Sequential administration of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine for patients with HER2-negative and locally advanced or node-positive breast cancer.

Abstract

Capecitabine is effective against metastatic breast cancer (MBC). We hypothesized that sequential treatment with dose-dense epirubicin/cyclophosphamide (EC) and docetaxel/capecitabine would be active and tolerable in the adjuvant/neoadjuvant setting.
In this prospective phase II clinical trial patients with HER2-negative and node-positive or locally advanced tumors were eligible to receive four cycles of EC (100/600 mg/m2) every 2 weeks with G-CSF on days 3-10, followed by four cycles of docetaxel/capecitabine (75/1,000 mg/m2 b.i.d., days 1-14) every 3 weeks.
Fifty-five patients were enrolled with median age of 49, and 80% had hormone receptor-positive disease. The median tumor size was 2.5 cm, with a median of two axillary nodes involved. Seventy-five percent of the first 20 patients had grade 2/3 hand-foot syndrome (HFS). Dose reduction of capecitabine to 800 mg/m2 reduced the grade 2/3 HFS incidence to 31% in the remaining patients. No grade 4/5 toxicities were observed. All 20 patients treated preoperatively responded, with 5 (25%) pathologic complete responses and 3 additional pT0N1 tumors. At a median follow-up of 48 (range 28-60) months, the event-free and overall survival rates are 91 and 98%, respectively.
Sequential treatment with dose-dense EC followed by docetaxel/capecitabine, using a lower capecitabine dose than that approved for MBC, has an acceptable toxicity profile and encouraging activity when used as neoadjuvant or adjuvant treatment of breast cancer.

Full text

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Cancer Chemother Pharmacol
DOI 10.1007/s00280-009-1049-y
123
ORIGINAL ARTICLE
Sequential administration of dose-dense
epirubicin/cyclophosphamide followed by docetaxel/capecitabine
for patients with HER2-negative and locally advanced
or node-positive breast cancer
Yago Nieto · José Manuel Aramendía · Jaime Espinós · Susana De la Cruz · Oscar Fernández-Hidalgo ·
Marta Santisteban · Leyre Arbea · Javier Aristu · Rafael Martínez-Monge · Marta Moreno · Luis Pina ·
Josu Sola · Gerardo Zornoza · Fernando Martínez Regueira
Received: 8 May 2009 / Accepted: 1 June 2009
© Springer-Verlag 2009
Abstract
Purpose
breast cancer (MBC). We hypothesized that sequential
treatment with dose-dense epirubicin/cyclophosphamide
(EC) and docetaxel/capecitabine would be active and toler-
able in the adjuvant/neoadjuvant setting.
Methods
In this prospective phase II clinical trial patients
with HER2-negative and node-positive or locally advanced
tumors were eligible to receive four cycles of EC (100/
600 mg/m2) every 2 weeks with G-CSF on days 3–10, fol-
lowed by four cycles of docetaxel/capecitabine (75/
1,000 mg/m2 b.i.d., days 1–14) every 3 weeks.
Capecitabine is eVective against metastatic
Results
age of 49, and 80% had hormone receptor-positive dis-
ease. The median tumor size was 2.5 cm, with a median of
two axillary nodes involved. Seventy-Wve percent of the
Wrst 20 patients had grade 2/3 hand-foot syndrome (HFS).
Dose reduction of capecitabine to 800 mg/m2 reduced the
grade 2/3 HFS incidence to 31% in the remaining patients.
No grade 4/5 toxicities were observed. All 20 patients
treated preoperatively responded, with 5 (25%) patho-
logic complete responses and 3 additional pT0N1 tumors.
At a median follow-up of 48 (range 28–60) months, the
event-free and overall survival rates are 91 and 98%,
respectively.
Conclusions
Sequential treatment with dose-dense EC
followed by docetaxel/capecitabine, using a lower capecita-
bine dose than that approved for MBC, has an acceptable
toxicity proWle and encouraging activity when used as neo-
adjuvant or adjuvant treatment of breast cancer.
Fifty-Wve patients were enrolled with median
Keywords
Adjuvant · Neoadjuvant · Breast cancer
Phase II trial · Capecitabine · Docetaxel ·
Introduction
Recent advances in the treatment of node-positive breast
cancer include the development of dose-dense anthracyline
schemas [1] and combinations of anthracyclines and tax-
anes. Several trials have shown the beneWt of both sequen-
tial and concurrent combinations of anthracyclines and
paclitaxel or docetaxel [2–6].
Capecitabine is an eVective agent in metastatic breast
cancer (MBC). O’Shaughnessy and colleagues have shown
the superiority of docetaxel/capecitabine over docetaxel
alone in patients with metastatic disease [7]. The synergy
Y. Nieto · J. M. Aramendía · J. Espinós · S. De la Cruz ·
O. Fernández-Hidalgo · M. Santisteban
Department of Medical Oncology,
Clínica Universitaria de Navarra, Pamplona, Spain
L. Arbea · J. Aristu · R. Martínez-Monge · M. Moreno
Department of Radiation Oncology,
Clínica Universitaria de Navarra, Pamplona, Spain
L. Pina
Department of Radiology,
Clínica Universitaria de Navarra, Pamplona, Spain
J. Sola
Department of Pathology,
Clínica Universitaria de Navarra, Pamplona, Spain
G. Zornoza · F. M. Regueira
Department of Breast Surgery,
Clínica Universitaria de Navarra, Pamplona, Spain
Y. Nieto (&)
UT MD Anderson Cancer Center, 1515 Holcombe Blvd,
Unit 423, Houston, TX 77030, USA
e-mail: ynieto@mdanderson.org

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Cancer Chemother Pharmacol
123
between these two agents seems to result from docetaxel-
induced upregulation in tumor cells of thymidine phosphor-
ylase (TP) [8, 9], the enzyme responsible for the intracellular
activation of capecitabine from its intermediate metabolite
5?-deoxy-5-Xuorouridine (5?-FUDR) to the active form
5-Xuorouracil (5-FU). Numerous studies have demonstrated
that higher TP content in tumor cells has a favorable eVect
on patient outcomes after treatment with capecitabine
[10–13].
In view of its eVectiveness in metastatic disease, capecit-
abine holds substantial promise in the treatment of nonmeta-
static breast cancer, a setting where it has not been studied
extensively. Prior treatment with doxorubicin/cyclophos-
phamide (AC) or epirubicin/cyclophosphamide (EC), but
not with a 5-FU-containing regimen, has been shown to
upregulate the expression of TP in breast cancer cells [14].
We hypothesized that sequential treatment with TP-upregu-
lating dose-dense epirubicin/cyclophosphamide (EC) fol-
lowed by docetaxel/capecitabine would be active and well
tolerated in the adjuvant or neoadjuvant settings. Given the
observed antagonism between the anti-HER2 antibody
trastuzumab and 5-FU (and, by extension, capecitabine) in
preclinical studies [15, 16], we restricted enrollment to
patients with HER2-negative disease, who do not beneWt
from trastuzumab.
We report here a prospective phase II study of four
cycles of dose-dense EC followed by four cycles of doce-
taxel/capecitabine as adjuvant or neoadjuvant treatment of
patients with HER2-negative, node-positive or locally
advanced breast cancer.
Patients and methods
This trial was conducted at the Clinica Universitaria de
Navarra, Spain, between 2005 and 2006. The study proto-
col was approved by the Ethics Committee of our institu-
tion. All patients gave informed consent prior to
enrollment. Eligible patients were 18–70 years of age and
had histologically proven breast cancer, stage IIA to IIIC,
with either involvement of axillary nodes or locally
advanced disease that was deemed suitable for preoperative
chemotherapy; performance status 0–2; normal end-organ
function (creatinine clearance >50 ml/min, left ventricle
ejection fraction >50%, glutamic oxaloacetic transaminase
(GOT, AST)/glutamic pyruvic transaminase (GPT, ALT)/
bilirubin <2£ upper limit of normal, and normal peripheral
blood counts); and HER2-negative tumors (0 or 1+ by
immunohistochemistry or negative by Xuorescence in situ
hybridization). Exclusion criteria were pregnancy, presence
of metastases, and previous chemotherapy.
The study endpoints were: (1) to deWne the hematologic
and nonhematologic toxicities of the proposed sequential
regimen as adjuvant or neoadjuvant treatment, (2) to assess
the event-free survival (EFS) and overall survival (OS) of
the study population after this treatment, and (3) to deter-
mine the clinical response rate and pathological complete
response (pCR) rate in the subset of patients treated
preoperatively.
Treatment plan
Surgery of the primary tumor consisted of modiWed radical
mastectomy or lumpectomy, with or without sentinel
lymph node biopsy. Adjuvant chemotherapy was to start
within 6 weeks following surgery. Pretreatment workup
included a complete blood count with diVerential, chemical
proWle (creatinine, urea, lactate dehydrogenase, bilirubin,
alkaline phosphatase, transaminases), chest X-ray, liver
ultrasonography or abdominal computed tomography, bone
scan, tumor markers (CEA and CA 27.29), and an echocar-
diography or radionuclide ventriculography.
Patients received four cycles of EC, with epirubicin
(100 mg/m2) and cyclophosphamide (600 mg/m2) adminis-
tered intravenously (IV) every 14 days. Granulocyte col-
ony-stimulating factor was administered subcutaneously at
5 ?g/kg daily from day (d) 3 to 10. Starting 2 weeks after
the fourth cycle of E100C, patients were given four cycles of
docetaxel/capecitabine, with docetaxel (Taxotere®) (75 mg/
m2 IV, d1 of each cycle) and capecitabine (Xeloda®) at
1,000 mg/m2 twice a day (b.i.d.) orally (PO), d1–14,
administered every 21 days. During the four cycles of doce-
taxel/capecitabine, patients received levoXoxacin at 500 mg
daily PO, on d5–18 of each cycle, and pyridoxine 50 mg
PO three times daily.
Patients receiving treatment preoperatively were
required to undergo magnetic resonance imaging (MRI)
and breast ultrasonography with axillary assessment prior
to starting chemotherapy. These tests were repeated upon
completion of treatment to evaluate clinical response.
Response Evaluation Criteria in Solid Tumors (RECIST)
criteria were used for clinical response evaluation [17]. Sur-
gery was performed 4–6 weeks after the last cycle. Patho-
logical response was evaluated in the surgical specimens
from the breast and axilla. A pCR required the eradication
of viable invasive ductal carcinoma cells at both sites, with
or without presence of ductal carcinoma in situ in the breast
pathological specimen.
Dose modiWcations
In the case of incomplete hematologic recovery from the
previous cycle (absolute neutrophil count <1,000/mm3 and
or platelets <75,000/mm3), treatment was delayed until
recovery. After each episode of grade 3–4 nonhematologi-
cal toxicity treatment was withheld until resolution of

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Cancer Chemother Pharmacol
123
toxicity to ·grade 1, and the doses of epirubicin and cyclo-
phosphamide (if after EC) or of capecitabine (if after doce-
taxel/capecitabine) were reduced by 20%. The dose of
docetaxel was not reduced for nonhematological toxicity.
After each episode of neutropenic fever the doses of epiru-
bicin and cyclophosphamide or docetaxel were reduced by
20%. The dose of capecitabine was not reduced for hemato-
logical toxicity.
Post-chemotherapy and post-surgical treatment
Since all patients in the study had axillary involvement or
locally advanced tumors, the need for locoregional radio-
therapy was assessed in all cases. Following completion of
chemotherapy, premenopausal patients with hormone
receptor-positive tumors received adjuvant hormonal ther-
apy with tamoxifen for 5 years and a luteinizing hormone-
releasing hormone analogue for 2 years; postmenopausal
patients were treated with an aromatase inhibitor for
5 years. Patients were monitored every 6 months for
5 years upon treatment completion, and on a yearly basis
thereafter.
Statistical design
Previous reports have established the separate feasibility of
the two components of the treatment sequence, epirubicin/
cyclophosphamide [18] and docetaxel/capecitabine [7], at
the doses used in this study. In this trial, we intended to
study the tolerability and activity of their sequential admin-
istration in the nonmetastatic setting. Toxicity was graded
according to the Common Toxicity Criteria of the National
Cancer Institute [19].
The trial followed a two-stage design. Twenty patients
were accrued in the Wrst stage of the study. If Wve or more
patients experienced grade 3–4 toxicity, the lower limit of
the 95% conWdence interval of incidence of grade 3–4 tox-
icity would be greater than 5%. The dose of capecitabine (if
nonhematological toxicities) and/or docetaxel (if hemato-
logical toxicities) would then be decreased by 20% for all
patients.
If fewer than Wve patients among the Wrst 20 experienced
grade 3–4 toxicity then another 20 patients would be
enrolled at the same dose. If the cumulative number of
grade 3–4 toxic events among the 40 patients was 8 or
more, the conclusion, with 95% probability, would be that
the grade 3–4 toxicity rate exceeds 5%. If the cumulative
number of grade 3–4 toxic events among the 40 patients
was 15 or more, the conclusion would be that the grade 3–4
toxicity rate exceeds 20%, with 95% probability. This two-
stage design has greater than 90% power to detect a 20%
rate of grade 3–4 toxicity, with a type I error rate of 5%
[20].
Event-free survival (EFS) was estimated from the Wrst
chemotherapy day until tumor progression, relapse, or
death from any cause. Overall survival (OS) was estimated
from the start of chemotherapy until death. The compari-
sons between the toxicity grades encountered in both trial
stages employed the chi-square test.
Results
Patient enrollment
Fifty-Wve patients were enrolled and treated in this study
between 1/2005 and 12/2006. Patient characteristics are
listed in Table 1. Thirty-Wve patients with node-positive
tumors after primary surgery received the treatment post-
operatively. Twenty patients with locally advanced breast
cancer who were deemed candidates for neoadjuvant
chemotherapy were treated preoperatively.
Toxicity (Table 2)
Twenty patients treated in the Wrst stage of the trial experi-
enced skin toxicity, with 45% incidence of grade 3 hand–
foot syndrome (HFS) and an additional 30% incidence of
grade 2 HFS. One patient with grade 3 HFS discontinued
treatment after her seventh cycle. This prompted a reduc-
tion in the dose of capecitabine from 1,000 to 800 mg/m2 in
the second stage of the trial, which enrolled 35 patients.
Skin toxicity then became signiWcantly less severe, with
grade 3 and grade 2 HFS in 14 and 17% of the patients,
respectively (P = 0.009 for grade 3, and P = 0.009 for com-
bined grade 2–3 HFS).
None of the other observed toxicities necessitated a dose
reduction, and their incidences did not diVer signiWcantly
between the Wrst and second stages of the trial. Grade 2 nail
changes were seen in 30 and 23% of patients in the Wrst and
second stages, respectively (P = 0.5), and grade 1 nail
changes were observed in 30 and 11% of patients, respec-
tively. Stomatitis was mild throughout the study: the inci-
dences were 10% for grade 2 and 5% for grade 1 in the Wrst
stage and 11% for grade 2 and 6% for grade 1 in the second
stage. No patients in this study experienced peripheral neuro-
pathy or a drop in the left ventricle ejection fraction. Five
patients experienced neutropenic fever with grade 3 neutro-
penia after EC and three after docetaxel/capecitabine. The
incidences of neutropenic fever in the Wrst and second
stages were 20 and 14%, respectively (P = 0.6). No grade
3–4 anemia or thrombocytopenia was observed. No grade
4–5 toxicities of any sort were seen throughout the trial.
None of the surgeries had to be delayed for patients
treated preoperatively. There were no post-surgical compli-
cations in those cases.

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Cancer Chemother Pharmacol
123
Tumor responses
All 20 patients treated preoperatively responded clinically as
determined by MRI, ten of them with a CR. Fifteen patients
underwent breast-conserving surgery and Wve patients had a
modiWed radical mastectomy. Five patients (2 with stage
IIIA and 3 with stage IIB tumors) experienced a pCR (25%,
95% conWdence interval, 6–44%). Three additional patients
had pT0N1 tumors in their surgical specimens.
Post-chemotherapy treatment
Following completion of chemotherapy, 43 patients with
hormone receptor-positive tumors were prescribed hor-
mone treatment for 5 years. Locoregional radiotherapy was
administered to 54 (98%) patients without unexpected side
eVects.
Outcome
At a median follow-up of 48 (range 28–60) months, Wve
patients have had disease relapse, and one of them has died
from progressive disease. The EFS and OS rates are 90.9
and 98.2%, respectively (Fig. 1).
The Wve patients whose tumor relapsed did not diVer sig-
niWcantly from the other 50 patients in age (P = 0.2) or his-
tological grade (P = 0.9). However, their tumors seemed to
be larger (median 5.5 vs. 2.4 cm, P = 0.1), presented with
more involved axillary nodes (median 6 vs. 2, P = 0.00001)
and a higher axillary nodal ratio, deWned as the quotient
between the no. positive nodes and the no. dissected nodes
(0.55 vs. 0.105, P = 0.00001), and showed a higher
proliferative fraction (70 vs. 15% Ki67-positive cells,
P = 0.01). Two of the Wve relapsing patients were treated
neoadjuvantly, with a clinical CR and a partial response,
respectively. The pathological stages in their surgical
specimens were pT1N0 and pT2N2, respectively.
Discussion
The sequential combination of dose-dense EC followed by
docetaxel/capecitabine in patients with node-positive or
locally advanced tumors was well tolerated and showed
very encouraging activity in this feasibility study. This new
Table 1 Patient Demographics (N = 55)
Nodal ratio: no. positive nodes/no. dissected nodes
ER estrogen receptors, PR progesterone receptors, BCS breast-con-
serving surgery, MRM modiWed radical mastectomy
Age, median (range)49 (27–73) years
Menopausal status
Peri/Premenopausal
Postmenopausal
Histology
Ductal
Lobular
Stage
IIA
IIB
IIIA
IIIB
IIIC
Tumor size, median (range)
Nodal status
No. + nodes: median (range)
Nodal ratio: median (range)
Hormone receptors
ER+ PR+
ER+ PR¡
ER¡ PR+
ER¡ PR¡
HER2 overexpression
P53
Negative
Positive
Undetermined
Tumor grade
1–2
3
Undetermined
Ki67, % + cells: median (range)
Initial treatment
Chemotherapy
Surgery
BCS
MRM
25 (45%)
30 (55%)
48 (87%)
7 (13%)
22 (40%)
9 (16%)
19 (34%)
3 (5%)
2 (4%)
2.5 (1–13) cm
2 (1–13)
0.3 (0.1–0.9)
38 (69%)
4 (7%)
2 (4%)
11 (20%)
0 (0%)
41 (73%)
12 (22%)
2 (4%)
18 (33%)
27 (49%)
10 (18%)
15% (2–98%)
20 (36%)
24 (44%)
11 (20%)
Fig. 1 Event-free survival (EFS) and overall survival (OS) curves of
the study population
0
1020 304050 60
70
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative Proportion
OS
EFS

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Cancer Chemother Pharmacol
123
sequential schema incorporates capecitabine, an eVective
agent in the metastatic setting, into the adjuvant or neoadju-
vant treatment of breast cancer.
We elected to add capecitabine to a sequential frame-
work of anthracyclines followed by docetaxel, because
emerging data suggest that sequential treatment with these
agents might be superior to their concurrent administration.
Francis et al. compared both sequential and concurrent
doxorubicin and docetaxel to a control arm of doxorubicin
with or without cyclophosphamide, followed in all cases by
cyclophosphamide/methotrexate/5-FU,
improved EFS in the sequential, but not the concurrent,
experimental arm compared to control treatment [21].
Results of other randomized neoadjuvant trials are in keep-
ing with these observations. Sequential doxorubicin–doce-
taxel resulted in higher response and pCR rates than
doxorubicin alone in several studies [22–24]. In contrast,
concurrent doxorubicin/docetaxel was not shown to be
more active than doxorubicin/cyclophosphamide [25].
Finally, the use of a sequential arm of doxorubicin/cyclo-
phosphamide followed by docetaxel resulted in higher
response and pCR rates than a dose-dense regimen of con-
current doxorubicin/docetaxel [26].
The combination of docetaxel and capecitabine is attrac-
tive because of their diVerent mechanisms of action and
largely nonoverlapping side eVects, namely, myelotoxicity
and cutaneous/mucosal toxicity, respectively. In metastatic
disease, docetaxel/capecitabine achieved superior RR, EFS
and OS compared to docetaxel alone [7]. The synergy of
the combination may be due to docetaxel-induced tumor
upregulation of TP [8, 9], the enzyme responsible for the
intracellular activation of capecitabine from 5?-FUDR to
5-FU. Preclinical observations have shown that transfecting
cells with TP sensitizes them to 5?-FUDR[27–29] and that
this compound is more active in TP-overexpressing tumor
xenografts [30]. Furthermore, TP expression in tumor cells
is a favorable predictive factor after treatment with 5?-
FUDR in patients with breast cancer [10–12, 31, 32]. In a
recent study, TP expression in metastatic tumor samples
correlated directly with time to progression after treatment
with docetaxel/capecitabine [13]. Further supporting the
hypothesis of docetaxel-induced tumor sensitization to
capecitabine, concurrent treatment of xenografts with doce-
taxel and capecitabine resulted in synergistic activity,
and reported
whereas the combination of docetaxel with either 5-FU or
uracil plus tegafur, neither of which require activation by
TP, showed only additive activity [13].
The therapeutic schema tested in this trial pursues addi-
tional upregulation of TP by EC administered prior to doce-
taxel/capecitabine. Toi et al. [14] have described increased
expression of TP in breast cancer specimens after preopera-
tive chemotherapy with AC or EC but not after using 5-FU-
containing regimens (i.e., FAC or FEC). It is possible that
5-FU selectively kills or suppresses TP-overexpressing
cells or that, at high concentrations, 5-FU, a pyrimidine
substrate, downregulates the expression of TP. Additional
considerations about toxicity prompted us to use EC instead
of FEC for the initial dose-dense part of the therapeutic
sequence. In one adjuvant study, biweekly FEC was associ-
ated with excessive pericardial, pleural and pulmonary
toxicity [33], whereas dose-dense EC can be administered
without diYculty [34]. Thus, EC was a better Wt for our
strategy of administering dose-dense TP-upregulating che-
motherapy followed by TP-dependent chemotherapy.
In the original phase I evaluation of docetaxel/capecita-
bine, the dose of capecitabine considered to be feasible was
identiWed as 1,250 mg/m2 b.i.d. for 14 days, combined with
75 mg/m2 of docetaxel, every 3 weeks [35]. When com-
pared to docetaxel in MBC, these doses of docetaxel/cape-
citabine were associated with a manageable 24% incidence
of grade 3 HFS [7]. Subsequent reports of dose reductions
of capecitabine to 950 mg/m2 suggested that the toxicity of
the regimen could be ameliorated without compromising its
eYcacy [36]. In contrast to the latter observations, our start-
ing capecitabine dose of 1,000 mg/m2 caused excessive
HFS. A subsequent protocol-mandated dose reduction to
800 mg/m2 improved the tolerability of docetaxel/capecita-
bine. The paradoxical observation of greater toxic eVects
from capecitabine in our nonmetastatic patients than in
prior reports from the metastatic setting may be explained
by the upregulation of TP by EC. Since TP is preferentially
expressed in tumor cells [37, 38], the combined eVect of TP
upregulation and subsequent dose reduction of capecitabine
should, at least in theory, improve its therapeutic index.
There is growing interest in the use of capecitabine in
the adjuvant setting. Joensuu and colleagues [39] recently
reported an interim safety analysis in a subset of 600
patients enrolled in a randomized trial of docetaxel/
Table 2 Grade 2–3 toxicities
HFSNailsMucositisNeutropenic fever
G2 (%) G3 (%)G2 (%)G3 (%)G2 (%) G3 (%)G3 (%)
1st stage (N = 20)
2nd stage (N = 35)
P value
30
17
45
14
0.009
30
23
0.5
0
0
10
11
0
0
20
14
0.6

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Cancer Chemother Pharmacol
123
Table 3 Trials testing docetaxel/capecitabine as neoadjuvant treatment
apCR assessed in breast and axilla
HR hormone receptors, pCR pathologic complete response, IV intravenously, PO orally, BID twice daily, EC epirubicin/cyclophosphamide, AC doxorubicin/cyclophosphamide, Doc docetaxel,
Cap capecitabine
Study
N
Schema
Docetaxel/capecitabine schedule
T stage
HR
HER2
pCR ratea
T1
T2
T3
T4
Negative
Positive
Negative
Positive
GeparQuattro
1,510
EC ! Doc
Doc: 75 mg/m2 IV, d1
Not speciWed
Not speciWed
70%
30%
21% in all
three arms
EC ! Doc/Cap
Cap: 900 mg/m2 PO BID, d1–14,
EC ! Doc ! Cap
Every 3 weeks
(+Trastuzumab if HER2+)
Lee
103
Doc/Cap
Doc: 75 mg/m2 IV, d1
79%
21%
38%
62%
46%
32%
15%
Cap: 1,000 mg/m2 PO BID, d1-14
Every 3 weeks
22% unknown
Natoli
41
EC ! Doc/Cap
Doc: 36 mg/m2 IV, d1, 8 and 15
0%
70%
30%
0%
41%
59%
61%
39%
17%
Cap: 1,250 mg/m2 PO BID, d5–18
Every 4 weeks
Layman
26
Doc/Cap ! AC
Doc: 36 mg/m2 IV, d1, 8 and 15
8%
69%
23%
0%
58%
42%
77%
23%
27%
Cap: 1,000 mg/m2 PO BID, d5–21
Every 4 weeks
Present
20
EC ! Doc/Cap
Doc: 75 mg/m2 IV, d1
5%
35%
45%
15%
20%
80%
100%
0%
25%
Cap: 800-1,000 mg/m2 PO BID,
d1-14 every 3 weeks

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Cancer Chemother Pharmacol
123
capecitabine at a similar dose and schedule but in the
inverse therapeutic sequence to ours. These authors com-
pared in 1,500 patients with node-negative and node-posi-
tive disease the use of three cycles of docetaxel (60 mg/
m2)/capecitabine (900 mg/m2 b.i.d., d1–15) followed by
three cycles of cyclophosphamide (600 mg/m2)/epirubicin
(75 mg/m2)/capecitabine (900 mg/m2 b.i.d., d1–15), to a
control arm that received three cycles of docetaxel alone
(75 mg/m2) followed by three cycles of FEC, all cycles
administered every 3 weeks. The toxicity proWle (9.6%
incidence of grade 3–4 HFS) of docetaxel/capecitabine
seen in this patient subset was similar to that we observed
in the second stage of our study.
The preoperative activity of our regimen, evidenced by a
25% pCR rate in the small subset of patients with LABC, is
encouraging, particularly in view of the fact that our
patients had tumor phenotypes (HER2-negative and largely
hormone receptor-positive) associated with lower pCR rates
after preoperative chemotherapy [40–42]. Our use of tri-
weekly docetaxel is supported by reports of single-agent
docetaxel having greater activity when given every 3 weeks
as compared to weekly, in both the adjuvant [43] and meta-
static settings [44]. Lee and collaborators compared neo-
adjuvant docetaxel/capecitabine (at the same doses as in the
Wrst stage of our trial) with AC, both given every 3 weeks
[45]. This trial enrolled 209 patients, mostly with stage II
tumors. The pCR rate in the breast and axilla was higher
after docetaxel/capecitabine than after AC (15 vs. 7%).
Other authors have tested preoperatively a variant schedule
in which docetaxel/capecitabine was administered monthly,
with weekly doses of docetaxel at 36 mg/m2 (days 1, 8 and
15) and capecitabine at 500–625 mg/m2 bid for 14–17 days
from day 5 of each cycle. Layman et al. [46] treated 26
patients, most of whom had T1–T2 and hormone receptor-
negative tumors, with the variant docetaxel/capecitabine
schedule. The pCR rate in their trial was only 7.6% after
four cycles of docetaxel/capecitabine, but it increased to
26.9% after an additional four courses of dose-dense AC.
Natoli et al. [47] employed a similar sequence to ours, with
four cycles of dose-dense EC (90/600 mg/m2) followed by
four cycles of variant docetaxel/capecitabine in 44 patients,
most of them with T2 tumors. The pCR rate in their trial was
17% (8% among 24 patients with HER2-negative tumors).
The randomized GeparQuattro trial compared the pre-
operative use of four cycles EC (90/600 mg/m2) every
3 weeks followed by either four cycles of docetaxel alone at
100 mg/m2, four cycles of concomitant docetaxel/capecita-
bine (60/900 mg/m2 every 12 h £ 15 days) every 3 weeks,
or the sequential use of four cycles of docetaxel (75 mg/m2)
followed by four cycles of capecitabine (900 mg/m2 every
12 h) [48, 49]. This study enrolled 1,510 patients with oper-
able tumors. Trastuzumab was added to chemotherapy for
the 30% of patients with HER2-positive tumors. The Wrst
interim analysis of toxicity showed a 27.6% incidence of
grade 3–4 HFS in the concomitant docetaxel/capecitabine
arm, which appears higher than that observed in the second
phase of our study (14%), perhaps due to the use of a
slightly higher dose of capecitabine. The Wrst preliminary
analysis of responses showed no diVerences between the
three arms, with pCR rates of around 21% in all three.
Important diVerences between this study and ours were the
inclusion in GeparQuattro of patients with smaller tumors
and with HER2-positive disease, the latter group treated
with concurrent trastuzumab-chemotherapy. Both groups of
patients typically achieve higher pCR rates than the popula-
tion of patients with larger and HER2-negative tumors we
targeted in our trial [40–42].
Although the subset of patients treated preoperatively in
our study had bigger tumors and a higher prevalence of hor-
mone receptor-positive and HER2-negative disease, the
pCR rate appears to compare favorably with that achieved
in those other neoadjuvant trials (Table 3). Therefore, it is
conceivable that diVerences in total duration (4, 6, or 8
cycles) and schedule (anthracyclines followed by doce-
taxel/capecitabine or vice versa) of chemotherapy, or the
use of triweekly versus weekly docetaxel may be relevant
to the antitumor activity of docetaxel/capecitabine, as well
as possible diVerences in activity between dose-dense and
triweekly EC. While our preoperative results are limited by
the small size of this subset of patients and our outcome
observations need longer follow-up, we believe that this
regimen, as tested in this trial, is highly promising and wor-
thy of further testing.
In conclusion, sequential treatment with dose-dense EC
followed by docetaxel/capecitabine, using a lower capecita-
bine dose than that approved for MBC, has an acceptable
toxicity proWle and encouraging activity when used as neo-
adjuvant or adjuvant treatment of breast cancer.
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