ORIGINAL ARTICLE

Incidence of febrile neutropenia among early-stage breast

cancer patients receiving anthracycline-based chemotherapy
Alexandre Chan & Christy Chen & Joen Chiang &
Sze Huey Tan & Raymond Ng
Received: 5 May 2011 / Accepted: 17 July 2011 / Published online: 5 August 2011
# Springer-Verlag 2011
Abstract
Objectives The aim of this study was to investigate the
incidence of febrile neutropenia (FN) with adjuvant AC
(doxorubicin and cyclophosphamide) chemotherapy among
Asian early-stage breast cancer (ESBC) patients, to evaluate the
impact of FNon chemotherapy delivery, and to identify specific
risk factors that would predispose ESBC patients to FN.
Methods This was a single-center, observational, retrospec-
tive cohort study conducted in Singapore. All ESBC
patients who have received the AC regimen as adjuvant
chemotherapy between January 2007 and July 2010 were
included into the study. Patients did not receive granulocyte
colony-stimulating factors (G-CSF) as primary prophylaxis.
Results One hundred and eighty-nine patients and
729 cycles of chemotherapy were analyzed in this study,
of which, majority were Chinese (84%). Median age of the
patients was 54 years old (IQR 4958). In total, 26 patients
(13.8%) manifested at least one episode of FN, of which 17
patients developed FN during the first cycle of treatment.
Patients who manifested FN received similar dose intensi-
ties of chemotherapy, compared to those patients who did
not manifest FN (100% versus 98%, p=0.95). After
adjusting for age, race, and presence of comorbidities, low
body mass index (BMI) (<23 kg/m
2
) was found to be
associated with a higher risk of FN (OR 4.4, 95% CI=
1.6512.01, p=0.003).
Conclusions Asian patients are at moderate risk for FN
when they receive the AC regimen for treatment of ESBC.
Further studies should evaluate the role of G-CSF to reduce
the occurrence of FN in Asian patients with low BMI.
Keywords Breast cancer
.
Colony stimulating factors
.
Anthracycline
.
Doxorubicin
.
Febrile neutropenia
.
G-CSF
Introduction
Adjuvant chemotherapy is an important treatment modality
in women manifesting early-stage breast cancer (ESBC). In
order to achieve maximal benefits from adjuvant chemother-
apy, it is important to maintain planned dose intensity.
Previous studies have shown that maintaining planned dose
intensity is associated with better overall survival and disease-
free survival in ESBC patients [1, 2]. Anthracycline-based
chemotherapy containing doxorubicin and cyclophospha-
mide (AC) is one of the most commonly used adjuvant
chemotherapy regimens globally for treatment of ESBC [3,
A. Chan (*)
:
C. Chen
Department of Pharmacy, Faculty of Science,
National University of Singapore,
Block S4, 18 Science Drive 4,
Singapore 117543, Singapore
e-mail: phaac@nus.edu.sg
A. Chan
:
J. Chiang
Department of Pharmacy, National Cancer Centre Singapore,
Singapore, Singapore
S. H. Tan
Division of Clinical Trials & Epidemiological Sciences,
National Cancer Centre Singapore,
Singapore, Singapore
S. H. Tan
Centre for Quantitative Medicine,
Duke-NUS Graduate Medical School,
Singapore, Singapore
R. Ng
Department of Medical Oncology,
National Cancer Centre Singapore,
Singapore, Singapore
Support Care Cancer (2012) 20:15251532
DOI 10.1007/s00520-011-1241-6
4]. This regimen, however, is also known for its myelosup-
pressive properties and may lead to unwanted complications
such as febrile neutropenia (FN) [5].
FN is a serious complication of chemotherapy. FN may
lead to treatment delays and dose reductions, which may
potentially compromise the efficacy of chemotherapy. Patients
manifesting FN often require hospitalization and administra-
tion of antibiotics to manage FN. Furthermore, mortality may
increase substantially if patients are also present with
concomitant infections, particularly in patients who possess
multiple comorbid conditions [6]. Hence, it is prudent to take
all precautions to prevent the occurrence of FN, such as
judicious usage of granulocyte colony-stimulating factor
(G-CSF) prophylaxis. Current clinical guidelines recommend
routine usage of G-CSF in patients who are receiving
chemotherapy regimens with an inherent risk of FN that is
above 20% [7, 8]. In the literature, the documented risk of
FN associated with AC regimen is approximately 3.312%
(among studies that were conducted in the non-Asian
population). Based on such data, G-CSF prophylaxis with
AC is not recommended at this time.
Recently, a study has shown that the incidence of taxanes
and doxorubicin-induced hematologic toxicities differs
between Chinese and Caucasians [9]. In another study, we
have also reported the high incidence of FN associated with
another ESBC treatment regimen, TC (docetaxel and
cyclophosphamide) among Asian patients [10]. Therefore,
there are reasons to believe that the risk of FN associated
with AC regimen may be higher in our Asian population
than what has been described in the literature. Numerous
studies have evaluated the prediction of FN events by
utilizing baseline risk factors; however, results of these
studies lack consistency. Hence, there is a continual need to
identify clinically important risk factors that are specific to
the Asian ESBC patients. In view of these concerns, this
study was designed to evaluate the incidence of FN and the
impact of FN in chemotherapy delivery in Asian ESBC
patients receiving AC chemotherapy. In addition, we have
also attempted to identify the risk factors predisposing these
patients to FN.
Patients and methods
Study design
This was a single-center, observational, retrospective cohort
study conducted at the National Cancer Centre, Singapore
(NCCS). NCCS is the largest ambulatory cancer center in
Singapore that treats two thirds of the solid tumor patients
in the country. This study was approved by the Institutional
Review Board of NCCS. Patient informed consent was not
required in this study.
Patients
All ESBC patients (stages I to IIIA) receiving doxorubi-
cin, 60 mg/m
2
and cyclophosphamide, 600 mg/m
2
every
21 days from January 2007 to July 2010 at NCCS as
adjuvant chemotherapy were included into the study. In
this study, any patients who were receiving G-CSF as
primary prophylaxis for prevention of FN or patients with
missing data were excluded. In order to be included in the
analysis of impact of FN on chemotherapy delivery, all
patients must have completed at least two consecutive
cycles of chemotherapy.
Data collection
A data collection form was developed to collect informa-
tion on patient demographics, past medical history, pre-
treatment laboratory parameters and chemotherapy details.
The length of hospitalization, subsequent dose reductions
and chemotherapy delays, and treatment given were
recorded for every FN episode.
Definitions
FN was defined as a single temperature greater than 38.3C
or a temperature greater than 38C for over an hour and an
absolute neutrophil count of <0.510
9
/L or <1.010
9
/L
and predicted to decline to 0.510
9
/L over the next 48 h
[7]. Chemotherapy dose delay was defined as a delay of
planned chemotherapy for more than 3 days. Chemotherapy
dose reduction was defined as (1dose received/dose
planned) in percentage. A reduction of greater than 15% was
considered clinically significant [11]. Relative dose intensity
(RDI) was defined as [(dose received/dose planned)/(actual
cycle days/planned cycle days)]. The overall dose intensity
for the AC regimen was defined as the average of the dose
intensities of doxorubicin and cyclophosphamide combined
[12]. In this study, recent surgery was defined as surgery
within 1 month of commencement of chemotherapy.
Healthy weight was defined by a body mass index
(BMI) of <23 kg/m
2
, while patients with BMI above
23 kg/m
2
were considered as overweight. This cutoff
(23 kg/m
2
) was chosen in accordance with the Singapore
Health Promotion Board's revised BMI cutoff points in
Singapore [13].
Statistical methods
Descriptive statistics were utilized to summarize patient
demographics, disease characteristics, chemotherapy
details, and the complications of FN such as length of
hospitalization stay, chemotherapy dose reductions and
delays. MannWhitney U test was used to compare the
1526 Support Care Cancer (2012) 20:15251532
RDI received between patients who experienced FN and
those who did not. Univariable logistic regression model
was utilized to investigate whether patients' demographics
and clinical variables (such as age, race, ER, PR, etc.) were
associated with the incidence of FN. Variables with p value
less than 0.2 in the univariable analysis, and clinical
parameters (i.e., age, race, and presence of comorbidities)
clinically known to be associated with incidence of FN
were included in a multivariable logistic model to inves-
tigate if the variables were independently associated with
the incidence. Backward selection was used whereby
variables (except for age, race, and presence of comorbid-
ities) that were not statistically significant (with p<0.05)
were removed from the model. All analyses were per-
formed in SPSS version 16.0 and STATAversion 11.0. Two-
sided p values less than 0.05 were considered statistically
significant.
Results
Patient characteristics and treatment details
A total of 325 cancer patients received the AC regimen at
NCCS from January 2007 to July 2010. A total of 189
patients met the study criteria and were eligible for analysis.
All patients were female, and the median age was 54 years
old (inter-quartile range [IQR] 49, 58). The median BMI
was 23.4 kg/m
2
(IQR 21.0, 27.0). Majority were Chinese
(158 patients, 84%) and 124 patients (66%) were post-
menopausal. Majority of the patients had no comorbidities
(116 patients, 61%), and the most common comorbidity
was hypertension (50 patients, 27%). Hormone receptor
status was positive for 136 patients (72%). Seventy patients
(37%) were HER2-positive. Most patients did not receive
any chemotherapy or radiation prior to receiving the AC
regimen (Table 1).
A total of 729 chemotherapy cycles were evaluated. Four
patients (2%) received only 1 cycle of AC chemotherapy
due to manifestation of serious side effects (such as rashes
and FN). One hundred eight-five patients (98%) received at
least 2 cycles of chemotherapy, 180 patients (95%) received
at least 3 cycles of chemotherapy, and 174 patients (92%)
received all four planned cycles of the AC regimen. The
median dose of doxorubicin administered was 59.9 mg/m
2
,
and the median dose of cyclophosphamide administered
was 600 mg/m
2
.
FN characteristics
Twenty-six (13.8%) patients developed at least one episode
of FN, of which 17 patients developed FN at cycle 1
(Table 2). There were a total of 27 episodes of FNonly 1
out of 26 patients manifested two episodes of FN
(breakthrough FN despite secondary G-CSF prophylaxis
Table 1 Patient demographics and disease characteristics (n=189)
Characteristics N (%)
Age
Median 54
Inter-quartile range (49, 58)
Race
Chinese 158 (84)
Malay 13 (6.9)
Indian 5 (2.7)
Others 13 (6.9)
Body surface area (m
2
)
Median 1.6
Inter-quartile range (1.46, 1.63)
Body mass index (kg/m
2
)
Median 23.4
Inter-quartile range (21.0, 27.0)
Menopausal status
Pre-menopausal 53 (28)
Peri-menopausal 12 (6.4)
Post-menopausal 124 (66)
Cancer stage
Stage I 46 (24)
Stage IIA 72 (38)
Stage IIB 47 (25)
Stage IIIA 24 (13)
Number of comorbidities
0 116 (61)
1 39 (21)
2 21 (11)
3 13 (6.9)
Types of comorbidities
Hypertension 50 (27)
Dyslipidemia 36 (19)
Diabetes mellitus 19 (10)
Hyperthyroidism 4 (2.1)
Others 14 (7.4)
Receptor status
Hormone receptor
Positive 136 (72)
HER2/neu
Positive 70 (37)
Negative 116 (61)
Equivocal 3 (1.6)
Prior radiation
No 186 (98)
Prior chemotherapy
No 175 (93)
Support Care Cancer (2012) 20:15251532 1527
at cycle 3). The incidence of FN per patient was 13.8%
(95% CI, 9.220%). The incidence of FN for each cycle of
chemotherapy was 9.1% (95% CI, 5.414%), 2.2% (95%
CI, 0.65.5%), 1.7% (95% CI, 0.354.8%), and 1.7% (95%
CI, 0.354.9%) for cycles 1, 2, 3, and 4, respectively. All
patients were hospitalized for observation and management.
Among the 26 patients who developed FN, 5 patients
(19%) manifested infections that were demonstrated by
positive blood cultures, and 18 patients (69%) received
additional doses of G-CSF for treatment of FN. For each
episode of FN that occurred during cycles 1 to 4, the
mean length of hospitalization was 4 (range, 19) days.
On average, FN occurred on day 13 post-chemotherapy.
Impact of FN on chemotherapy delivery
Across all chemotherapy cycles, the median interval
between chemotherapy cycles was 21.5 days among those
who manifested FN. Subsequent dose reductions had
occurred in three patients (Table 2); with two patients
experiencing a 10% dose reduction and only one patient
experiencing a 20% dose reduction for subsequent cycles of
chemotherapy. The RDI of doxorubicin, cyclophosphamide,
and the overall dose intensity of the AC regimen adminis-
tered are shown in Table 3. Overall, RDIs were well-
preserved in all patients (p>0.05, Table 3).
Association of risk factors predisposing patients to FN
Several clinical and treatment characteristics associated with a
higher risk of FN were identified by univariable analysis.
Odds ratio (OR) for variables examined in univariable logistic
regression analysis are presented in Table 4. Univariable
logistic regression analysis showed that BMI (as continuous
variable) and body surface area (BSA) (as continuous
variable) (p=0.02) was associated with the occurrence of
FN, and patients with BMI<23 kg/m
2
had 3.6 times the odds
of having FN as compared to patients with BMI23 kg/m
2
(OR 95% CI 1.44 to 9.05; p=0.006).
In the multivariable modeling analysis, age, race, HER-
2, presence of comorbidities, presence of other comorbid-
ities, hemoglobin, creatinine clearance, BMI, and BSAwere
investigated for association with FN. Except BMI, all
factors did not demonstrate any association to FN. The
univariable OR estimate for BMI is 3.6 (patients with BMI<
23 kg/m
2
had 3.6 times the odds of having FN as compared
Table 2 Incidence and complications of FN for each individual cycle
Incidence and complications of FN Cycle 1 (n=17) Cycle 2 (n=4) Cycle 3 (n=3) Cycle 4 (n=3)
Incidence in each cycle (95% CI) 9.1% (5.414%) 2.2% (0.65.5%) 1.7% (0.354.8%) 1.7% (0.354.9%)
Number of patients with dose
reductions
3 0 0 NA
Number of patients with
chemotherapy delays
4 1 0 NA
Length of hospitalization in
days (mean, range)
3.88 (29) 3.5 (26) 5.67 (57) 2.67 (14)
Interval to next cycle in days
(median, IQR)
21.5 (21, 26) 24 (21.75, 27) 21 (21, 21) NA
CI confidence interval, NA not applicable, IQR inter-quartile range (defined by the 25th and 75th percentiles)
Patients with FN (n=25) Patients without FN (n=160) P value
Doxorubicin RDI
Median 100% 98% 0.76
Interquartile range (90%, 101%) (94%, 100%)
Range (76105%) (72105%)
Cyclophosphamide RDI
Median 98% 98% 0.72
Interquartile range (90%, 101%) (94%, 100%)
Range (71105%) (67107%)
Overall RDI
Median 100% 98% 0.93
Interquartile range (90%, 100%) (94%, 100%)
Range (73105%) (70105%)
Table 3 A comparison of
chemotherapy dose intensity
among patients who received
more than one treatment cycle
Inter-quartile range is defined by
the 25th and 75th percentiles
RDI relative dose intensity
1528 Support Care Cancer (2012) 20:15251532
Table 4 Univariable logistic regression investigating the incidence of FN
Characteristics Occurrence of febrile neutropenia
Incidence/N OR 95% CI p value
Demographics
Age (per 10 years) 1.1 (0.63, 1.88) 0.8
Race
Chinese 21/158 1
Indian 2/5 4.3 (0.69, 27.58) 0.1
Malay 1/13 0.5 (0.07, 4.40) 0.6
Others 2/13 1.2 (0.25, 5.73) 0.8
Menopausal status
Post-menopausal 19/124 1
Peri/pre-menopausal 7/65 0.7 (0.26, 1.68) 0.4
Stage
I 7/46 1
IIA 11/72 1.0 (0.36, 2.81) 1.0
IIB 6/47 0.8 (0.25, 2.64) 0.7
IIIA 2/24 0.5 (0.10, 2.65) 0.4
HER2/neu
Negative 13/116 1 (0.78, 4.16) 0.2
Positive 13/70 1.8
Equivocal 0/3 (omitted)
Hormone receptor status
Negative 7/53 1
Positive 19/136 1.1 (0.42, 2.71) 0.9
Node
Negative 15/97 1
Positive 11/92 0.7 (0.32, 1.71) 0.5
Presence of comorbidities
No 15/116 1
Yes 11/73 1.2 (0.52, 2.77) 0.7
Past chemotherapy
No 23/175 1
Yes 3/14 1.8 (0.47, 6.95) 0.4
Recent surgery
No 21/132 1
Yes 5/54 0.5 (0.19, 1.51) 0.2
Body surface area (per 0.1 U increase) 0.7 (0.48, 0.95) 0.02
Body mass index
23 kg/m
2
7/100 1
<23 kg/m
2
19/89 3.6 (1.44, 9.05) 0.006
Complete blood count
a
Total white blood cell count (cells/mm
3
) 0.9 (0.76, 1.18) 0.6
Absolute neutrophil count (cells/mm
3
) 1.0 (0.74, 1.25) 0.8
Absolute lymphocyte count (cells/mm
3
) 1.1 (0.60, 1.96) 0.8
Hemoglobin (g/dL) 0.8 (0.52, 1.09) 0.1
Serum chemistry
a
Creatinine clearance (mL/min) 0.9 (0.70, 1.06) 0.2
Alanine aminotransferase (U/L) 1.0 (0.70, 1.34) 0.9
Aspartate aminotransferase (U/L) 1.1 (0.77, 1.65) 0.5
Support Care Cancer (2012) 20:15251532 1529
to patients with BMI23 kg/m
2
) and the multivariable-
adjusted OR for BMI, after adjusting for age, race, and
presence of comorbidities, is 4.4 (95% CI 1.65 to 12.01;
p=0.003). (Table 5)
Discussion
In this study, the incidence of FN among Asian ESBC
patients receiving AC regimen was 13.8%, and majority of
patient developed FN while they were receiving chemo-
therapy during their first treatment cycle. This is compara-
ble to a small, prospective, community study conducted in
UK which reported a similar incidence of 12% [12]. On the
other hand, a large randomized control trial (B-22)
conducted by the National Surgical Adjuvant Breast and
Bowel Project reported an incidence of 3.3% amongst 764
patients who received four standard courses of AC
chemotherapy [14]. The variation of incidences reported
by different studies may be explained by the different study
designs. Being a randomized control trial, patients are
generally well selected before inclusion into the trial; thus,
the incidence of FN can be much lower than what a
clinician would observe in the clinical setting. Our study
cohort is fairly homogeneous with regards to patient and
treatment characteristics. Hence, the design of this study is
more appropriate to describe and to evaluate the incidence
of FN and other associated complications.
In terms of FN complications such as dose reductions and
dose delays, these complications were not commonly
observed in our patients. Only 3 out of 26 patients with FN
had dose reductions in their subsequent cycles. The intervals
between treatment cycles were also well-preserved without
significant delays. These observations are encouraging as
they reflect that patients' chemotherapy dose intensities are
well-preserved. This is extremely important because ESBC
is curative in nature and it is imperative that patients receive
the maximal dose intensities possible. Although FN can
contribute to lower RDI with chemotherapy treatment, the
RDI in those patients who experienced FN did not differ
from those who did not. For most patients, chemotherapy
dose intensities were well-kept above 85%, the cutoff at
which adjuvant chemotherapy is associated with improved
overall survival and disease-free survival [11].
Myeloid growth factors have been proven to effectively
reduce the incidence of FN when they are prophylactically
given 2472 h after chemotherapy [15, 16]. However, due
to cost reasons, these agents are generally not routinely
prescribed to all patients [17]; both ASCO and NCCN
guidelines recommend routine prophylaxis only with
chemotherapy regimens that possess FN risk greater than
20% [7, 8]. As the incidence of FN in our patients receiving
the AC regimen was 13.8%, this regimen falls under the
category of moderate FN risk (1020%). Individualized
considerations should be undertaken to determine whether
G-CSF prophylaxis is needed in specific patients. Identifi-
cation of risk factors that may increase a patient's risk for
FN may also guide cost-effective usage of G-CSF.
A further analysis was performed to examine whether
clinical predictors (including clinical and laboratory char-
acteristics) can identify patients who were at risk for FN
before the first cycle of chemotherapy. FN, being a serious
complication of chemotherapy, can potentially reduce the
RDI of chemotherapy delivered to patients. Since FN can
be effectively prevented with the use of G-CSF as primary
prophylaxis, it is therefore best to prevent FN from the
point when patients begin chemotherapy. A study by
Jenkins et al. suggested that patients' intrinsic chemo-
sensitivity appears to be more important than cumulative
toxicity in the development of FN [18]. This highlights the
importance to utilize baseline parameters to identify risk
factors that predispose patients to FN, particularly in
situations that are not as straightforward; for example, in
Table 4 (continued)
Characteristics Occurrence of febrile neutropenia
Incidence/N OR 95% CI p value
Alkaline phosphatase (U/L) 1.0 (0.81, 1.27) 0.9
Bilirubin (mol/L) 0.6 (0.21, 1.64) 0.3
Albumin (g/L) 1.1 (0.49, 2.66) 0.8
a
Each variable represents 1 U of increase
Data in italics are categories
Table 5 Multivariable logistic regression investigating on incidence
of FN (adjusted for age, ethnicity, and presence of comorbidities)
Characteristic Febrile neutropenia
Adjusted OR 95% CI p value
Body mass index
23 kg/m
2
1
<23 kg/m
2
4.4 (1.65, 12.01) 0.003
1530 Support Care Cancer (2012) 20:15251532
patients who receive chemotherapy regimens that possess
an incidence of FN below 20%.
Only one risk factor (BMI<23 kg/m
2
) was found to be
associated with the occurrence of FN. Patients whose BMI
was below 23 kg/m
2
, had a 4.4 times higher risk to develop
FN. One study suggested that patients with high BMI or
BSA of 2 m
2
or greater experienced greater dose reductions
in dose intensity and that those reductions were planned by
physicians [19]. Therefore, we have considered the possi-
bility that the protective effect against FN conferred by a
higher BMI could be due to a lower RDI delivered to this
group of patients. However, a further analysis was carried
out, and it was shown that the RDI received by overweight
and healthy weight patients were not significantly different
(data not shown). It is understood that overweight breast
cancer patients may be at lower risk for FN because they
have lower plasma concentrations of doxorubicin than
patients of normal weight [20]. Plasma concentrations of
doxorubicin are significantly lower in overweight patients
due to an increase in the volume of distribution of
doxorubicin at steady state [20]. Another study also showed
that BSA is positively correlated with the clearance of
doxorubicin [21]. Further studies need to be conducted to
confirm the correlation between plasma levels of doxoru-
bicin and occurrence of FN. Data in this analysis can only
be considered as hypothesis generating; well-designed
prospective studies should be conducted to evaluate the
therapeutic role of G-CSF to reduce FN occurrence in
Asian patients with low BMI.
There were a number of limitations in this study. The
sample size of our subgroup analysis was small; however, it
can still be hypothesis-generating. Due to the retrospective
design of this study, measures were undertaken to ensure
that the data reported in this study were not influenced by
precision and would not affect the outcome. Patients with
missing data were excluded from our analyses and the
study endpoints chosen are comprised of objective data
points such that our study can be free from information bias
as much as possible. Hence, the external validity is well-
preserved even though this analysis is retrospectively
performed. In addition, the management of EBSC patients
at the institution is generally uniform across oncologists;
hence, we believe that the retrospective design would not
influence the precision of the data presented in this
analysis. Our study was also unable to determine any of
the suggested risk factors in both the ASCO and NCCN
guidelines that predispose patients to FN, such as older age
(65 years), presence of serious comorbidities and ECOG
status. This highlights the need for studies to look into risk
factors for FN specific to a particular type of cancer, and in
this case, ESBC patients. Performance status of our patients
was not available for analysis due to the retrospective
nature of this study. Our cohort of patients was relatively
young as there were only 14 patients (7%) who were
elderly; hence, we are unable to determine whether
increased age is associated with FN occurrence.
Conclusion
The incidence of FN among Asian ESBC patients receiving
the AC regimen was found to be 13.8%, with 65% of these
patients experiencing FN at cycle 1 of chemotherapy. The
use of G-CSF as primary prophylaxis against FN is not
indicated in all patients receiving the AC regimen as
adjuvant chemotherapy. FN did not significantly affect the
RDI delivered (median dose intensity was above 85%). The
identified risk factor that predisposes patients to FN is a
BMI of less than 23 kg/m
2
. However, further studies
(including pharmacokinetic studies) may need to be done
to prove that a lower BMI indeed predisposes patients to
FN. Furthermore, prospective studies should be conducted
to evaluate the role of G-CSF to reduce the occurrence of
FN in Asian patients with low BMI.
Acknowledgments Authors would like to acknowledge the Depart-
ment of Pharmacy, National University of Singapore for providing the
Final Year Project funding for this project.
Conflict of interest The authors have no conflicts of interest that are
directly relevant to the content of this study.
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