 9,796 early breast cancer
patients showed that, for those receiving cumulative doses
of epirubicin 720 mg/m 2 and cyclophosphamide 6,300
mg/m 2 , the 8-year cumulative probability of developing
AML/MDS was 0.31% (95% CI, 0.14%0.48%), and for
all patients receiving epirubicin (including those receiving epirubicin >720 mg/m2) it was 0.51% (95% CI, 0.30%
0.71%) [42]. Because most of the breast cancer patients who
received anthracyclines also received cyclophosphamide,
an alkylating agent linked independently to secondary
leukemia, it is difficult to determine the precise contribution of the anthracycline component to the development of
hematologic cancer in these patients. Direct comparisons
of clinical trials are usually inappropriate; however, in the
context of large studies and meta-analyses, epirubicinbased regimens have no more risk than doxorubicin-based
regimens in terms of producing secondary leukemia, and

www.TheOncologist.com

some studies [41] suggest a trend toward a lower risk in epirubicin-treated patients.
Cardiotoxicity is known to be associated with use of
anthracyclines in cancer chemotherapy and is generally
linked with higher cumulative dosages. Epirubicin, like
doxorubicin, can result in cardiomyopathy and congestive
heart failure (CHF) in a dose-dependent manner. However,
several analyses have indicated that epirubicin may be less
cardiotoxic than doxorubicin at equimolar doses [14, 43]. A
recent evaluation of 1,576 patients with early breast cancer
(HER-2positive, node-negative or -positive) documented
frequent reductions in left ventricular ejection fraction
(LVEF) after four cycles of AC (cumulative dose of doxorubicin, 240 mg/m2) [44]. In this NCCTG trial, 359 patients
(23.4%) had either grade 1 (16.8%) or grade 2 (6.6%) LVEF
cardiotoxicity, and 37 patients (2.5%) had a >15% decrease
in LVEF [44].
High cumulative doses of anthracyclines, including
epirubicin, produce significant cardiotoxicity, but epirubicin doses can generally be increased by approximately

788

80% over doxorubicin before inducing the same probability of CHF. For instance, in patients with metastatic breast
cancer, a significantly higher rate of CHF was observed
with cumulative epirubicin doses >950 mg/m 2 , whereas
the same risk for doxorubicin would be observed at 550
mg/m 2 [45]. A 7-year follow-up meta-analysis of 3,577
patients in the FASG trials found that the risk for developing left ventricular dysfunction was 1.36% (95% CI,
1.10%1.62%) in a total of 2,553 patients who received
cumulative doses of epirubicin ranging from 300 mg/m 2
to 628 mg/m 2 , compared with 0.2% (95% CI, 0.06%
0.36%) in patients on other regimens (p = .004) [41]. A
long-term (>10 years) prospective follow-up study (FASG
05) assessed cardiac function in 150 disease-free patients;
65 had received cumulative doses of epirubicin of 300 mg/
m 2 (FEC50), and 85 had received epirubicin doses of 600
mg/m 2 (FEC100) [46]. Two patients receiving FEC100
experienced CHF that was possibly related to epirubicin,
while a total of 18 FEC100 patients developed asymptomatic left ventricular dysfunction that was possibly or
probably related to the treatment. No patient experienced
a de novo reduction in LVEF 5 years after completion of
treatment; all patients with cardiac dysfunction observed
5 or more years after treatment had had some evidence of
cardiac dysfunction within the 5-year treatment period.
All FASG 05 patients had received postoperative irradiation to the chest wall and lymph nodes. Of the 18 patients
who developed asymptomatic left ventricular cardiac
dysfunction, all had received left chest wall and nodal
irradiation. Thus, the combination of FEC and postoperative irradiation resulted in an acceptable incidence of cardiac dysfunction [46]. It should be noted, however, that at
equimolar doses, epirubicin and doxorubicin result in the
same response rates and 1-year survival rates, as well as
OS rates, in patients with metastatic breast cancer [47].
Taken together, these studies suggest that the significant
survival benefits of high-dose epirubicin-containing regimens, such as FEC100 and particularly FEC100 followed
by docetaxel, clearly outweigh the limited risk for CHF
in node-positive and also in high-risk node-negative [13]
early breast cancer patients.
Although the use of trastuzumab as a component of
chemotherapy regimens provides additional benefits to
many patients, its use is also associated with cardiotoxicity
[48], which raises concern about its administration in combination with anthracyclines. Because the cardiac profile
of epirubicin is more favorable than that seen with doxorubicin at the most effective dosages, epirubicin was chosen
in the M. D. Anderson Cancer Center (Houston, TX) trial
of sequential combination neoadjuvant regimens. Cardiac
monitoring with LVEF and cardiac troponin T, a sensitive

Adjuvant Chemotherapy for Early Breast Cancer

and specific marker of myocardial injury, was performed

in all patients. There was no evidence of elevated cardiac
troponin T levels, and in two patients, transient LVEF
reductions returned to baseline, thus demonstrating that
the sequential administration of epirubicin and trastuzumab is both feasible and well tolerated; a remarkably
high pathological response rate was identified with a combination of paclitaxel followed by FEC75 in a preliminary
analysis [49]. The BCIRG 006 and the NCCTG N9831
trials using trastuzumab following anthracycline-based
chemotherapy recently reported cardiac safety data (Table
4). An interim analysis of cardiac events in 2,277 patients
enrolled in three arms of the NCCTG N9831 trial found a
higher incidence of cardiac toxicity with trastuzumab following AC and paclitaxel or following AC concurrent with
paclitaxel (12 cases of CHF and one probable cardiac death)
compared with the same regimen without trastuzumab (no
cardiac events) [50]. This marked difference did not reach
the threshold of 4%, which had been prospectively designated as the stopping point, and was therefore judged to
be within the acceptable safety margin. The BCIRG study
tested doxorubicin-based combinations with and without
trastuzumab versus a combination of docetaxel, carboplatin (Paraplatin; Bristol-Myers Squibb), and trastuzumab,
with no anthracycline in the third arm. No cardiotoxicity
has been seen to date in that trial, including in the nonanthracycline arm [51]; further results from that study are
awaited. Together, these studies suggest that sequencing
of the HER-2targeted agent trastuzumab after anthracycline-based chemotherapy is a well-tolerated option with
the potential to yield additional benefits.
While the data summarized above strongly support
adjuvant combination regimens that include epirubicin,
taxanes, and trastuzumab, recent evidence suggests that
epirubicin may have particular advantages over doxorubicin in terms of cardiotoxicity and, more recently, in terms of
efficacy when used in combination with docetaxel. A major
mechanism by which anthracyclines cause cardiac toxicity
is the formation of secondary alcohol metabolites within
cardiac tissue [52]. Human myocardium obtained during
cardiac bypass surgery was tested in cytosol preparations in
vitro to assay cardiac conversion of epirubicin and doxorubicin into their respective secondary toxic metabolites, epirubicinol and doxorubicinol. Paclitaxel was seen to strongly
stimulate the conversion of doxorubicin, but not epirubicin,
into its secondary alcohol metabolite [53]. A previous study
by the same groups found significantly less formation of the
alcohol metabolite epirubicinol compared with doxorubicinol in human myocardium, a pattern consistent with the
reportedly lower cardiotoxicity of epirubicin compared
with doxorubicin [52]. This suggests that, in regimens that

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involve taxanes, epirubicin may be a safer choice in terms

of cardiotoxicity; this advantage allows the use of higher
doses of epirubicin and thus a greater clinical benefit, as
shown by many studies summarized above as well as those
reviewed previously [47].

Conclusions
Within specific patient subsets, there are compelling
reasons to choose adjuvant treatment with epirubicin, as
indicated by studies that have focused on specific patient
groups. Epirubicin-based polychemotherapy benefits
node-positive and node-negative patients in the adjuvant
setting and has demonstrated superior efficacy in HER2positive patients, elderly patients, and patients receiving
preoperative neoadjuvant treatment. Results from more
than a decade of research on anthracyclines in breast cancer treatment clearly favor epirubicin as the anthracycline
of choice across the entire spectrum of patients. Epirubicin
has a superior safety profile compared with doxorubicin in
terms of secondary leukemia and cardiotoxicity, two key
concerns in determining optimal therapy for breast cancer.
Dosing and toxicity studies have identified a strong doseresponse relationship for epirubicin and revealed that this
compound is tolerated at higher doses than doxorubicin,
resulting in significantly better efficacy. For instance, the
less severe cardiotoxicity of epirubicin relative to doxorubicin permits higher dosing without adverse cardiac
events; cumulative doses of epirubicin of 600 mg/m 2 are
possible, compared with doses of doxorubicin of 360 mg/
m2. This allows more dose intensity using epirubicin rather
than doxorubicin. When given at optimal doses, particularly with G-CSF support to permit dose-dense and doseintense regimens, epirubicin is a key component of combination therapy regimens that improves both the safety
and survival of patients with breast cancer. The ability to
combine these regimens with other powerful therapies,
especially the taxanes and monoclonal antibodies such as
trastuzumab, further expands the treatment options avail-

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789

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Disclosure of Potential Conflicts

of Interest
Dr. Glck has acted as a consultant for and has received support from sanofi-aventis, Genentech, Pfizer, and Novartis.
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