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CLINICAL TRIAL
Dose-dense paclitaxel versus docetaxel following FEC as adjuvant
chemotherapy in axillary node-positive early breast cancer:
a multicenter randomized study of the Hellenic Oncology
Research Group (HORG)
Emmanouil Saloustros •Nikolaos Malamos •Ioannis Boukovinas •
Stylianos Kakolyris •Charalampos Kouroussis •Athanasios Athanasiadis •
Nikolaos Ziras •Nikolaos Kentepozidis •Parisis Makrantonakis •
Aristidis Polyzos •Charalampos Christophyllakis •Vassilios Georgoulias •
Dimitrios Mavroudis
Received: 12 August 2014 / Accepted: 9 November 2014 / Published online: 16 November 2014
ÓSpringer Science+Business Media New York 2014
Abstract Adding a taxane to anthracycline-based adju-
vant chemotherapy prolongs survival in node-positive early
breast cancer. However, which is the preferable taxane in a
dose-dense regimen remains unknown. We conducted a
randomized study to compare the efficacy of dose-dense
paclitaxel versus docetaxel following 5-fluorouracil, epi-
rubicin, and cyclophosphamide (FEC) as adjuvant che-
motherapy in women with node-positive early breast
cancer. Following surgery women with HER2-negative
breast cancer and at least one infiltrated axillary lymph
node were randomized to receive four cycles of FEC (700/
75/700 mg/m
2
) followed by four cycles of either paclitaxel
(175 mg/m
2
) or docetaxel (75 mg/m
2
). All cycles were
administered every 14 days with G-CSF support. The pri-
mary endpoint was disease-free survival (DFS) at 3 years.
Between 2004 and 2007, 481 women were randomized to
paclitaxel (n=241) and docetaxel (n=240). After a
median follow-up of 6 years, 51 (21 %) and 48 (20 %)
women experienced disease relapse (p=0.753) and there
was no significant difference in DFS between the paclit-
axel- and docetaxel-treated groups (3-year DFS 87.4 vs.
88.3 %, respectively; median DFS not reached;
p=0.633). Toxicities were manageable, with grade 2–4
neutropenia in 21 versus 31 % (p=0.01), thrombocyto-
penia 0.8 versus 3.4 % (p=0.06), any grade neurotoxicity
17 versus 7.5 % (p=0.35) and onycholysis 4.9 versus
12.1 % (p=0.03) for patients receiving paclitaxel and
docetaxel, respectively. There were no toxic deaths. Dose-
dense paclitaxel versus docetaxel after FEC as adjuvant
chemotherapy results in a similar 3-year DFS rate in
women with axillary node-positive early breast cancer. Due
to its more favorable toxicity profile, paclitaxel is the
taxane of choice in this setting.
Keywords Paclitaxel
Docetaxel Taxanes Dose-dense Adjuvant
chemotherapy Breast cancer
Introduction
Adjuvant chemotherapy substantially reduces the risk of
disease recurrence and death among women with early
breast cancer [1]. The addition of taxane to an anthracy-
cline-containing regimen, either sequentially or concur-
rently, further reduces the risk of relapse. Two studies in
which patients received four cycles of paclitaxel every
3 weeks after four cycles of doxorubicin and cyclophos-
phamide (AC regimen) established a new standard of care
for operable breast cancer patients and led to regulatory
approval of paclitaxel for axillary lymph node-positi-
ve early breast cancer [2,3]. Another study demonstrating
ClinicalTrials.gov Identifier: NCT00431080.
E. Saloustros N. Malamos I. Boukovinas S. Kakolyris
C. Kouroussis A. Athanasiadis N. Ziras N. Kentepozidis
P. Makrantonakis A. Polyzos C. Christophyllakis
V. Georgoulias D. Mavroudis
Hellenic Oncology Research Group (HORG), Lomvardou 55,
11470 Athens, Greece
D. Mavroudis (&)
Department of Medical Oncology, University Hospital of
Heraklion, Voutes, P.O. Box 1352, 71110 Heraklion, Crete,
Greece
e-mail: medoncsec@med.uoc.gr
123
Breast Cancer Res Treat (2014) 148:591–597
DOI 10.1007/s10549-014-3202-5
that the concurrent administration of docetaxel with doxo-
rubicin and cyclophosphamide was more effective than
fluorouracil, doxorubicin, and cyclophosphamide led to
regulatory approval of docetaxel for node-positive disease
[4]. Recently, BCIRG 001 investigators provided evidence
that the initial therapeutic benefit of the docetaxel-con-
taining regimen seen at the 5-year follow-up was main-
tained at 10 years, both in terms of disease-free [hazard
ratio (HR) 0.80, 95 % CI 0.68–0.93; p=0.043] and overall
survival (HR 0.74, 95 % CI 0.61–0.90; p=0.02) [5].
Nowadays, taxanes in combination with anthracyclines are
considered a standard treatment approach for women with
either node-negative or node-positive disease, based on the
results of the aforementioned studies as well as others [6–
10].
Initial preclinical and indirect clinical evidence sug-
gested that docetaxel was more effective than paclitaxel
and that weekly paclitaxel was better than the conventional
3-weekly schedule of administration [11]. In the metastatic
setting, phase III trials demonstrated that docetaxel every
3 weeks [12] or weekly paclitaxel [13] were indeed supe-
rior to 3-weekly paclitaxel. However, in the adjuvant set-
ting, weekly paclitaxel after standard adjuvant
chemotherapy with AC has been shown to improve dis-
ease-free and overall survival compared to docetaxel
(administered either weekly or every 3 weeks) and
3-weekly paclitaxel [14].
Administration of adjuvant chemotherapy on an accel-
erated administration (dose-dense therapy) aims to improve
treatment results over standard dosing schedules. A meta-
analysis of dose-dense versus standard dosing regimens
including data from ten trials and over 11,000 women,
reported that dose-dense treatment was associated with an
improvement in both disease-free and overall survival [15].
Thus far, no study has compared head-to-head the two
taxanes in the dose-dense adjuvant setting. To address this
question we conducted a randomized trial of dose-dense
G-CSF-supported paclitaxel versus docetaxel, administered
every 2 weeks following 5-fluorouracil-epirubicin-cyclo-
phosphamide (FEC) regimen as adjuvant chemotherapy in
women with axillary lymph node-positive early breast
cancer.
Patients and methods
This randomized study was conducted mainly at 11 sites of
the Hellenic Oncology Research Group (HORG). The
protocol and related materials were approved by the insti-
tutional review boards and independent ethics committees
and registered under the NCT00431080 identifier at the
clinicaltrials.gov website. The study was conducted in
compliance with Good Clinical Practice and the
Declaration of Helsinki. Written informed consent was
required from all patients to enter the study.
Eligible patients should have undergone either lumpec-
tomy or modified radical mastectomy with tumor-free
surgical margins plus axillary node dissection. The tumor
had to be invasive adenocarcinoma with at least one
positive axillary lymph node on pathologic examination.
Determination of the estrogen receptor (ER) and proges-
terone receptor (PR) status of the primary tumor had to be
performed before random assignment and patients with
HER2-positive tumors (as determined by local institutional
laboratories) were not eligible for this study. Normal
hematologic parameters and adequate hepatic, renal, and
cardiac function were mandatory. Patients with previous
history of invasive breast cancer or ductal carcinoma-
in situ (in either breast) were ineligible, as were patients
who had received any prior radiation, chemotherapy, or
hormonal therapy.
Chemotherapy
All women received upfront epirubicin (75 mg/m
2
of body-
surface area, given by slow intravenous (iv) push during a
period of 5–15 min), cyclophosphamide (700 mg/m
2
by iv
infusion for 30–60 min), and 5-fluorouracil (700 mg/m
2
by
slow iv push during a period of 5–15 min) every 2 weeks
for four cycles. This therapy was followed by the taxane
treatment with the randomization performed before the
commencement of FEC. Women were randomly assigned
to 175 mg/m
2
of paclitaxel given by iv infusion over 3 h
every 2 weeks for four doses or 75 mg/m
2
of docetaxel
given by iv infusion for 1 h every 2 weeks for four doses.
All patients received primary prophylaxis with filgrastim
(5 lg/kg rounded to either 300 or 480-lg total dose) on
days 3–10 of each cycle.
Hormonal & radiation therapy & follow-up
Patients who had breast-conserving surgery received stan-
dard radiotherapy after the completion of chemotherapy.
Women who had a modified radical mastectomy were also
permitted to receive radiotherapy after completion of
chemotherapy, if they had large ([5 cm) primary tumors
and/or more than three infiltrated axillary nodes. Patients
with hormone receptor-positive disease received 20 mg of
tamoxifen daily or an aromatase inhibitor both for a 5-year
period depending on the menopausal status at diagnosis.
Premenopausal patients treated with tamoxifen were also
given an LHRH agonist for the initial 2–3 years at the
discretion of the treating physician.
Patients were followed every 3–4 months for the first
2 years, every 6 months for the subsequent 3 years and
yearly thereafter. History, physical examination and
592 Breast Cancer Res Treat (2014) 148:591–597
123
routine labs were performed at each visit, surveillance
mammograms were done yearly and imaging studies were
ordered when clinically indicated and at the discretion of
the treating physician.
Study endpoints
The primary endpoint of the study was to compare the
3-year disease-free survival (DFS) rates between the pac-
litaxel- and docetaxel-treated groups. The DFS was defined
as the time from randomization to the date of breast cancer
recurrence (either locoregional or distant), contralateral
breast cancer diagnosis, non-breast second primary cancer
or death from any cause, whichever occurred first. Sec-
ondary end-points were overall survival (OS), defined as
the time from the date of random assignment to death from
any cause and the toxicity profile of the regimens. Toxicity
grading used the Common Terminology Criteria for
Adverse Events of the National Cancer Institute version
3.0.
Statistical analysis
Based on the assumption of a 3-year DFS rate equal to
85 % for the paclitaxel arm, 239 patients were required to
enroll on each arm for the trial to detect an 8 % difference
between the two arms with 80 % power and a type I error
of 5 % (two sided). Stratification parameters for the ran-
dom assignment were the menopausal status (pre versus
post), the number of infiltrated axillary nodes (1–3 vs. 4–10
vs.[10) and the tumor hormone receptor status (ER and/or
PR positive vs. both negative). All patients who received at
least one cycle of treatment were included in the analysis.
The DFS and OS rates were calculated by the Kaplan–
Meier method. The comparison of the treatment arms was
assessed using the log-rank test. The independent effect of
treatment and other prognostic factors on DFS and OS was
analyzed by Cox’s proportional hazards model. Quantita-
tive factors were compared by Pearson’s v2 contingency
table analysis or Fisher’s test whenever appropriate. All
pvalues \0.05 were considered statistically significant for
all comparisons. Clinical data were held centrally (Clinical
Trial Office, Hellenic Oncology Research Group) and
analyzed using the SPSS (version 22.0) program. Data
were current as of March 2014.
Results
Patients
Between September 2004 and December 2007, 495
patients were assessed for enrollment, of whom 481 (97 %)
were eligible for the study. Eight patients did not meet all
the eligibility criteria and six patients withdrew their con-
sent. Therefore 481 patients were centrally randomized to
either paclitaxel (n=241 patients) or docetaxel (n=240
patients) (Fig. 1; CONSORT diagram of the study). The
two patient groups were well balanced regarding their
prognostic characteristics (Table 1). The median age was
55 years (range 26–75). One-third of the patients were
premenopausal at diagnosis. Approximately, 55 % had 1–3
positive nodes, while 13 % had more than ten axillary
nodes with tumor involvement. The tumor was positive for
estrogen receptor, progesterone receptor, or both in roughly
85 % of patients and negative for both hormonal receptors
in 15 %.
Treatment
The proportion of women who received all four cycles of
FEC were 99.6 % versus 99.2 % for the paclitaxel and
docetaxel arm, respectively (p=0.560). Similarly, the
proportion of women who received all four taxane cycles
was 90.0 %, and 96.3 %, for the paclitaxel and docetaxel
group, respectively (p=0.007). The mean number of
taxane cycles received was 3.7 for the paclitaxel group
and 3.8 for the docetaxel group (p=0.074). The reasons
for treatment discontinuation in the paclitaxel group
were adverse events (n=16), patient refusal to continue
(n=7), and disease progression (n=1) while in the
docetaxel group were adverse events (n=4), and patient
refusal to continue (n=5). Treatment was administered
on time without delay in 93.6 % and 92.6 % of cycles in
the paclitaxel and docetaxel group, respectively
(p=0.251). Similarly, dose reduction due to toxicity
was required in 2.8 % and 1.7 % of administered cycles
in the paclitaxel and docetaxel group, respectively
(p=0.025).
Disease-free and overall survival
After a median follow-up of 73 and 72.7 months, 51
(21 %) and 48 (20 %) patients had experienced disease
recurrence (p=0.753), while 27 (11 %) and 25 (10 %)
patients had died in the paclitaxel and docetaxel arm,
respectively (p=0.781). Although the median DFS has
not been reached yet, there was no significant difference in
DFS between the paclitaxel- and the docetaxel-treated
group (HR 1.101; 95 % CI 0.742–1.633; p=0.633). Fig-
ure 2a illustrates the Kaplan–Meier curves for disease-free
survival in the two treatment groups. The 3-year DFS rates
were 87.4 % for the group treated with paclitaxel and
88.3 % for the docetaxel group. Similarly, there was no
difference in overall survival between the two groups
(p=0.814; Fig. 2b).
Breast Cancer Res Treat (2014) 148:591–597 593
123
Adverse events
Fifty-three percent of patients receiving paclitaxel developed
grade 2–4 adverse events, compared to 60.4 % of those treated
with docetaxel (p=0.106). Table 2shows the toxicity profile
of each taxane arm. The higher proportion of toxicity in the
group receiving docetaxel was mainly due to the 31 % inci-
dence of neutropenia as compared with 21 % for the paclitaxel
group (p=0.01). However, this did not result in a higher rate
of febrile neutropenia (5 and 4 cases, respectively), thanks to
prophylaxis with filgrastim. The incidence of grade 3 or 4
neuropathy in the two groups was quite low (2.1 vs. 0.8 %),
but overall the group receiving paclitaxel had a numerically
higher incidence of neuropathy of any grade (17 %) compared
to the docetaxel treatment group (7.5 %) (p=0.35). Finally,
onycholysis grade 2–4 was the only non-hematologic toxicity
with significant difference between the two groups (1.2 % for
the paclitaxel and 4.6 % for the docetaxel group, p=0.03).
Hopefully, there were no toxic deaths.
Discussion
This trial was designed to compare the efficacy of dose-
dense paclitaxel with that of docetaxel in nearly 500
women with axillary lymph node-positive early breast
cancer. After a median follow-up of nearly 6 years, no
significant difference in disease-free or overall survival
between the two groups was found. In comparison with
patients treated with paclitaxel, those who received doce-
taxel had significantly more severe neutropenia and nail
toxicity. The higher toxicity observed in the docetaxel arm
is consistent with a previous study that compared doce-
taxel, epirubicin, and cyclophosphamide every 3 weeks
with dose-dense 2-weekly schedules of epirubicin and
cyclophosphamide followed by docetaxel or the reverse
sequence [16]. As in our study, they found that the most
frequent hematologic toxicity was neutropenia; also it was
more frequent in the group receiving epirubicin and
cyclophosphamide followed by docetaxel.
Assessed for eligibility (n= 495)
Patients randomly assigned
(n=481)
Discontinued FEC→Docetaxel = 9
•due to AE= 4
• Patients refusal= 5
Allocated to
FEC→Docetaxel
(n= 240)
Lost to follow-up (n= 16)
Discontinued FEC→Paclitaxel = 23
•due to AE= 16
• Patients refusal= 7
Lost to follow-up (n= 18)
Allocated to
FEC→Paclitaxel
(n= 241)
Excluded (n= 14)
Not meeting inclusion criteria (n= 8)
Inform consent withdrawal (n= 6)
Fig. 1 Fig. 1 CONSORT diagram of
the trial. FEC 5-fluorouracil,
epirubicin and cyclophosphamide, AE
adverse events
594 Breast Cancer Res Treat (2014) 148:591–597
123
For patients with node-positive early breast cancer, the
combination of a taxane with an anthracycline as adjuvant
therapy has been investigated in several studies [2–10,14,
17,18]. Most of the studies have been focusing on the
optimal sequence of the anthracyclines and taxanes as well
as the preferable taxane and the optimal schedule of
administration. Some of those studies concluded that the
dose-dense regimens (2-week intervals) not only prolong
disease-free and overall survival but also that they are as
safe and as well tolerated as the 3-weekly conventional
regimens [19–21]. Two important aspects of current adju-
vant chemotherapy including taxane in early breast cancer,
have been addressed in a study reported by Sparano et al.
[14]. The 2 92 factorial design of the trial allowed the
comparison of paclitaxel every 3 weeks for four cycles
with three experimental regimens: paclitaxel every week
for 12 cycles, docetaxel every 3 weeks for four cycles, or
docetaxel every week for 12 cycles. Each regimen was
given after standard AC. The comparison of the three
experimental groups with the group receiving standard
Table 1 Patient characteristics
FEC 5-flourouracil, epirubicin
and cyclophosphamide,
nnumber of patients, ER
estrogen receptor, PR
progesterone receptor
Treatment groups pvalue
FEC-[paclitaxel (241) FEC-[docetaxel (240)
N%N%
Age
Median 55 55 0.630
Range (min–max) 29–75 26–75
Histology type
Ductal 196 81.3 204 85.0 0.624
Lobular 32 13.3 28 11.7
Mixed 7 2.9 5 2.1
Other 6 2.5 3 1.3
Menopausal status
Pre-menopausal 80 33.0 75 31.3 0.648
Post-menopausal 161 67.0 165 68.8
Infiltrated axillary nodes
1–3 132 55.0 136 56.7 0.920
4–10 77 32.1 73 30.4
[10 31 12.9 31 12.9
Hormone receptors
ER(?)/PR(?) 172 71.4 168 70.0 0.918
ER(?)/PR(-) 25 10.4 22 9.2
ER(-)/PR(?) 9 3.7 10 4.2
ER(-)/PR(-) 29 12.0 35 14.6
Unknown 6 2.5 5 2.1
Histologic grade
1 13 5.4 20 8.3 0.602
2 114 47.3 100 41.7
3 84 35.0 88 36.7
Undifferentiated 7 2.9 9 3.8
Unknown 23 9.5 23 9.6
Type of surgery
Breast conserving surgery 130 53.9 128 53.3 0.894
Mastectomy 111 46.1 112 46.7
Adjuvant hormonotherapy
Yes 196 81.3 184 76.7 0.209
No 45 18.7 56 23.3
Adjuvant radiotherapy
Yes 186 77.2 187 77.9 0.846
No 55 22.8 53 22.1
Breast Cancer Res Treat (2014) 148:591–597 595
123
paclitaxel treatment showed that the group of weekly
paclitaxel had significantly improved disease-free and
overall survival while the group receiving docetaxel every
3 weeks had significantly improved disease-free survival
only. This came at the cost of more moderate-to-severe
neuropathy for the patients treated with weekly paclitaxel
and more severe neutropenia and its associated complica-
tions for the group receiving docetaxel every 3 weeks.
More recently, breast cancer patients with node-positive
or high-risk node-negative disease have been shown to
obtain the same disease control benefit with weekly low-
dose paclitaxel (80 mg/m
2
for 12 cycles) as compared with
a higher dose given every 2 weeks (175 mg/m
2
for six
cycles) [22]. That study also had a 2 92 factorial design to
compare additionally the weekly administration of doxor-
ubicin/cyclophosphamide versus the dose-dense schedule.
The estimated 5-year survival rate was 82 % among
patients receiving weekly paclitaxel and 81 % among those
treated with the dose-dense regimen. The rates of grade
3–4 adverse events were also similar, but the profiles dif-
fered. The weekly regimen was associated with more
neutropenia (6 vs. 1 %), whereas the dose-dense regimen
with more allergy-related reactions (14 vs. 6 %), muscu-
loskeletal pain (11 vs. 3 %), and neuropathy (17 vs. 10 %).
Overall, the toxicity profile favored weekly paclitaxel, but
we have to note that the higher toxicity profile of dose-
dense paclitaxel might be due to the higher cumulative
dose (six cycles of therapy instead of the usual four).
Our study has certain limitations that should be taken
into consideration. Since this was not conducted as a
conventional non-inferiority study, we cannot exclude that
there is a small difference in the 3-year DFS. However, the
Kaplan–Meier curves and computed hazard ratios suggest
very little, if any difference between the two arms. In
addition, at the time when the study was commenced, none
of the arms could have been considered as standard treat-
ment for node-positive early breast cancer in Europe. This
was in contrast to the practice in the USA where the dose-
dense AC followed by paclitaxel regimen was quickly
adopted as a standard regimen, based on the report of
CALGB 9741 in 2003 [19]. Following the report of the
studies by Sparano et al. [14] and the SO121 by SWOG
Fig. 2 Disease-free (a) and overall (b) survival according to
treatment group
Table 2 Grade 2-4 adverse
events of FEC regimen followed
by either paclitaxel or docetaxel
FEC 5-flourouracil, epirubicin
and cyclophosphamide,
nnumber of patients, ns non-
significant
Treatment groups pvalue
FEC-[paclitaxel (241) FEC-[docetaxel (240)
N%N%
Hematologic toxicities
Neutropenia 51 23 74 31 0.01
Febrile neutropenia 3 1.2 4 1.7 ns
Anemia 56 23 48 20 ns
Thrombocytopenia 2 0.8 8 3.2 0.06
Non-hematologic toxicities
Onycholysis 3 1.2 11 4.6 0.03
Neurotoxicity 11 4.6 7 2.9 ns
Diarrhea 6 2.5 9 3.7
Mucositis 5 2.1 11 4.6
Fatigue 20 8.3 18 7.5
Hand-foot syndrome 3 1.2 3 1.3
596 Breast Cancer Res Treat (2014) 148:591–597
123
[22], we believe that our study completes the puzzle of
taxanes in the adjuvant setting of women with early breast
cancer. Weekly paclitaxel after dose-dense AC remains the
regimen of choice due to its more favorable toxicity profile.
However, when a shorter course of treatment is important
for patients (e.g., young professionals) the dose-dense
administration of paclitaxel should be preferred over
docetaxel, due to less toxicity.
In conclusion, treatment with dose-dense paclitaxel or
docetaxel after dose-dense FEC results in a similar 3-year
DFS rate as adjuvant treatment for women with node-
positive early breast cancer. However, the toxicity of the
two taxanes is different with docetaxel causing more
neutropenia, thrombocytopenia, and onycholysis and pac-
litaxel more neurotoxicity. Therefore due its more favor-
able toxicity profile, paclitaxel remains the taxane of
choice in this setting.
Acknowledgments We acknowledge the assistance of Dora Hatzi-
daki and Vasso Athanasaki in the preparation of this manuscript.
Conflict of interest The authors have declared no pertinent conflicts
of interest.
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