Critical Reviews in Oncology/Hematology 75 (2010) 70–77

Weekly paclitaxel versus weekly docetaxel in elderly or frail patients with

metastatic breast carcinoma: A randomized phase-II study of the Belgian
Society of Medical Oncology夽
Benoit Beuselinck a , Hans Wildiers a , Wim Wynendaele b , Luc Dirix c , Jean-Pierre Kains d ,
Robert Paridaens a,∗
a University Hospitals Leuven, Catholic University Leuven, Medical Oncology Department, Belgium
b Medical Oncology Departments of Algemeen Ziekenhuis Imelda, Bonheiden, Belgium
c Algemeen Ziekenhuis St-Augustinus, Wilrijk, Belgium
d Hôpitaux Iris Sud, Ixelles, Belgium

Accepted 2 July 2009

Contents

1. Background—rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.1. Patient population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.2. Study design and assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
2.3. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.4. Statistical methods/analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.2. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.3. Comparison between both taxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Abstract
This randomized phase-II trial investigated the efficacy and tolerability of weekly docetaxel or paclitaxel in metastatic breast cancer (MBC)
patients considered unfit for a 3-weekly therapy.
The primary study endpoint was antitumor activity, the second endpoint was tolerability, time to progression (TTP) and overall survival
(OS). In intent-to-treat analysis, we observed for paclitaxel and docetaxel respectively partial response (PR) in 48% versus 38%, stable disease
(SD) in 24% versus 16%, PD in 15% versus 30%. Median TTP was 21.1 weeks versus 12.7 weeks and median OS 55.7 weeks versus 32
weeks. Toxicity profiles were acceptable with more anemia and neurotoxicity for paclitaxel and more edema and fatigue for docetaxel.

夽 The safety data in this study were presented at the 9th SIOG meeting on Geriatric Oncology in Montreal, Canada on 18 of October 2008. The trial was
also presented as a poster at the 31st Annual San Antonio Breast Cancer Symposium, Texas, 10–14 December 2008.
∗ Corresponding author at: University Hospitals Leuven, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 34 69 00;

fax: +32 16 34 69 01.

E-mail address: robert.paridaens@uz.kuleuven.ac.be (R. Paridaens).

1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2009.07.001
 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77
In patients with MBC unfit for 3-weekly docetaxel or paclitaxel, weekly administration of either compound may certainly be considered. They
display different, but acceptable toxicity profiles, with levels of antitumoral efficacy comparable to those previously reported for 3-weekly
regimens.
© 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metastatic breast cancer; Taxanes; Frail and elderly patients
1. Background—rationale
The elderly population affected by breast cancer is expand-
ing. Due to the improvements in locoregional and systemic
therapy, life expectancy of breast cancer patients, for any
stage, is constantly increasing. The decision to start or to
pursue chemotherapy for MBC in elderly patients, frequently
rendered frail by comorbidity, advancing disease or previous
therapies, is ever more frequent.
Taxanes are currently considered as the treatment of
choice in MBC after exposure to anthracyclines or when car-
diac function does not allow their use. Administered at the
recommended dose in a 3-weekly regimen, docetaxel (TAX-
OTERE, Sanofi-Aventis) is significantly associated with a
better OS and TTP than paclitaxel (TAXOL, Bristol-Myers
Squibb) [1]. Both compounds frequently display excessive
toxicity, mainly myelosuppression, which may preclude their
use in elderly and/or frail patients. More recently, weekly
schemes were also developed, which seemed to be more
tolerable without losing efficacy.
In a large randomized study published by Seidman et al.
[2], the overall response rate (RR) of 40% under weekly pacli-
taxel was significantly higher than the 28% RR observed
in patients having received a 3-weekly schedule. Accord-
ingly, RR under weekly paclitaxel in other studies range
from 21 to 68% [3–8]. Toxicity is generally mild (low inci-
dence of grade 3–4 neutropenia, nearly without any reported
episode of febrile neutropenia), except for peripheral neu-
ropathy maybe more pronounced after a weekly scheme
than after a 3-weekly scheme, resulting in treatment inter-
ruption in some patients [9]. In a subgroup analysis of a
phase-II trial [3] having accrued 212 patients, Perez et al.
[10] reported that RR, OS and toxicity were not worse in
elderly patients, taking a cut-off of 65 years. In a series of 23
patients aged 70 or more, Ten Tije et al. [11] reported under
weekly paclitaxel a RR of 38% with a median duration of
response of 194 days. Treatment was generally well tolerated,
but cumulative toxicity consisting of fatigue and neuropathy
led to treatment discontinuation in eight and three patients,
respectively.
Weekly docetaxel trials report RR between 26 and 50%,
acceptable tolerance with low grade 3–4 neutropenia inci-
dence and rarely neutropenic fever [12–19]. Cumulative
toxicity consists mainly in fatigue, lacrimal duct stenosis
and fluid retention which can lead to treatment interrup-
tion [9]. Focusing on elderly patients, Hainsworth et al.
evaluated weekly docetaxel in 41 elderly (age ≥ 65) or
poor-performance status patients with MBC [20]. Objective
71
response was seen in 36% and the median survival of the
entire group was 13 months. Our group also published in
2004 an encouraging RR of 30% observed among 41 elderly
and/or frail patients included in a phase-II trial [21]. Grade
3–4 neutropenia and neutropenic fever, which occurred in 10
and 4 patients, respectively, were more frequent than in other
series, probably reflecting the inclusion of frail patients with
pre-existing hematological abnormalities.
In view of our favorable results obtained with weekly doc-
etaxel, and taking into consideration the fact that weekly
paclitaxel is definitely less toxic and more efficient than 3-
weekly paclitaxel, we decided to conduct the present trial,
which is the first prospective randomized phase-II study
investigating in parallel the efficacy and tolerability of weekly
docetaxel or paclitaxel in frail and elderly MBC-patients con-
sidered unfit for a 3-weekly therapy.
2. Patients and methods
2.1. Patient population
This multicentric open-label non-comparative two arm
randomized phase-II trial accrued elderly or frail MBC-
patients with progressive disease and measurable lesions,
previously exposed to anthracyclines in adjuvant or
metastatic setting, unless cardiac function did not allow their
use.
Elderly patients were defined as patients aged 70 or more.
Criteria for frailty were one or more of the following:
(a) expected hematological problems with proven bone
marrow invasion and/or hematological problems with
previous chemotherapy and/or prior extensive radio-
therapy (irradiation of 33% or more of bone marrow
reserves according to Ellis et al., see Ref. [22]) and/or
low starting neutrophils (1000–1999/␮L) and/or platelets
<100,000/␮L;
(b) liver function abnormalities with increased bilirubin up to
3× upper limit of normal (ULN) and/or AST/ALT >2.5×
ULN and/or AST/ALT >1.5× ULN with ALP >5× ULN;
(c) grade 2 side effects due to previous treatment with tax-
anes in a 3-weekly schedule.
Patients with uncontrolled arterial hypertension, unstable
angina, cardiomyopathy or atrial or ventricular arrhythmias
requiring treatment were excluded, as well as patients with
marked cholestasis and/or severe liver function impairment
with bilirubin more than three times the ULN. Patients with
72 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77

pre-existing motor or sensory neurotoxicity more than grade
2 were also excluded.
Prior therapy with taxanes was allowed only if it had been
administered as adjuvant therapy or in a palliative setting,
with at least a 4-month treatment-free delay after a good
response. The dose of taxanes was calculated according to
body surface area, with a maximum of 2.0 m2 . Standard pre-
medication with corticosteroids (methylprednisone 32 mg on
the day before and on the day of taxane administration) was
given to all patients. When the trial was conceived, HER2/neu
status and trastuzumab administration were not part of rou-
tine treatment. Therefore, none of our patients received
trastuzumab. Nevertheless, as soons as trastuzumab was
available, HER2/neu positive patients were not included any-
more in this trial. HER2/neu positive patients, included before
trastuzumab was available, were switched to a trastuzumab
containing regimen as soon as they had PD. Growth factors
were not given systematically. In case of grade 3 hematologic
and non-hematologic adverse events, a 25% dose-reduction
was performed.
2.2. Study design and assessments
Six Belgian hospitals contributed to the accrual of
patients, who were centrally randomized after stratifica-
tion by institution and number of prior chemotherapies
(adjuvant only, first line metastatic ± adjuvant, second line
metastatic or more ± adjuvant). The patients received either
weekly paclitaxel 80 mg/m2 or weekly docetaxel 36 mg/m2
both administered i.v. over 1 h. Treatment was repeated
weekly for 8 weeks, on the provision that neutrophils were
≥1000/␮L. During the ninth week, response evaluation was
assessed, including a thoraco-abdominal CT-scan, according
to RECIST criteria [23]. Patients with complete remis-

Table 1
Baseline characteristics of patients.
Paclitaxel (33 patients) Docetaxel (37 patients) Total
Age
Below 70 21 21 42
70 or more 12 16 28
ECOG performance status at inclusion
0 10 (30%) 14 (38%) 24 (34%)
1 16 (48%) 17 (46%) 33 (47%)
2 5 (15%) 4 (11%) 9 (13%)
Unknown 2 (6%) 2 (5%) 4 (6%)
Tumor characteristics and metastatic sites
Estrogen receptor+ 21 (63%) 23 (62%) 44 (65%)
Progesteron receptor+ 14 (42%) 23 (62%) 37 (54%)
Bone metastases 25 (75%) 31 (83%) 56 (80%)
Liver metastases 29 (88%) 29 (78%) 58 (83%)
Lung metastases 9 (27%) 12 (32%) 21 (30%)
Prior chemotherapy
None 1 (3%) 2 (5%) 3 (4%)
Adjuvant only 4 (12%) 5 (14%) 9 (13%)
1 metastatic line 17 (51%) 17 (46%) 34 (49%)
2 or more metastatic lines 11 (33%) 13 (35%) 24 (34%)
Prior anthracycline treatment 33 (100%) 36 (97%) 69 (99%)
Prior taxanes treatment 3 (9%) 2 (5%) 5 (7%)
Baseline indicators of poor hematologic reserves
Anemia
Grade 1 (10 g/dL–LLN hemoglobin) 11 (33%) 13 (35%) 24 (34%)
Grade 2 (8–10 g/dL hemoglobin) 8 (24%) 6 (16%) 14 (20%)
Grade 3 (6.5–8 g/dL hemoglobin) 1 (3%) 1 (3%) 2 (3%)
Thrombopenia
Grade 1 (100,000–75,000/␮L) 5 (15%) 6 (16%) 11 (16%)
Grade 2 (74,999–50,000/␮L) 2 (6%) 0 2 (3%)
Grade 3 (49,999–10,000/␮L) 1 (3%) 0 1 (3%)
Leucopenia
Grade 1 (<LLN–3000/␮L)a 3 (9%) 4 (11%) 7 (10%)
Grade 2 (2999–2000/␮L) 2 (6%) 1 (3%) 3 (4%)
Prior extensive radiotherapy 12 (36%) 10 (27%) 22 (31%)
Baseline liver dysfunction
Bilirubine elevation
Grade 1 (1–1.5 mg/dL) 3 (9%) 1 (3%) 4 (6%)
Grade 2 (1.5–3 mg/dL) 1 (3%) 4 (11%) 5 (7%)
a LLN = lower limit of normal.
 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77
sion (CR), PR or SD pursued their treatment until PD
or unacceptable toxicity. The maintenance schedule con-
sisted in 3-weeks-on/1-week-off if no interruption or major
problem had occurred during the first 8 weeks period;
otherwise, 2-weeks-on/1-week-off therapy was prescribed.
Clinical assessment was performed every week.
2.3. Objectives
The primary objective was to evaluate the antitumor
activity of weekly paclitaxel and docetaxel; the secondary
objectives were to evaluate toxicity, TTP and survival of these
regimens.
2.4. Statistical methods/analysis
The study accrual was performed according to a “Gehan 2-
stage-design” [24]. In the first step, 14 patients evaluable for
response were accrued in each arm. If there was no response
in one or both arms, the trial had to be terminated, because the
probability of a true RR ≥20% would only be 5%. This was
not the case and the trial continued to step two, with addition
of 21 patients to each arm. This design allows estimating a
95% confidence interval (CI) around the observed response
rate to paclitaxel or docetaxel with a maximum width of 33%.
3. Results
Seventy patients, 33 in the paclitaxel-arm and 37 in the
docetaxel-arm, were accrued from January 2002 to August
2005. The mean age of all included patients was 63.7 years
with a range from 31 to 84 years. The mean age of the elderly
patients included in the paclitaxel and docetaxel-arm was 75.3
and 75.5 years, respectively. All but one patient had received
prior treatment with anthracyclines, either given as adjuvant
treatment and/or for advanced disease. Only five patients
received previous therapy with taxanes, two for neoadjuvant
purpose and three in a metastatic setting.
Table 2
Treatment efficacy by age and treatment.
PR
Patients ≥ 70 years (28 pts) 10 (36%)
Paclitaxel (12 pts) 6 (50%)
Docetaxel (16 pts) 4 (25%)
Patients < 70 years (42 pts) 20 (48%)
Paclitaxel (21 pts) 10 (48%)
Docetaxel (21 pts) 10 (48%)
All patients (70 pts) 30 (43%) (95% CI: 31–55%)
Paclitaxel (33 pts) 16 (48%) (95% CI: 31–65%)
Docetaxel (37 pts) 14 (38%) (95% CI: 22–54%)
a Most of these patients were not evaluable because of early trial interruption before the CT evaluation foreseen in week 9. One patient retired her informed
consent. Two patients died from other reasons. One patient was lost to follow-up. The other patients died from disease progression or worsening of general
condition.
73
The baseline characteristics of our patients and a summary
of their previous treatments presented in Table 1 clearly show
the frailty of the study population. Many of them would have
been ineligible for inclusion in any classical phase-II study,
as for example those patients with baseline liver function
impairment with hyperbilirubinemia (13%) and those with
thrombocytopenia due to bone marrow invasion (22%).
The number of chemotherapy administrations and the
average duration of treatment to every single patient were
higher with paclitaxel (median 11.0 – max 32) (101 days –
max 263) than with docetaxel (median 8.0 – max 22) (71 days
– max 191). The mean delivered dose per administration was
129 mg (76 mg/m2 ) for paclitaxel and 57.5 mg (34.4 mg/m2 )
for docetaxel. During the first 8 weeks of treatment, the
mean dose-intensity was 62 mg/(m2 week) for paclitaxel
and 29.5 mg/(m2 week) for docetaxel, representing, respec-
tively 78 and 82% of the intended dose-intensity. During
the whole treatment, the mean dose-intensity was lower:
56.6 mg/(m2 week) for paclitaxel and 27.0 mg/(m2 week) for
docetaxel.
In the docetaxel-arm, 16 patients continued treatment after
week 9, 11 on a 3/4-week and 5 on a 2/3-week schedule.
In the paclitaxel-arm, 22 patients continued treatment after
week 9, 12 on a 3/4-week and 10 on a 2/3-week schedule.
Dose-reductions were necessary in only six patients in each
treatment arm.
The breakdown of RR by age and treatment arm, calcu-
lated according to intent-to-treat without any exclusion, are
presented in Table 2. No CR was observed. For the whole pop-
ulation, the RR was 43%. All subgroups of patients showed
responses. For elderly aged 70 or more RR was 36%, seem-
ingly higher in the paclitaxel than in the docetaxel-arm (50%
versus 25%); for heavily pretreated patients, we observed a
PR in 5 patients out of 9 with paclitaxel and 3 patients out of
10 with docetaxel.
The Kaplan–Meier curves for TTP and OS are presented
in Figs. 1 and 2. The median TTP was 21.1 weeks (95%
CI: 14.9–29.0) under paclitaxel and 12.7 weeks (95% CI:
8.4–29.3) under docetaxel. A 6-week longer median TTP was
observed regardless of the treatment arm in younger patients
SD PD Unable to determine
5 (18%) 6 (21%) 7 (25%)
2 (17%) 2 (17%) 2 (17%)
3 (19%) 4 (25%) 5 (31%)
9 (21%) 10 (24%) 3 (7%)
6 (29%) 3 (14%) 2 (10%)
3 (14%) 7 (33%) 1 (5%)
14 (20%) 16 (23%) 10 (14%)a
8 (24%) 5 (15%) 4 (12%)
6 (16%) 11 (30%) 6 (16%)
74 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77

compared to elderly. Most of the patients died from PD after

Fig. 1. Kaplan–Meier curve illustrating time to progression under paclitaxel
(33 patients) and docetaxel (37 patients).
Fig. 2. Kaplan–Meier curve illustrating Survival in the paclitaxel-arm (33
patients) and in the docetaxel-arm (37 patients).
a median survival of 55.7 weeks in the paclitaxel-arm and
32.0 weeks in the docetaxel-arm.
Univariate analysis of the efficacy results adjusted for age
or previous therapy reveals that none of these categories was
prognostic for the RR. The efficacy of taxanes is maintained
in patients aged 70 or more.
Adverse events, laboratory toxicities and other toxicities
are reported in Table 3 using NCIC-CTC 2.0 grades. Treat-
ment was interrupted for toxicity in 17 patients (45%) of
the docetaxel-arm and in 12 patients (36%) of the paclitaxel-
arm. The 95% CIs calculated for the main toxicities observed
under both treatments arms were largely overlapping, except
for all grades of neutropenia which were definitely higher
with paclitaxel than with docetaxel (88% versus 50% grades
1–4, respectively).
Under docetaxel, 14 patients required transfusion with a
mean of 4.4 units packed cells and treatment was interrupted
because of protracted anemia in 1 of them. Under paclitaxel,
13 patients needed transfusion with a mean of 3.7 units and
a single patient required a platelets transfusion. Granocyte-
colony-stimulating factors were not used systematically.
As far as toxicity is concerned (Table 4), the main rea-
son for interrupting treatment was fluid retention, edema and
pleural effusion under docetaxel (8/37 patients) and sensory
neuropathy under paclitaxel (8/33 patients). In the docetaxel-
arm, sensory neuropathy led to treatment discontinuation in
only three cases. Nail toxicity led to the end of the study
in three patients on docetaxel and in only one on paclitaxel.
Changes in liver tests reflected the evolution of liver metasta-
sis and were never interpreted as a treatment-related toxicity.
Two toxic deaths (one of a septic shock and one due
to exhaustion considered as a side effect of the therapy)

Table 3
Toxicities.
Docetaxel weekly (n = 37) Paclitaxel weekly (n = 33)

Gr I % Gr II % Gr III % Gr IV % TOTAL % Gr I % Gr II % Gr III % Gr IV % TOTAL %

Anemia 32 30 5 0 68 30 24 18 3 76
Neutropenia 17 14 17 3 50 6 36 30 15 88
Thrombopenia 30 8 3 0 41 30 3 6 6 46
Febrile neutropenia 0 0 0 0 0 0 3 6 0 9
Infection 11 24 11 0 46 9 24 15 0 49
Anorexia 38 27 0 0 65 27 21 0 0 49
Stomatitis 22 5 16 0 43 12 15 3 0 30
Nausea 32 22 0 0 54 27 24 0 0 52
Emesis 32 5 3 0 41 36 9 0 0 46
Diarrhea 38 8 0 0 46 30 6 6 0 43
Alopecia 11 30 0 0 41 15 24 0 0 39
Sensory neuropathy 35 8 3 0 46 27 21 9 0 57
Fatigue – asthenia 22 41 8 0 70 9 52 6 0 67
Edema 19 14 3 0 35 18 9 0 0 27
Increased lacrimation 14 11 0 0 24 6 3 0 0 9
Nail toxicity 19 16 0 0 35 21 12 0 0 33
Myalgia 3 5 0 0 8 15 9 0 0 24
Bilirubin elevation during treatment 6 0 3 0 9 9 12 0 0 21
AST elevation during treatment 9 3 6 0 18 12 12 9 0 33
ALT elevation during treatment 12 6 3 0 21 30 6 9 0 46
 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77 75

Table 4 incidences of 5 and 9%, respectively. Likewise grade 3–4

Adverse events leading to treatment discontinuation.a . thrombopenia occurred in 12% of our patients, while it was
Docetaxel (n = 37) Paclitaxel (n = 33) anecdotically reported (2%) by Seidman et al. [2].
Anemia 1 The non-hematologic adverse events, which generally
Pericardial effusion 1 were less frequent and milder than in 3-weekly regimens,
Conjunctivitis, increased 1 1 occurred in the same proportion as in other weekly taxane
lacrimation, blurred vision
Ascites 1
trials conducted in non-elderly or non-frail patient groups.
Diarrhea 1 For docetaxel weekly, the main side effects were fluid reten-
Stomatitis 1 1 tion, sensory neuropathy, fatigue, nail toxicity and increased
Fatigue, asthenia, general health 3 3 lacrimation. The main non-hematologic reason for stopping
deterioration treatment was by far fluid retention and the high proportion of
Oedema, pleural effusion, fluid 8
retention
treatment interruptions for toxicity of docetaxel in our study
Infections 1 (45%) is nearly identical to the 46% reported by Tabernero et
Myalgia 1 al. [12]. Under paclitaxel, 36% of the patients interrupted
Dysgeusia 1 treatment before occurrence of tumor progression, cumu-
Paresthesia, sensory neuropathy 3 8 lative neurotoxicity and debilitating fatigue being the main
Dyspnea 2
Erythema – photosensitivity 1 2
reasons therefore. We observed 9% of grade 3 sensory neu-
reaction – flushing ropathy, comparable to the 12% reported by Perez et al. [3]
Onychalgia, nails disorders 3 1 and 67% grade 1–3 fatigue, the same incidence as in Ten
Number of patients who 17 (45%) 12 (36%) Tije’s elderly cohort, where it was the main reason for treat-
discontinued treatment ment interruption. The mild toxicity profile in our elderly and
a Several reasons in one patient possible. frail population confirms the subanalysis of Perez et al. [10]
in which there was no clear difference in tolerance between
patients younger or older than 65 years treated with paclitaxel
were reported, both occurring in elderly patients under weekly.
docetaxel. Obviously, the occurrence and severity of some side
effects may be influenced by the burden of disease and by
previous treatments. This, combined with aging, frailty and
4. Discussion comorbidity, explains why we observed a definitely higher
hematologic toxicity in the present study, while Sparano et
4.1. Toxicity al. [25] in the adjuvant setting rarely reported grade 3–4 neu-
tropenia or infections with weekly paclitaxel (2 and 3%) or
Our results clearly show that taxanes administered weekly docetaxel (3 and 4%). Of note, however, the incidence of
to elderly and/or frail patients are generally well tolerated. severe sensory neuropathy and fatigue observed in our MBC-
Treatment interruption for toxicity reasons in our patients patients was not obviously different from the adjuvant data
may seem frequent (docetaxel 45%, paclitaxel 36%), but it of Sparano.
should be realised that our threshold to stop treatment in a
palliative setting was rather low (mainly grade 2) in order to 4.2. Efficacy
preserve the quality of life of the patients.
There was a low incidence of severe hematologic toxic- Our results clearly indicate that both taxanes administred
ity and a much lower risk of neutropenic fever than the risk weekly in elderly and/or frail patients are effective. Indeed,
reported in 3-weekly regimens (1). However, when we com- the RR achieved and the median TTP observed in both arms
pare the present series to other trials having tested weekly in frail and elderly MBC-patients, are comparable to those
taxanes in non-elderly and non-frail patients, we definitely observed in a non-frail and non-elderly cohort receiving opti-
observe a higher incidence of grade 3–4 neutropenia with mally dosed taxanes in a weekly or a 3-weekly regimen. The
both products, and a high incidence of grade 3–4 anemia randomized study of Jones et al. [1] reported a mean RR of
and thrombopenia with paclitaxel as well. With docetaxel, 32% for 3-weekly docetaxel 100 mg/m2 and 25% for pacli-
we find 19.5% grade 3–4 neutropenia, which is the highest taxel 175 mg/m2 with median TTPs of 24.6 and 15.6 weeks,
incidence in comparison to the literature data ranging from respectively. In weekly trials, RR ranged from 21 to 50% with
3 to 19%. Corresponding figures with paclitaxel are 45% of docetaxel [12–19] and from 21 to 68% with paclitaxel [3–8].
grade 3–4 neutropenia complicated with neutropenic fever in Univariate analysis of the efficacy results adjusted for age
9% of patients in the present series, compared with an inci- or previous therapy reveals that none of these categories was
dence ranging from 2 to 15% for grade 3–4 neutropenia and a prognostic for the RR. The efficacy of taxanes is maintained
very low risk of febrile neutropenia (only 1% in the series of in patients aged 70 or more. This confirms the conclusion
Perez et al. [3]) in other trials. We observed 21% of grade 3–4 made by Perez that weekly paclitaxel remains a valuable ther-
anemia, while Seidman et al. [2] and Perez et al. [3] reported apeutic option after the age of 65 [10]. Similarly, the efficacy
76 B. Beuselinck et al. / Critical Reviews in Oncology/Hematology 75 (2010) 70–77
observed in the present study in patients previously exposed
to two or more chemotherapy regimens for MBC, confirm
Burstein’s observation made on a small series of 29 patients
treated with 40 mg/m2 weekly docetaxel [13]. As far as effi-
cacy and tolerance are concerned, it is important to emphasize
that most of the 42 frail non-elderly patients included in the
present study could never be eligible for the above described
trials testing taxanes in a weekly schedule. Classical phase-II
study protocols generally declare ineligible patients with low
hematologic counts, or at high risk of deep myelosuppres-
sion. Our cohort is thus unique in so far it accrued ‘real-life’
oncologic patients with poor hematologic reserves as those
with grade 1–2 leuco- or thrombopenia, myelophtysia, prior
extensive radiotherapy or patients having experienced febrile
neutropenia during previous chemotherapies.
4.3. Comparison between both taxanes
Although this randomized phase-II study was neither
designed nor powered to make a true statistically valid com-
parison as in a phase-III trial, we may draw clinically relevant
conclusions on the respective merits of both compounds
administered weekly in an elderly and frail population.
First, our results show without ambiguity that both prod-
ucts have a significant antitumoral efficacy even in heavily
pretreated patients. The higher RR and the longer TTP
observed with paclitaxel as compared to docetaxel should
be interpreted with great caution because the 95% CI’s for
these efficacy parameters were largely overlapping. How-
ever, the RR and duration of response of either drug, seen
in all subgroups, regardless of age, are at such a level that the
administration of weekly taxanes should be considered as a
valid option to be offered to elderly and frail patients. These
efficacy results confirm the observation made by Sparano
et al. [25] in the adjuvant setting on a very large series of
patients receiving adjuvant paclitaxel after four cycles of
doxorubicine and cyclophosphamide, showing that weekly
paclitaxel administration represents the most efficient sched-
ule for this drug.
As far as toxicity is concerned, just as for 3-weekly
administration, weekly paclitaxel or docetaxel behave dif-
ferently. In 3-weekly schemes, all toxicities except myalgia
are more frequent under docetaxel than under paclitaxel
[1]. By weekly administration, nausea, vomiting and diar-
rea occurred more or less in the same proportion in both
arms and were rarely severe; grade 3–4 stomatitis, anorexia
and edema occurred more with docetaxel, while neurotoxic-
ity and myalgia were more often seen with paclitaxel. The
dose intensity achieved with docetaxel (36 mg/(m2 week)
in weekly versus 33 mg/(m2 week) in 3-weekly administra-
tion) does not seem to be schedule dependent. Similarly,
toxicity will impose interruption of a weekly or 3-weekly
treatment in many patients at nearly the same cumulative dose
of 400–600 mg/m2 [10]. On the contrary, weekly paclitaxel
results in a much higher dose intensity (80 mg/(m2 week) in
weekly versus 58 mg/(m2 week) in 3-weekly administration)
and a definitely better efficacy than by 3-weekly adminis-
tration [2]. We observed in the present study that a weekly
treatment with paclitaxel could generally be administred
longer (28% more administrations and 40% longer duration
of treatment) than with docetaxel. Of course, a longer expo-
sure to treatment could explain differences in hematotoxicity
like more clinically relevant anemia and more neutropenic
events observed in the weekly paclitaxel-arm.
5. Conclusion
We can conclude that both paclitaxel and docetaxel admin-
istered weekly display significant antitumor efficacy with
acceptable tolerability in elderly or frail patients. Both
compounds display antitumor efficacy levels comparable to
those previously reported for 3-weekly regimens. Choosing
between weekly paclitaxel or docetaxel should be driven by
their anticipated toxicity profiles. Nevertheless, a true valid
comparison between both taxanes would require extension
into a phase-III trial.
We clearly show in this study that weekly taxanes may
represent a valid option to be discussed with elderly or frail
patients, even for those cumulating high age and frailty,
in whom conventional 3-weekly administration can not be
considered. The population of elderly patients is increasing,
justifying trials focusing on this category and using a specific
methodology, including geriatric assessment scoring systems
and quality of life measurements as emphasized by Quaglia
et al. [26].
Conflict of interest statement
The authors do not declare any conflict of interest.
Reviewers
Etienne G.C. Brain, M.D., Ph.D., Rene Huguenin Cancer
Centre, Department of Medical Oncology, 35 rue Dailly, F-
92210 Saint-Cloud, France.
Alistair Ring, M.R.C.P., M.D., Senior Lecturer in Oncol-
ogy, Royal Sussex County Hospital, Sussex Cancer Centre,
Eastern Road, Brighton BN2 5BE, United Kingdom.
Professor Tanja Cufer, University Clinic Golnik, Medical
Faculty, SI-4204 Golnik, Slovenia.
Chantal Bernard-Marty, M.D., Institut Jules Bordet,
Chemotherapy Unit, Department of Medicine, 121 Boulevard
de Waterloo, B-1000 Brussels, Belgium.
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Biography
Robert Paridaens, M.D. and Ph.D., is Professor and Head
of the Medical Oncology Clinic since 1991 at the U.Z.
Gasthuisberg, the academic Hospital of the Catholic Uni-
versitity of Leuven, Belgium.
Between 1978 and 1987, after having trained in internal
medicine, he further specialized in medical oncology at the
Institut Jules Bordet in Brussel, where he also exerted the
functions of assistant director of the cancer screening unit,
and of assistant director at the EORTC (European Organi-
zation for Research and Treatment of Cancer) Data centre.
He developed a special interest in breast cancer and con-
ducted in parallel clinical and fundamental investigations on
the theme of hormone-dependence of tumors. After his PhD
thesis in 1987, he moved to the academic hospital Sart Tilman
(Université de Liège) where he exerted there the functions
of Professor and Head of the department of Oncology and
Radiotherapy until 1991.
Dr. Paridaens serves on several editorial boards, and is a
member of all major Belgian and of most international soci-
eties that focus on cancer research and treatment. He played
an active role in many cooperative groups of the EORTC and
was the recipient of the Belgian Endocrine Society Award
(1987), of the Golden Helix Award for quality improvement
in European health care (1995) and of the Astra Zeneca Foun-
dation Lectures in Medicine Award (2004). He was chairman
of the Belgian Society of Senology, of the Belgian Society of
Medical Oncology and of the Belgian Association for Can-
cer Research. He trained numerous medical oncologists and
radiotherapists in their clinical practice and also for getting
accustomed with clinical trials. He very actively contributed
to the development of modern forms of endocrine therapy,
as shown by his numerous international publications in the
field. In parallel with his clinical and academic functions, he
presently pursues fundamental research on hormone depen-
dence and cancer proteases.