Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials
Breast Cancer Research
Vol10No5 Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials
Sibylle Loibl 1 2
Gunter von Minckwitz 1 2
Nadia Harbeck 0
Wolfgang Janni 5
Dirk Elling 4
Manfred Kaufmann 1
Holm Eggemann 4
Valentina Nekljudova 2
Harald Sommer 5
Marion Kiechle 0
Sherko Kümmel 3
0 Department of Obstetrics and Gynecology, Technical University of Munich , Ismaninger Strasse 22, Munich 81675 , Germany
1 Department of Obstetrics and Gynecology, J.W. Goethe-University , Theodor-Stern Kai 7, Frankfurt 60590 , Germany
2 German Breast Group , Schleussnerstrasse 42, Neu-Isenburg 63263 , Germany
3 Department of Obstetrics and Gynecology, University Hospital Essen , Hufelandstrasse 55, Essen 45122 , Germany
4 Department of Obstetrics and Gynecology, Otto-von-Guericke University , Gerhart-Hauptmann Strasse 35, 39108 Magdeburg , Germany
5 Department of Obstetrics and Gynecology, Ludwig-Maximilians University , Maistrasse 11, Munich 8337 , Germany
Introduction Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients. Methods Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (< 60 years, between 60 and 64 years, and > 64 years) with primary breast cancer received taxane-based chemotherapy. Results Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from FN: febrile neutropenia; TAC: docetaxel/doxorubicin/cyclophosphamide
The incidence of breast cancer in women aged 65 years and
older is the highest in all age groups. These older patients are
generally underrepresented or even excluded from clinical
trials, however, leading to a gap in data about the compliance,
safety, and efficacy of highly active taxane-based treatments in
older patients. From several clinical trials, there is a growing
55.3% in patients aged < 60 years to 65.5% in patients aged >
64 years (P < 0.001), and neutropenia increased from 46.9% to
57.4% (P < 0.001). There was no difference, however, in
clinically more relevant febrile neutropenia between the different
age groups. Thrombopenia shows a similar age-dependent
increase, whereas there is no difference between the age
groups concerning anemia. Hot flushes and elevated liver
enzymes decreased with increasing age.
Conclusions The present pooled analysis of a substantial
cohort of older primary breast cancer patients demonstrates
that taxane-containing (neo)adjuvant chemotherapy is feasible in
older patients and that toxicity can be reduced by sequential
awareness that older primary breast cancer patients achieve
significant survival benefits with (neo)adjuvant chemotherapy
regimens. Regarding the steady increase of life expectancy
today, this should be considered in treatment of older patients
in clinical routine.
There is evidence in breast cancer that the use of taxanes in
adjuvant chemotherapy yields a survival benefit – especially
from the PACS 01 study, demonstrating a particular benefit in
women aged 50 years or older [
]. There are relatively few
data, however, on the use of these agents in older patients [
Owing to concerns about tolerability, there remains a
tendency in clinical routine to use less dose-intensive
chemotherapy in older patients with the avoidance of those agents
perceived to be more toxic. We therefore combined data of
different adjuvant and neoadjuvant trials with
taxane-containing regimens. Here we present the results of the first
systematic pooled analysis of tolerability data for taxane-based
regimens in older primary breast cancer patients.
Materials and methods
A pooled analysis of four German prospective, randomized
clinical trials, conducted during 1999 to 2005, was
performed. These trials included primary breast cancer patients
receiving taxane-containing neoadjuvant or adjuvant
chemotherapy. The meta-database was closed in October 2006; the
number of patients in the present analysis may therefore differ
from the separate study publications. For every study,
however, the number of patients included in the present analysis
exceeds 75% of those evaluable. Toxicity data from the
studies were analyzed for taxane-containing chemotherapy in older
patients (aged > 64 years) compared with toxicity data from
patients aged < 60 years and those aged 60 to 64 years
treated in the same studies. The treatment regimens of the four
trials included are depicted in Figure 1.
Study design of the ffoouurr ttrriiaallss. CR, complete response; PR, partial response; NC, no clinical response. EC-T, epirubicin, cyclophosphamide followed
by docetaxel; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; EC-P, epirubicin, cyclophosphamide followed by paclitaxel; AC-T, doxorubicin,
cyclophosphamide followed by docetaxel; E-P, epirubicin followed by paclitaxel; AT, doxorubicin, docetaxel; TAC, docetaxel, doxorubicin,
cyclophosphamide; NX, vinorelbine, capecitabine. q2W, every 2 weeks; q3W, every 3 weeks; q4W, every 4 weeks. i.v., intravenously; p.o., per orally; d, day.
In the ADEBAR trial (NCT00047099), patients (n = 1,106/
1,502) received four cycles of adjuvant chemotherapy either
with epirubicin/cyclophosphamide every 3 weeks followed by
four cycles of docetaxel every 3 weeks, or six cycles of
5-fluorouracil, epirubicin on days 1 and 8 and cyclophosphamide on
days 1 to 14 every 4 weeks [
In the ASG 1–3 trial (NCT00668616), patients (n = 772)
received four cycles of adjuvant chemotherapy either with
epirubicin/cyclophosphamide every 3 weeks then four cycles of
paclitaxel every 3 weeks, or with four cycles of epirubicin every
2 weeks and then four cycles of paclitaxel every 2 weeks
(unpublished data, Kümmel S. et al).
In the GeparDuo trial (NCT00543829), patients (n = 902)
received four cycles of neoadjuvant chemotherapy with
doxorubicin/cyclophosphamide every 3 weeks followed by four
cycles of docetaxel every 3 weeks or four cycles of
doxorubicin/docetaxel every 2 weeks [
In the GeparTrio trial (NCT00544765), patients (n = 1,988/
2,072) received two cycles of neoadjuvant chemotherapy with
docetaxel/doxorubicin/cyclophosphamide (TAC) followed by
either four cycles of TAC or six cycles of TAC or four cycles of
vinorelbine plus capecitabine every 3 weeks [
For the purpose of the analysis, chemotherapy regimens were
divided into four chemotherapy schedules: combination
taxane schedule, TAC 75/50/600 mg/m2; sequence schedule,
doxorubicin(epirubicin)cyclophosphamide 60(90)/600 mg/m2
followed by docetaxel 100 mg/m2 or paclitaxel 175 mg/m2;
combination dose-dense schedule, dose-dense doxorubicin/
docetaxel 50/75 mg/m2; and sequence dose-dense schedule,
dose-dense epirubicin/dose-dense paclitaxel 120/175 mg/
Supportive care during the studies
Various strategies for supportive therapy and premedication
were used in the studies analyzed. All patients were given
prophylactic 5-HT3 antagonists, however, and all patients
receiving taxane regimens also received dexamethasone. Primary
neutropenia prophylaxis was not administered to patients
receiving nontaxane chemotherapy and was not mandatory for
patients receiving the sequence schedule. All patients
receiving combination dose-dense schedules and sequential
dosedense schedules received prophylaxis with filgrastim or
lenograstim on days 5 to 10. Among the patients receiving the
combination taxane schedule, 16% received no primary
prophylaxis with granulocyte-colony stimulating factor, 23%
received filgrastim or lenograstim on days 5 to 10, and 61%
received pegfilgrastim on day 2 [
]. No patients receiving the
sequence schedule, the combination dose-dense schedule or
the sequence dose-dense schedule received primary
antiinfective prophylaxis – while among those patients who
received the combination taxane schedule, 44% received no
prophylaxis and 56% received ciprofloxacin on days 5 to 14.
In the GeparTrio study, supportive care changed during the
study from ciprofloxacin alone in the pilot phase to filgrastim or
lenograstim prophylaxis, then to pegfilgrastim and, finally, to
pegfilgrastim plus ciprofloxacin [
Data collection and statistical analyses
Data were collected on dose delays/reductions,
hospitalizations, treatment discontinuation, deaths, and hematologic and
nonhematologic toxicity. For hematologic toxicity, not all
records of all cycles in the four studies included the same data
on events: febrile neutropenia (FN) data were recorded for
patients on the TAC regimen; all other patients were
considered to have FN of at least grade 3 in a given chemotherapy
cycle if they had grade 3/4 neutropenia, more than grade 1
fever, and no infection. All FN cases reported as serious
adverse events with severity grade were also considered. In
cycles where at least one of the three parameters
(neutropenia, fever, infection) was missing, and FN was not reported in
the serious adverse events description, the cycle was
considered a missing value for FN.
All statistical analyses were exploratory and no adjustments
were made for multiple comparison. Calculations were
performed using SPSS 12.0.1 for Windows (SPSS Inc. Chicago,
IL, USA). Grading systems for toxicities in different studies
were checked for consistency and were converted into
NCICTCAE 3.0 grades. Pearson's chi-squared test was
performed to compare incidences of toxicity endpoints in the
three different age groups of patients.
Across the four studies, 422 patients aged ≥ 65 years (out of
4,227 patients), with a median age of 67 years (range 65 to
80 years), received 1,674 cycles of taxane-containing
chemotherapy regimens. Furthermore, 3,160 patients aged < 60
years, with a median age of 47 years (range 23 to 59 years),
received 14,146 cycles of taxane-containing chemotherapy
regimens. Across the studies, 2,674 cycles were given to
patients aged between 60 and 64 years. Demographic and
clinical characteristics of the patients who received a
taxanecontaining chemotherapy and the summary data for all 'older'
patients (aged > 64 years and aged 61 to 64 years) and
'younger' patients (aged < 60 years) are presented in Table 1.
Dose delays/reductions, hospitalizations, therapy discontinuations, and deaths during the trials
Dose delays (evaluated from first taxane cycle in sequential
regimens), reductions, and therapy discontinuation for any
reason increased with age (Figure 2).
Overall during the taxane cycles, dose delays were reported in
9.0% of patients younger than 60 years versus 12.6% of
patients aged between 60 and 64 years and 13.7% of
patients aged 65 years and older (P = 0.001). Dose
Demographic and clinical characteristics of patients at baseline
Receptor status (ER-positive and/or PgR-positive versus both negative)
tions were reported in 5.1% of patients aged < 60 years, 6.7%
of patients aged 60 to 64 years, and 8.1% of patients aged ≥
65 years (P = 0.019), hospitalization was reported in 16.0%,
23.4%, and 18.1% (P < 0.001), treatment discontinuation
was reported in 11.8%, 17.2%, and 18.7% (P < 0.001), and
deaths were reported in 0.2%, 0.3%, and 1.0%, respectively
Overall among taxane schedules, the incidences of dose
delays (13.8%) and of hospitalization (25%) were markedly
higher with the sequence dose-dense schedule (dose-dense
epirubicin/dose-dense paclitaxel regimen) versus other taxane
schedules. There are, however, age-specific differences. The
patient age groups < 60 years and 60 to 64 years performed
similarly, whereas patients older than 64 years had the highest
incidences of dose delays (20%) and hospitalizations (50%)
Data presented as n (%). All percentage values are valid. ER, estrogen receptor; PgR, progesterone receptor.
aDnodsedereadthucpteiornp,adtioesnet,dvelrasyu,shaogsepitgarloizuaption, therapy discontinuation,
and death per patient, versus age group.
Dose reduction, dose delay, hospitalization, therapy discontinuation, and death versus schedule. (a) For all patients. (b) For patients younger than
60 years old. (c) For patients aged 60 to 64 years. (d) For patients older than 64 years of age.
with the combination dose-dense schedule (dose-dense
doxorubicin/docetaxel) (Figure 3b,c,d).
In older patients versus younger patients, the per-patient
incidences of grade 3 to grade 4 hematologic adverse events
generally increased with age (Figure 4). Leucopenia increased
from 55.3% in patients < 60 years old to 65.5% in patients >
64 years old (P < 0.001), and neutropenia increased from
46.9% to 57.4% (P < 0.001). There was no difference,
however, in FN between the different age groups.
For taxane therapy, the incidences of grade 3 to grade 4
leucopenia were all statistically significantly different per patient
between the age groups and for docetaxel-treated patients (P
< 0.001), whereas for paclitaxel-treated patients an age
difference was only seen for leucopenia (Table 2). Overall there was
no age difference in developing FN. In patients younger than
60 years of age FN was only significantly more common in the
docetaxel-containing regimen, whereas there was no
difference between the docetaxel and paclitaxel regimen in patients
older than 60 years. Anemia and thrombopenia were
significantly more common in the paclitaxel-containing regimen but
only in the age group below 60 years of age. The rate of
thrombopenia increased with age, whereas there is no age
difference with anemia.
Among taxane schedules, the taxane combination (TAC) was
overall associated with the highest incidence of hematologic
toxicity, and the dose-dense paclitaxel part of the sequence
dose-dense schedule with the lowest incidence (Table 3). For
the TAC regimen, grade 3 to grade 4 leucopenia was reported
in 57.3% of patients < 60 years old, 65.3% for the patient
group between 60 and 64 years old, and 64.9% for the
patients older than 64 years. Similar results are presented for
grade 3 to grade 4 neutropenia in 37.5%, and 56.7%, and
Iangceidgernocueps of grade 3 and grade 4 hematologic adverse events versus
age group. Leucopenia: age <60 years, n = 1,730; age between 60
and 64 years, n = 406; age >64 years, n = 272 (P < 0.001).
Neutropenia: age <60 years, n = 1,152; age between 60 and 64 years, n = 326;
age >64 years, n = 225 (P < 0.001). Febrile neutropenia: age <60
years, n = 181; age between 60 and 64 years, n = 43; age >64 years,
n = 29 (P = 0.430). Anemia: age <60 years, n = 97; age between 60
and 64 years, n = 16; age >64 years, n = 14 (P = 0.674).
Thrombopenia: age <60 years, n = 70; age between 60 and 64 years, n = 14; age
>64 years, n = 21 (P = 0.002).
55.2% and for FN in 9.3%, 11.3%, and 14.3% for the different
age groups, respectively. Thrombopenia shows a similar
agedependent increase, whereas there is no difference between
the age groups concerning anemia.
For the dose-dense doxorubicin/docetaxel regimen, grade 3 to
grade 4 leucopenia was reported in 50.2%, 61.3%, and
62.5% of patients in the age groups < 60 years, 60 to 64
years and > 64 years. There was no difference between the
age groups for neutropenia, FN, and anemia and
thrombopenia grade 3 to grade 4.
In contrast to the combination schedules, the highest
incidence of grade 3 to grade 4 toxicity in the sequence
schedules occurred for neutropenia, which was reported in 65.5%
of patients older than 64 years when treated with the
nontaxane-containing regimen (epirubicin/cyclophosphamide or
doxorubicin/cyclophosphamide). The sequential paclitaxel
regimen was also comparatively well tolerated – especially,
the sequential dose-dense paclitaxel schedule had
significantly fewer toxicity cases compared with the epirubicin
dosedense schedule, with a peak incidence of 8.7% for grade 3 to
grade 4 neutropenia per patient (with no cases of FN
reported) in the age group younger than 60 years.
Not all of the nonhematologic toxicity data were consistently
recorded for all chemotherapy regimens and cycles in the
trials. The nonhematologic toxicity associated with taxane
chemotherapy is summarized in Table 4.
In older patients versus younger patients there were
significantly higher incidences (P < 0.05) of grade 3 to grade 4
fatigue (14.5% in patients aged < 60 years versus 19.5% in
patients aged 60 to 64 years versus 23.5% in patients aged >
64 years), grade 1 to grade 3 loss of appetite (67.0% versus
73.8% versus 84.4%, respectively), grade 1 to grade 4
nausea and vomiting (77.5% versus 79.3% versus 85.5%,
respectively), grade 1 to grade 4 diarrhea (40.6% versus
42.2% versus 50.6%, respectively), and raised creatinine
levels grade 1 to grade 4 (3.4% versus 6.3% versus 7.8%,
respectively) with the docetaxel regimen with increasing age.
With paclitaxel, grade 3 to grade 4 mucositis (1.6% versus
5.9% versus 6.3%, respectively) and raised creatinine levels
grade 1 to grade 4 (81.3% versus 4.2% versus 7.0%,
respectively) significantly increased with age. Infection with
neutropenia grade 1 to grade 4 overall was statistically significantly
increased with age.
Conversely, there was a significantly higher incidence of grade
1 to grade 3 hot flushes (64.6% versus 59.1% versus 51.1%,
P = 0.031) and grade 1 to grade 4 changes in liver enzymes
(53.5% versus 50.3% versus 42.9%, P < 0.001) in younger
patients versus older patients.
There is a growing awareness that age per se is a less
important determinant of choice of therapy concepts and outcome
in older cancer patients than physical status, functional status,
and mental/emotional status. Indeed, it is becoming more and
more evident that older, but otherwise healthy, patients with
primary breast cancer can accrue the same benefits from
standard chemotherapy as younger patients – especially when
regarding the steady increase in life expectancy and quality of
life in western societies. The clinical assumption that most
older patients are too frail to receive standard chemotherapy –
reflected in, for example, less use of adjuvant chemotherapy in
older breast cancer patients [
] – is being challenged
]. There is a paucity of published data from
chemotherapy trials comparing older with younger cancer patients,
however, which has hampered efforts to improve treatment
strategies for this population. This lack of data arises from the
common underrepresentation, if not routine exclusion, of older
patients from many clinical trials [
]. Additionally, there
are pharmacokinetic data demonstrating that both taxanes can
be used in older patients without dose modifications but in the
case of an impaired liver function neither paclitaxel nor
docetaxel should be applied due to their high liver
The present analysis constitutes the largest pooled analysis to
date of the use of taxanes in older patients with primary breast
cancer. The incidences of dose delays, dose reductions,
treatIncidence of grade 3 to grade 4 hematologic toxicity, per age interval and per taxane
Data presented as n (%). All percentage values are valid. P values all for incidence of difference between age groups.
ment discontinuations, and hospitalizations all increased with
age. With regard to taxane therapy, the combination
dosedense doxorubicin/docetaxel schedule was the most
problematic overall, with a particularly high incidence of
hospitalizations compared with other schedules. One cannot conclude,
however, that nontaxane therapies are the preferred option. In
a previous analysis of the data, the regimen of 5-fluorouracil,
epirubicin on days 1 and 8 and cyclophosphamide on days 1
to 14 [
] was by far the most toxic regimen overall [
Amongst the taxane schedules, TAC was overall associated
with the highest incidence of toxicity. In our analysis, paclitaxel
had significantly less hematologic toxicity compared with
docetaxel – which is consistent with data from a prospective
adjuvant trial directly comparing those taxanes [
in an adjuvant anthracycline/taxane sequential regimen,
weekly paclitaxel shows the same efficacy as docetaxel [
This might therefore be the preferred taxane regimen, at least
for older patients. The relatively low incidence of hematologic
toxicity, with the exception of low-grade anemia, with the
sequence dose-dense schedule is notable and may reflect the
sequential dosing schedule and the obligatory use of
granulocyte-colony stimulating factor therapy.
With regard to higher grade nonhematologic toxicity,
mucositis, loss of appetite, infection with neutropenia, and fatigue
were more common with increasing age. In patients treated
with docetaxel, skin changes of grade 3 to grade 4 increased
Analysis of the data by age shows that there was generally a
higher incidence of dose delays/reductions, hospitalizations
and therapy discontinuations, of hematologic toxicity, and of
some nonhematologic toxicity such as loss of appetite and
grade 3 to grade 4 fatigue and mucositis in 'older' versus
younger patients. One might argue that such an age split in
Incidence of leukopenia and neutropenia per schedule according to different age intervals
three different groups is artificial, that a higher age should be
considered to constitute 'older' patients, and that simple
discrimination by age alone does not account for other factors
(such as physical status). Nevertheless, these data provide an
important insight into the acceptable tolerability of
chemotherapy in older patients with primary breast cancer and could be
confirmed by data from patients with ovarian cancer [
The patient cohort for the four trials analyzed reflects clinical
trial routine at that time and substantiates findings from other
], demonstrating that – even if the trials had no
upper age limit – older patients were generally included less
frequently or not included. This may have changed since the
data published by Muss and colleagues [
], which showed
that the benefit from chemotherapy did not differ across age
groups although treatment-related mortality was higher (1.5%
versus 0.42%) in the group aged > 65 years.
While the present analysis has provided a wealth of important
new data, it is important to acknowledge its limitations –
namely, the post hoc nature of the analysis, a relative paucity
of patients aged > 70 years, the probability that the patient
population is not representative of older patients as a whole
due to general exclusion of patients with comorbidities from
clinical trials, and the lack of any exact prognostic score such
as the Charlson score for enrolled older patients.
Heterogeneous use of growth factors between the studies analyzed and
their chemotherapy regimens may also have had an impact on
some of the variables assessed.
Data presented as n (%). All percentage values are valid. TAC, docetaxel/doxorubicin/cyclophosphamide; ATdd, doxorubicin/docetaxel dose-dense.
Sequence dose-dense schedule (n = 86)
In summary, our analysis indicates that – with pretreatment
older assessment and appropriate supportive care such as
granulocyte-colony stimulating factor therapy for neutropenia
prophylaxis – older patients can be considered for taxane
therapy and the maintenance of dose intensity should be feasible.
Older patients generally have an increased susceptibility for
]; this has recently been acknowledged by
the updated EORTC guidelines, which recommend general
use of granulocyte-colony stimulating factor prophylaxis if the
risk of FN is ≥ 20% and risk-adapted use in cases where the
FN risk is between 10% and 20% [
]. Our findings are in
accordance with other studies that have, for example,
suggested docetaxel therapy as a viable treatment option in older
cancer patients [
]. In particular, sequential therapy
should be preferred among older patients. It has therefore
become increasingly clear that (neo)adjuvant therapy
concepts for older patients should consider – next to oncological
needs – the patient's physical and functional status, and
should not be determined merely on the basis of their age as
in the ICE trial of the German Breast Group. Otherwise older
patients will continue to be undertreated and will not benefit
from the advances in medicine.
The pooled analysis of a substantial cohort of older primary
breast cancer patients demonstrates that taxane-containing
(neo)adjuvant chemotherapy is feasible in older patients and
that toxicity can be reduced by sequential therapy regimens
and consequent use of prophylactic treatment.
Nonhematologic toxicity per schedule in patients aged ≥ 60 years, n (%)
Liver enzymes grade 1 to grade 4
SL and VN had full access to all of the data in the study and
take responsibility for the integrity and the accuracy of the data
analysis. All of the authors had full responsibility in the design
of the study, the collection of the data, the analysis and
interpretation of the data, the decision to submit the manuscript for
publication, and the writing of the manuscript.
Gardiner-Caldwell Communications (Macclesfield, UK) assisted in the
writing of the manuscript. Funding was provided by Amgen Europe and
Sanofi-Aventis Germany. The results of the present analysis were
presented in part at the American Society of Clinical Oncology ASCO
2006 (Orlando, Florida, USA, June 2–6, 2006), European Society of
Medical Oncology 2006 (Istanbul, Turkey, September 29 – October 3,
2006) and San Antonio Breast Cancer Symposium 2006 (San Antonio,
Texas, USA, December 14–17, 2006)).
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