Abstract. Forty-six previously untreated patients with
advanced breast cancer were eligible for the present
randomised phase I study. It aimed to evaluate the toxicity and
activity of a therapeutic sequence with epirubicin on day 1
followed by paclitaxel on day 2 (sequence A) or the reverse
sequence, i.e., paclitaxel on day 1 followed by epirubicin on
day 2 (sequence B). The starting doses of epirubicin and
paclitaxel, administered either according to sequence A or B,
(level 1 cohort) were 90 mg/m2and 175 mg/m2, respectively.
Per cohort of 3 patients, the dose of paclitaxel was increased
by 25 mg/m2(levels 2 and 4) and of epirubicin by 10 mg/m2
(levels 3 and 5). Treatment was repeated with 3-week intervals.
The maximal tolerated dose (MTD) was achieved at level 1 in
sequence B (paclitaxel first) and level 3 (epirubicin100 mg/m2
followed by paclitaxel 200 mg m2) in sequence A. Dose limiting
toxicity (DLT) was neutropenia (+/- febrile) in both
sequences. Cardiac events occurred in 28% of the patients;
significant decrease in left ventricular ejection function
(LVEF) was observed in 8/33 and in 2/13 patients in sequence
A and B, respectively. This was associated with 5 and 1 cardiac
heart failure (CHF), respectively. In 43 evaluable patients, 10
CR and 25 PR were observed (overall response rate 81%). In
the 20 patients with locally advanced disease (LABC), the
respective numbers were 7 CR and 11 PR; in the 23 metastatic
(MBC) patients, 3 CR and 14 PR were recorded. The median
survival of the both groups was not reached at 33 + months.
In conclusion , the combination of epirubicin and paclitaxel
has significant activity in breast cancer. The recommended
sequence of both drugs in combination therapy, mainly to
avoid neutropenia, is epirubicin day 1 followed by paclitaxel
on day 2. Cardiac toxicity remains problematic in either
sequence of administration.
Advanced breast cancer (BC) is of major public health
concern as it represents the second cause of cancer related-
death for American and European women. Despite all
available hormonal and
metastatic breast cancer (MBC) remains largely incurable
with less than 10% disease-free patients 5 years after
diagnosis (1, 2). However, the patients more likely to have a
prolonged survival (and perhaps even cure) are those having
achieved a complete tumoral response in the early phase of
their disseminated disease (1, 2).
The most important anticancer agents available up to the
mid 1990’s were the anthracyclines (doxorubicin and
epirubicin) (3, 4). These were the cornerstone of any
palliative regimen for advanced BC for two decades. They
were proven to be superior to combinations not including
anthracyclines in randomised trials (3, 4). A dose-response
relationship was also clearly established (5); however,
despite frequent improvements in response rate, response
duration or time to progression, no clear improvement in
overall survival could be observed in individual trials (5).
Nevertheless, a recent meta-analysis emphasized the
relevance of the response quality (complete, partial or
none) as a surrogate endpoint of survival (1).
More recently, the taxanes, paclitaxel and docetaxel, have
been approved for the treatment of MBC (6, 7). The taxanes
are microtubule inhibitors that are reversibly bound to the
beta subunit of tubulin, inducing microtubule polymerization
and inhibiting microtubule depolymerization, leading to cell
arrest at the G2/M-phase of the cell cycle (6, 7). The taxanes
also induce apoptosis in cancer cells and inhibit tumor
angiogenesis (6, 7). Paclitaxel, as a single agent, produced
*Partly presented at the San Antonio Breast Cancer Symposium,
Correspondence to: C. Focan, M.D., Ph.D., CHC-Clinique Saint-
Joseph, Rue de Hesbaye 75, 4000 Liege, Belgium. Tel: 00 32 4 224
89 90, Fax: 00 32 4 224 89 91, e-mail: Christian.focan@CHC.be
Key Words: Breast cancer, epirubicin, paclitaxel, sequence.
ANTICANCER RESEARCH 25: 1211-1218 (2005)
Sequential Administration of Epirubicin and Paclitaxel for
Advanced Breast Cancer. A Phase I Randomised Trial*
C. FOCAN1, M.P. GRAAS1, M. BEAUDUIN2, J.L. CANON3, J.P. SALMON4,
G. JERUSALEM5, D. FOCAN-HENRARD1, J.P. LOBELLE6and D. SCHALLIER7
1CHC Clinique Saint-Joseph, Liège; 2CH Jolimont, Haine Saint-Paul;
3Clinique Notre Dame Reine Fabiola, Charleroi; 4CH Peltzer La Tourelle, Verviers;
5CHU-Sart-Tilman, Liège;6Pfizer Oncology (Benelux); 7Academic Hospital VUB – Jette, Belgium
equivalent survival compared to the previously common
combination of cyclophosphamide, methotrexate, fluorouracil
and prednisone in untreated MBC patients (6); response
rates in these comparisons were usually similar, as well. In
monochemotherapy, paclitaxel displayed a dose-response
relationship in a randomised comparison of two different
dosages (8). This drug was combined with doxorubicin, first
using prolonged infusions in the early trials (i.e., 24- to 72-h
infusion for paclitaxel and 48- to 72-h for doxorubicin) (9-11),
and afterwards in combined or sequential scheduling (12, 13).
These combinations led to impressive response rates
(sometimes ≥90%) but also to severe toxicity, i.e., cardiac
toxicity and neutropenia with a risk of congestive heart failure
(CHF) in ≥20% of patients (13, 14).
In 1997, at a time when no consensus existed regarding the
appropriate sequence of administration of paclitaxel and the
presumed least cardiotoxic anthracycline epirubicin in a
combination schedule (4), a randomised phase I trial was
initiated to determine the MTD of both drugs given 24 h
apart, starting with epirubicin followed by paclitaxel or the
reverse sequence. Detailed cardiac and hematological
monitoring was performed during the trial. The determination
of tumoral outcome was a secondary objective.
Materials and Methods
The study was conducted as a multicenter trial. It was performed in
accordance with the Helsinki Declaration on Human Rights and
after individual approval from the medical ethical committee of
each individual institution.
Women aged 18 to 60, with a histologically proven diagnosis of
locally advanced breast cancer (LABC) (stages IIIA or IIIB) or
recurrent MBC (stage IV), were eligible for the study. The
following conditions were required: WHO performance status ≤2,
life expectancy ≥3 months, no prior chemotherapy for MBC or
LABC, no prior adjuvant high-dose intensified chemotherapy with
autologous bone marrow or stem cell rescue, adjuvant
chemotherapy stopped at least 6 months before the study entry, no
(granulocytes ≥2, 000/mm3; platelets ≥150, 000/mm3), kidney
(creatinine ≤16 mg/l) or liver functions (SGOT, SGTP, total
bilirubins ≤1.5 and/or alkaline phosphatase ≤2.5 upper normal
limits in absence of bone metastases).
If patients had previously received an anthracycline or an
anthracenedione as adjuvant treatment, a maximum cumulative
dose of ≤300 mg/m2doxorubicin, ≤480 mg/m2epirubicin and ≤60
mg/m2mitoxantrone was allowed. Prior radiotherapy was permitted
provided it was not performed on measurable or evaluable lesions.
Normal left ventricular ejection function (LVEF) (≥55% by
isotopic or ultrasound testing) was required before starting the
treatment. Patients with an active cardiac event within the previous
6 months, as well as patients suffering from an actual severe and/or
active heart disease (class III or IV heart failure according to the
New York heart association) or with active central nervous system
(CNS) metastases, were excluded. Patients had to present at least
one measurable or evaluable lesion according to WHO as assessed
by a work-up including a general biology with tumor markers
adequate bone marrow
(CEA, CA 15.3), a recent mammography, CT scans of thorax and
abdomen and a bone scintigraphy.
After informed consent, patients entered into the phase I study.
They were stratified according to the centre and to the type of
advanced disease (either locally advanced or recurrent metastatic)
and randomised to receive chemotherapy according to sequence A
(epirubicin day 1, paclitaxel day 2) or sequence B (paclitaxel day
1, epirubicin day 2). In order to determine the MTD for each
sequence, according to the most recent recommendations on the
management of phase I trials, cohorts of 3-6 cases were allocated
either to sequence A or to sequence B (15). Successive dose-levels
were foreseen: in sequence A, epirubicin preceded paclitaxel at the
respective dose-levels of 90/175, 90/200, 100/200 and 100/225
mg/m2, while in sequence B, the reverse sequence, at the respective
dose levels of 175/90, 200/90, 200/100 and 225/100 mg/m2, was
programmed. Epirubicin was administered as a short infusion (30
min) and paclitaxel as a 3-h infusion with standard pre- and post-
medication. Paclitaxel was kindly supplied for the study by Bristol
Myers Squibb, Belgium.
Courses were repeated every 21 days. Prophylactic administration
of 5HT3-antagonists was standard, while that of growth factors was
excluded during the first 2 courses.
During the first course, patients were followed twice weekly for
hematological (WBC, granulocytes, platelets) and weekly for
clinical evaluation. As from course 2, hematological and clinical
controls were scheduled once between days 10-14.
Dose-limiting toxicities (DLT) were defined as follows:
granulocytes ≤500/mm3for at least 7 days; granulocytes ≤100/mm3
for at least 3 days; granulocytes <1,000/mm3at retreatment day
(21); febrile neutropenia (fever with granulocytes ≤500/mm3);
grade 4 thrombocytopenia (platelets ≤25,000/mm3); any grade 3
non-hematological toxicity, in particular grade 3 mucositis ≥5 days;
alopecia and tiredness were excluded. If no DLT was recorded
among 3 patients treated at a given dose-level, the following
patients were enrolled at the next dose-level and this separately for
sequence A or B. If at least one DLT was recorded among 3
patients treated at a given dose-level in a given sequence, 3 more
patients had to be enrolled at that dose-level.
MTD was defined as the epirubicin-paclitaxel or paclitaxel-
epirubicin dose at which ≥2 patients out of 6 from a particular
dose-level cohort reported DLT after the first course. Another
cohort of 6 patients had to be entered for confirmation of that dose-
level in the case that MTD was already reached at dose-level 1;
otherwise, a confirmatory cohort of 6 patients had to be recruited at
the previous inferior dose-level.
If a patient developed a DLT, she had to leave the study and the
clinician was free to choose further treatment and/or any dose
adaptation. Treatment had to be stopped in case of a drop in
LVEF below 55% and/or ≥15% with respect to the baseline
determination. LVEF determination by cardiac echography or
MUGA scan was foreseen every 2 courses.
In this phase I study, patients could receive a maximum of 8
courses with epirubicin and paclitaxel and, if necessary, 4 additional
courses with paclitaxel alone. Tumor evaluation was recommended
every 2 courses. In cases of documented CR, PR or no change after
4 courses, eligible patients could be oriented to intensification
protocols with peripheral stem cell rescue according to the decision
of the investigator or could receive 2 more courses. After 6 courses,
clinicians were free to choose further treatment (i.e., surgery +/-
radiotherapy in LABC, further identical treatment with a maximum
ANTICANCER RESEARCH 25: 1211-1218 (2005)
of 8 courses including epirubicin followed by courses with paclitaxel
as single agent, alternative chemotherapy and/or hormonotherapy).
The evolution of the patients with respect to progression and
survival was recorded; actuarial survivals (progression-free and
overall) were computed by the Kaplan Meier estimates for the
Due to the specific nature of this study, registration procedures,
case report form (CRF) completion and data management
collection were performed with pro-active exchange of information
through fax communication.
Patients’ characteristics. Forty-six patients were entered in the
trial from 02/17/1997 to 02/14/2000. Their main
characteristics are presented in Table I. Eleven patients had
received adjuvant chemotherapy 10 times including
anthracyclines or anthracenedione. Four patients received
the treatment outside the frame of the study (paclitaxel free
of charge as an expanded access cohort) at the previously
defined MTD, but were fully evaluated; one of those patients
with excellent performance status was older than 60 years.
Toxicity and MTD. Tables II and III present the toxicity at
cycle 1 for each dose-level in both sequences as well as the
number of DLT recorded. The total number of cycles
administered was 224, 145 in sequence A and 79 in
sequence B. The mean number of cycles per patient was 5.9
(range 2-9) in sequence A and 6.8 (range 1-9) in sequence
B. The main side-effect which occurred in both sequences
was grade 3 or 4 granulocytopenia accompanied by febrile
events. No toxic death was observed. Alopecia (grade 2) was
universal. While MTD was only reached above level 3 in
sequence A, MTD was already observed and confirmed at
level 1 for sequence B. Therefore, with respect to
myelosuppression, sequence A (E→P) was definitively
better tolerated than sequence B (P→E).
The results of detailed monitoring of cardiac function are
presented in Figure 1. Significant cardiac events (significant
drop in LVEF and/or cardiac heart failure (CHF) occurred
irrespective of the sequence: sequence A: 8/33 (24% with 5
CHF); sequence B: 2/13 (15% with 1 CHF). CHF occurred
Focan et al: Sequential Epirubicin – Paclitaxel for Breast Cancer
Table I. Patients’ characteristics.
32 – 69*
- T (1/2/3/4/x)
- N (0/1/2/3/x)
- IV (M1)
Previous adjuvant chemotherapy
*1 case >60y in the expanded access cohort
Table II. Dose-limiting toxicity (DLT) at cycle 1. Number of patients.
Sequence A Sequence B
Nb IncludedNb DLT Nb Included Nb DLT
Details of DLT C1
Sequence A: Level 1: 1 neutropenia
Level 4: 2 febrile neutropenia
Sequence B: Level 1: 1 neutropenia
4 febrile neutropenia
Table III. Toxicity at cycle 1 (grade 3+4). Number of patients.
Level 1 Level 2Level 3 Level 4
Sequence A 77 163
NV (gr 3)
Sequence B 13
Stom (gr 3)
Abbreviations: Hb: hemoglobin; WBC: leucocytes; NV: nausea-
vomiting; stom: stomatitits; diar: diarrhea; cut: cutaneous.
mainly in patients having received ≥7 courses (after a
median cumulative dose of epirubicin of 625mg/m2, range 90
to 900 mg/m2). Unexpectedly, one patient developed CHF
after one cycle of epirubicin in sequence B. Moreover 4/10
of these patients had previously received anthracyclines as
adjuvant treatment. Table IV details these observations.
Tumor outcome. Although the evaluation of antitumoral activity
was not a primary end-point, response could be evaluated in
43/46 patients (3 patients were unassessable, 1 for previous
surgical removal of the target and 2 for early withdrawal from
the study). As represented in Table V, a high response rate was
observed (81%) in both arms and was seemingly influenced by
previous adjuvant anthracycline treatment [1 CR + 4PR/10
(50%) in patients previously treated with anthracyclines versus
9 CR + 21 PR/33 (91%) in anthracycline-naïve patients].
Clinical complete response occurred in 10/43 patients (23.3%),
with 13% (3/23 patients) in MBC versus 35% (7/20 patients) in
LABC. Confirmed pathological CR (pCR) was less common in
LABC and observed only in 3 patients. Four other cases could
also be considered as ‘almost' pCR with only residual intra-
canalicular carcinoma in 2, a small residual millimetric
carcinoma in 1 and atypical cells altered by chemotherapy and
not necessarily neoplastic in another patient.
The median time to progression was 15.4 months for the
whole group (14.2 for metastatic and 33.4+ months for
loco-regional disease). Median survival for both sub- groups
was not reached at 33.3+ months.
Anthracyclines and taxanes are among the most active agents
for the treatment of breast cancer. The optimal way of
combining both drugs, either concomitantly in a combination
or sequentially as single agent, is still being debated. The
objective of the present study was to explore the optimal
sequence of administration of both drugs in a combination
in previously untreated patients with LABC or MBC.
The present study demonstrated that the sequence of
administration of paclitaxel and epirubicin both given as a
short intravenous infusion, 24 hours apart, is crucial with
respect to hematological toxicity. Higher doses of both
drugs could be delivered in sequence A (E→P) than in
sequence B (P→E). The DLT was (febrile) neutropenia in
both sequences, but this occurred at dose level 1 in
sequence B (paclitaxel 175/m2followed by epirubicin
90mg/m2) and at dose level 3 in sequence A (paclitaxel 200
mg/m2preceded by epirubicin 100 mg/m2). Interestingly,
significant cardiac events (decrease of LVEF and/or CHF)
were recorded in both sequences.
On reviewing the available preclinical literature about the
combination of taxanes and anthracyclines for the treatment
of human cancer, it is clear that no unanimous consensus has
been reached. On the one hand, some preclinical experiments
suggest the benefit of sequencing both drugs, favoring the
administration of paclitaxel first (16), while in another, the
reverse sequence appeared better (17). In other experiments,
only additive or even antagonistic interactions were observed,
especially with simultaneous exposure (18-21).
Early clinical trials incorporating prolonged infusion of
both paclitaxel (24 to 72h) and doxorubicin (48 to 72h)
resulted in severe hematological and non-hematological
toxicity (10, 11). Sequencing paclitaxel after doxorubicin and
reducing the duration of infusion of both largely reduced
the hematological toxicity, while still leading to a high
incidence of cardiac toxicity (14).
ANTICANCER RESEARCH 25: 1211-1218 (2005)
Figure 1. Evolution of left ventricular ejection fractions (LVEF) along time. Left: cumulative dose epirubicin <500mg/m2. Right: cumulative dose
administration of paclitaxel 3 to 24 h before doxorubicin
or epirubicin reduced the hepatic clearance and increased
the peak plasma drug concentration (C max) and Area
Under the Curve (AUC) of the latter (22-28). Also, the
active anthracycline metabolites, e.g. doxorubicinol and
epirubicinol, which are potentially more cardiotoxic, were
increased (29). In addition, an inverse correlation between
studies revealed that the
the AUC of epirubicin and neutrophil recovery was
reported (30). Finally, a reduction of the renal clearance
of epirubicin and epirubicinol has been related to the
interference with paclitaxel and/or its vehicle cremophor
(31, 32). The effect of paclitaxel appears dose- and
schedule-dependent. In order to reduce myelosuppression
in the paclitaxel – epirubicin combination, it seems logical
to give epirubicin first followed by paclitaxel with an
interval of at least 24 h (26, 27). It is less obvious to
recommend any strategies, based on pharmacokinetic or
pharmacodynamic observations, to reduce cardiac toxicity.
Indeed, in our study, cardiac toxicity occurred in both
sequences; at level 1 of sequence A, in which the least
cardiac events were to be expected, 3 out of 7 patients
developed CHF after cumulative dose of epirubicin (CDE)
of 284, 718 and 718mg/m2.
Focan et al: Sequential Epirubicin – Paclitaxel for Breast Cancer
Table IV. Cardiac events.
Sequence A 8/33 (24%) 5 CHF
Sequence B 2/13 (15%) 1 CHF
Level 1 # 3 CHF during further ABMT; had received 8 courses.
Survived (CDE: 718 mg/m2)
LVEF drop 84→50/25% + CHF post C7;
exitus (CDE: 718 mg/m2)
Died in CHF and anthracycline
- received only 3 courses (CDE: 284 mg/m2)
- end therapy 11/97, death 07/98
- received previous anthracyclines and
- no precise follow-up of LVEF
Level 2 # 20 LVEF drop 85→64% post C4 (CDE: 540 mg/m2)
Epirubicin stopped after C7; asymptomatic
# 24 LVEF progressive drop 63 → 55 → 45% (C3)
(CDE: 267 mg/m2)
# 27 CHF 3 months post C8 (LVEF 38%).
Previous anthracyclines. Survived
(CDE: 531 mg/m2)
Level 3 # 39 LVEF drop 57→52% post C2;
asymptomatic (CDE: 191 mg/m2)
Level 4 # 37 LVEF drop 44% post C8 –
CHF (CDE: 900 mg/m2)
Previous irradiation of left thorax: survived
Level 1 # 13 LVEF drop 71→57 → 62→53% post C6
(CDE: 720 mg/m2)
no clinical symptom. Previous anthracyclines
CHF post C1; previous anthracyclines
(CDE: 90 mg/m2)
Comments: cardiac problems in previous anthracyclines: 4/10
CHF occurred generally after ≥7 courses
Abbreviations: CHF: Cardiac Heart Failure
ABMT: Autologous Bone Marrow Transplantation
CDE: Cumulative Dose Epirubicin
LVEF: Left Ventricular Ejection Fraction
Table V. Response per disease category and per sequence.
CR PRNC PD
All (32)8 1842
M1 (16)1 1122
All (43) 102562
M1 (23)3 1442
M0 (20)7 1120
Note: 3 cases unevaluable (1 no target in sequence A; 2 study
withdrawals post C1 for febrile neutropenia in sequence B)
Abbreviations: CR: complete remission; PR: partial remission; NC: no
change; PD: progressive disease; MO: locally advanced breast cancer;
M1: metastatic disease.
Other strategies to decrease the incidence of cardiac
toxicity could be the use of the liposomal formulation of
doxorubicin, the limitation of the doxorubicin or epirubicin
dose to 50mg/m2or 75mg/m2per course or to 360mg/m2or
480mg/m2cumulative dose, respectively (26, 27, 33). Also the
use of the cardioprotectant dexrazoxone (33) or the use of
even longer administration intervals could be suggested (28).
Another way of overcoming potential troublesome
pharmacokinetic interferences and potential toxicities could be
not to combine paclitaxel and epirubicin at all, but rather to
use both drugs as single agents sequentially with 3-week
intervals (6). Sledge et al. have shown that sequential treatment
with single agent paclitaxel and doxorubicin produced identical
survival results in metastatic breast cancer patients compared
to the combination of both (9). In the latter study, the response
rate and time to treatment progression were, however, in favor
of the combination therapy (9).
The present trial indicates that the combination of
epirubicin and paclitaxel is active. A high response rate in
the protoadjuvant situation and/or in anthracycline-naïve
patients was achieved. The CR rate observed in the present
trial was almost double the standard epirubicin-based
treatment employed by our group in a previous trial (5). This
may represent a real improvement if one considers that only
complete responders to treatment may have a chance of
prolonged survival and even cure (2). Nevertheless, when the
CR in the LABC setting were carefully analyzed, the pCR
remained low, in the present report as well as in others (6).
In the metastatic setting, four recently published or
reported trials compared an epirubicin-paclitaxel arm to
standard anthracycline-cyclophosphamide (34-37). In only
one study was a significant difference in response rate, time
to progression and survival favoring the anthracycline-
paclitaxel arm observed (34-37).
Therefore, since toxicity is a relevant problem in these
patients, probably alternative approaches for the majority of
patients, including previously established combinations or
sequential use of anthracyclines and taxanes, have to be
Our trial has defined the MTD and the optimal sequence of
administration of epirubicin and paclitaxel in the first-line
treatment of advanced breast cancer. The sequence of
epirubicin on day 1 followed by paclitaxel on day 2 was the
better tolerated one, and the doses recommended for
further phase II or III studies, without growth factors, are,
respectively, 100 and 200 mg/m2.
Pharmacokinetic studies published elsewhere support the
conclusion that the paclitaxel effect on epirubicin
metabolism explains the enhanced toxicity in the sequence
in which paclitaxel is administered first.
An interesting response rate was observed, quite in
accord with most recent data on anthracycline-taxane
associations. The importance of this finding for the final
outcome of the patients remains to be established.
Finally, the observation of cardiac events leading to
potentially harmful CHF limits the application of such
therapy to younger patients, unexposed to anthracyclines. In
addition, we recommend limiting the number of courses to
6 in this patient population.
This study was supported in part by grants from Pfizer and Bristol
Myers Squibb, Belgium.
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trial of epirubicin and
Received September 29, 2004
Revised February 2, 2005
Accepted February 16, 2005
Focan et al: Sequential Epirubicin – Paclitaxel for Breast Cancer