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EPIDEMIOLOGY
A retrospective evaluation of chemotherapy dose intensityand supportive care for early-stage breast cancerin a curative setting
Gary H. Lyman • David C. Dale • Dianne Tomita •
Sadie Whittaker • Jeffrey Crawford
Received: 18 December 2012 / Accepted: 29 May 2013 / Published online: 16 June 2013
� Springer Science+Business Media New York 2013
Abstract Early-stage breast cancer (ESBC) is commonly
treated with myelosuppressive chemotherapy, and main-
taining full-dose chemotherapy on the planned schedule is
associated with improved patient outcome. Retrospective
analysis of patients with ESBC treated from 1997 to 2000
showed that 56 % of patients received a relative dose
intensity (RDI) \85 % (Lyman et al., J Clin Oncol
21(24):4524–4531, 2003). To determine current practice,
we evaluated treatment patterns at 24 US community- and
hospital-based oncology practices, 79 % of which partici-
pated in the previous study. Data were abstracted from
medical records of 532 patients with surgically resected
ESBC (stage I–IIIa) treated from 2007 to 2009, who were
C18 years old and had completed C1 cycle of one of the
following regimens: docetaxel ? cyclophosphamide (TC);
doxorubicin ? cyclophosphamide (AC); AC followed by
paclitaxel (AC-T); docetaxel ? carboplatin ? trastuzumab
(TCH); or docetaxel ? doxorubicin ? cyclophosphamide
(TAC). Endpoints included RDI, dose delays, dose reduc-
tions, grade 3/4 neutropenia, febrile neutropenia (FN), FN-
related hospitalization, granulocyte colony-stimulating
factor (G-CSF) use, and antimicrobial use. In this study, TC
was the most common chemotherapy regimen (42 %), and
taxane-based chemotherapy regimens were more common
relative to the previously published results (89 vs \4 %).
Overall, 83.8 % of patients received an RDI C85 %, an
improvement over the previous study where 44.5 %
received an RDI C85 %. Other changes seen between this
and the previous study included a lower incidence of dose
delays (16 vs 25 %) and dose reductions (21 vs 37 %) and
increased use of primary prophylactic G-CSF (76 vs*3 %).
Here, 40 % of patients had grade 3/4 neutropenia, 3 % had
FN, 2 % had an FN-related hospitalization, and 30 %
received antimicrobial therapy; these measures were not
available in the previously published results. Though RDI
was higher here than in the previous study, 16.2 % of
patients still received an RDI \85 %. Understanding factors
that contribute to reduced RDI may further improve che-
motherapy delivery, and ultimately, patient outcomes.
Keywords Relative dose intensity � Chemotherapy �Supportive care � Breast cancer
Introduction
The first adjuvant chemotherapy to show a benefit in breast
cancer was cyclophosphamide, methotrexate, and fluoro-
uracil (CMF) [1, 2]. Since the introduction of CMF, adju-
vant chemotherapy for early-stage breast cancer (ESBC)
has continued to evolve. Numerous studies have shown that
chemotherapy regimens using doxorubicin and cyclo-
phosphamide (AC) are equivalent to CMF [3–6], and
higher doses of anthracycline-based regimens have dem-
onstrated superiority to CMF [7]. The addition of taxanes
Electronic supplementary material The online version of thisarticle (doi:10.1007/s10549-013-2582-2) contains supplementarymaterial, which is available to authorized users.
G. H. Lyman (&) � J. Crawford
Duke Cancer Institute, Duke University, 2424 Erwin Road,
Suite 205, Durham, NC 27705, USA
e-mail: [email protected]
D. C. Dale
University of Washington, 1959 NE Pacific Street, Seattle,
WA 98195, USA
D. Tomita � S. Whittaker
Amgen Inc., One Amgen Center Way, Thousand Oaks,
CA 91360, USA
123
Breast Cancer Res Treat (2013) 139:863–872
DOI 10.1007/s10549-013-2582-2
has further improved patient outcomes and reduced the risk
of relapse and death [3, 8–10]. Additional studies have
focused on optimizing drug delivery through sequential
schedules and dose-dense regimens [11]. Advances in
adjuvant chemotherapy and wide-spread screening pro-
grams have contributed to a steady decrease in death rates
associated with breast cancer [12–15].
Chemotherapy dose and schedule are important clinical
variables that can impact patient outcomes. Relative dose
intensity (RDI) accounts for both dose and schedule of
drug and is defined as the received dose intensity relative to
the reference dose intensity [16]. For patients with ESBC,
high RDI of adjuvant chemotherapy (C85 %) is associated
with improved disease-free survival and overall survival
[17, 18]. Thus, maintaining high RDI is an accepted goal of
chemotherapy administration in the curative setting [19].
In our previous study (Study 1), we performed a retro-
spective analysis of more than 20,000 patients with ESBC
from 1997 to 2000. In Study 1, 56 % of patients received
an RDI \85 % [20]. Since the completion of Study 1,
breast cancer treatment has shifted from anthracycline-
based therapies to taxane-based therapies [21]. To deter-
mine how recent advances have affected chemotherapy
administration and supportive care and to evaluate the
incidence of chemotherapy-induced complications in
patients with ESBC, a retrospective chart review of US
community- and hospital-based outpatient oncology prac-
tices was conducted (Study 2). The primary objective of
this study was to evaluate RDI. Because 79 % of the sites
in this study also participated in Study 1, changes in clin-
ical practice over time could be described.
Patients and methods
Study design
Following approval by a central Institutional Review Board
(IRB), de-identified patient data were collected retrospec-
tively from 24 community- and hospital-based outpatient
oncology practices geographically distributed across the
United States (Supplemental Table 1). Each study site
identified sequential patient charts that met eligibility
requirements, and data were abstracted from patient charts
of 532 patients with ESBC treated from January 2007 to
December 2009.
Patient selection
Patients were included in the analysis if they were at least
18 years old, chemotherapy naı̈ve at study start, completed
definitive surgery for ESBC (stages I–IIIA), and received at
least one cycle of one of the following adjuvant chemotherapy
regimens during the study period: docetaxel ? cyclophos-
phamide (TC); doxorubicin ? cyclophosphamide (AC); AC
followed by paclitaxel; docetaxel ? carboplatin ? trast-
uzumab (TCH); or docetaxel ? doxorubicin ? cyclophos-
phamide (TAC) (Supplemental Table 2). Patients receiving
AC followed by paclitaxel were divided into four groups
based on dosing regimen (see Supplemental Table 2) as fol-
lows: 21-day AC followed by weekly (AC-Tweekly); 14-day
AC followed by 14-day paclitaxel (AC-T14); 14-day AC
followed by weekly paclitaxel (AC14-Tweekly); and 21-day
AC followed by 21-day paclitaxel (AC-T).
Patients were excluded if they had metastatic breast
cancer, had begun chemotherapy outside of the chart
abstraction period, or if, during the chart abstraction period,
they participated in a clinical trial requiring CSFs, received
granulocyte macrophage (GM)-CSF, or received investi-
gational agents.
Study endpoints
The primary endpoint of the study was RDI, calculated as
the ratio of actual dose intensity (ADI) to standard dose
intensity (SDI) as follows:
RDI ¼ ADI=SDI
ADI ¼ DoseActual=TimeActual
SDI ¼ DoseStandard=TimeStandard
where DoseActual is the total received dose of chemother-
apy, TimeActual is the total length of chemotherapy,
DoseStandard is the NCCN standard total dose of chemo-
therapy, and TimeStandard is the standard total length of
chemotherapy including all planned cycles. If a patient
received fewer than the planned number of cycles and had
no evidence of disease progression or death, then a dose of
zero was assigned for each missed cycle, and TimeActual
was the sum of the observed time for the cycles received
and the standard time required for the missed cycles. RDI
was calculated for each myelotoxic agent separately and
then averaged across the regimen. All agents except for
trastuzumab were included. For regimens containing
weekly paclitaxel, a cycle was defined as three weekly
doses of paclitaxel on day 1, 8, and 15. In general, RDI
should fall between 0 and 100 %. However, since this is an
observational study, RDI may be [100 % if a higher than
standard dose was given in any cycle, greater than the
planned number of cycles was administered, or the duration
of treatment was shorter than the standard duration.
Secondary endpoints were the incidence of chemother-
apy dose delays C7 days, dose reductions C15 % from
NCCN standard [22], grade 3/4 neutropenia, FN, FN-
related hospitalization, G-CSF use, and antimicrobial use.
Initial dose reductions were defined as C15 % from the
864 Breast Cancer Res Treat (2013) 139:863–872
123
NCCN standard [22], except for carboplatin. As area under
the curve (AUC) was not captured for carboplatin, the
initial reduction was defined as C15 % reduction relative to
the planned dose. Subsequent dose reductions were only
counted as separate events if the dose was reduced by
C15 % relative to previous dose reductions. Reasons for
dose delays were captured as the following discrete field
codes: other reasons related to chemotherapy, other reasons
not related to chemotherapy, personal/patient request,
neutropenia, and other hematological reasons. Reasons for
dose reductions were captured as the following discrete
field codes: other reasons related to chemotherapy, weight
change, neutropenia, thrombocytopenia, anemia, and dose
administration error. Grade 3/4 neutropenia was defined as
an absolute neutrophil count (ANC) \ 1.0 9 109/L. Grade
3/4 FN was defined as a clinical diagnosis of FN; tem-
perature C 38.0 �C and ANC \ 1.0 9 109/L within a 24-h
period; or hospitalization for FN. Grade 4 FN was defined
as ANC \ 0.5 9 109/L with clinical FN diagnosis or
temperature C38.0 �C or hospitalization for FN. Prophy-
lactic G-CSF was defined as initial use within 5 days of
chemotherapy administration. Primary prophylactic G-CSF
was defined as prophylactic use in the first cycle of che-
motherapy. Secondary prophylactic G-CSF was defined as
prophylactic use beginning with the second or subsequent
cycles of chemotherapy and could include patients who
first received G-CSF as treatment and received prophylaxis
in subsequent cycles. Treatment G-CSF was defined as
initial use for more than 5 days after chemotherapy
administration.
Statistics
A sample size of 500 patients was selected for this study.
With this sample size, the estimated half-width of a 95 %
confidence interval for a proportion would be B4.4 %. For
endpoints such as RDI with expected subsets with fewer
than 500 patients, the half-width would be B6.2 % for a
sample size of 250 patients, B8.8 % for 125 patients,
B12.7 % for 60 patients, B17.8 % for 30 patients, and
B25.3 for 15 patients (nQuery Advisor 7.0, Statistical
Solutions, Saugus, MA). Due to the retrospective, non-
comparative study design, only descriptive statistics are
provided. These descriptive statistics include means, 95 %
CIs, and ranges for continuous endpoints and frequencies,
percentages, and 95 % CIs for categorical endpoints.
Missing values were not imputed for these descriptive
analyses.
Multivariate analysis
Logistic regression modeling was used to explore the rela-
tionship between baseline patient factors and RDI \85 %.
After initial assessment of the baseline factors, both for-
ward and backward stepwise procedures were used to
identify factors with a P value\0.1 to include or exclude in
the model. Age, body surface area (BSA), weight, height,
and regimen schedule were entered as continuous vari-
ables. The following covariates were entered as categorical
variables: body mass index (BMI; \25, 25–30, C30),
number of positive nodes (0, 1–3, C4), tumor hormone
receptor status [estrogen receptor (ER) negative and pro-
gesterone (PR) negative, ER? and/or PR?, unknown],
post menopausal status (no, yes, unknown), Her2 overex-
pression (no, yes, unknown), histology (carcinoma—not
otherwise specified, Paget disease, undifferentiated carci-
noma; ductal; lobular), disease stage (I–IIa, IIb–IIIa), ANC
(\2, C2), hemoglobin count (\110, C110), platelet count
(\150, C150), G-CSF use (yes, no), and use of cyclophos-
phamide, doxorubicin, docetaxel, paclitaxel, or carboplatin
(yes, no). Covariates were removed if a convergence prob-
lem was detected.
Study 1 data collection
Data collection from Study 1 has been described [20]. In
brief, in Study 1, charts were reviewed from 20,799
patients with ESBC who were treated with adjuvant che-
motherapy in the community setting from August 1997 to
May 2000. RDI was calculated relative to reference stan-
dards based on the medical literature and practice guide-
lines. Data were collected in a similar manner for Study 2.
Results from both studies are described.
Results
Patient characteristics and chemotherapy regimens
This study included 532 female patients. Mean patient age
was 55.0 years (range: 29–85 years), and 22.0 % of
patients (n = 117) were C65 years. Mean BSA was
1.84 m2 (range: 1.3–3.0 m2). ECOG performance status
was known in 256 patients (48.1 %). Of these patients,
most had an ECOG performance status of 0 or 1 (n = 252,
98.4 %), and 4 (1.6 %) had an ECOG performance status
C2. Baseline disease characteristics are shown in Table 1.
A majority of patients received a taxane-based regimen
(89.1 %). The most common chemotherapy regimen was
TC (n = 221; 41.5 %). See Supplemental Table 2 for
additional regimens. Across all regimens, most patients
received the full number of planned cycles, which was
largely identical to the standard number of cycles as
defined by NCCN guidelines [22] and medical literature
(Supplemental Table 2).
Breast Cancer Res Treat (2013) 139:863–872 865
123
Relative dose intensity
Mean RDI ranged from 82.8 to 95.5 % across all regimens
(see Fig. 1 for the five most common chemotherapy regi-
mens). Overall, 83.8 % of patients received an RDI C85 %,
while 16.2 % received an RDI \85 % (Fig. 2), and 25.0 %
received an RDI \ 90 %. RDI was generally highest in
cycle 1 (95.3–97.3 %) and decreased with subsequent
cycles. For TC, the most common regimen, overall mean
(95 % CI) RDI was 93.0 % (91.1–94.9), while 85.5 % of
patients received an RDI C85 %, 14.5 % of patients
received an RDI \85 %, and 19.0 % received an
RDI \ 90 %. Similar to trends across all regimens, mean
(95 % CI) RDI for TC was 96.9 % (95.6–98.1) in cycle 1 and
decreased to 83.8 % (74.4–93.3) in cycle 6. In the AC fol-
lowed by T regimens, RDI was high in cycle 1 and decreased
gradually through cycle 4. In cycle 5, when most patients
began paclitaxel, RDI was generally high again and
remained elevated through the remainder of cycles.
RDIs were equivalent between patients \65 years and
patients C65 years for most regimens (Fig. 1). Across all
regimens, 15.4 % of patients \65 years received an
RDI \85 %, and 18.8 % of patients C65 years received an
RDI \85 %. Similarly, 23.9 % of patients \65 years
received an RDI \ 90 %, and 29.1 % of patients
C65 years received an RDI \ 90 %.
Most patients had a BSA B 2 m2 (n = 442; 83.1 %),
and 90 patients (16.9 %) had a BSA [ 2 m2. Mean RDI
was slightly lower among patients with a BSA [ 2 m2 than
patients with a BSA B 2 m2; 22.2 % of patients with a
BSA [ 2 m2 received an RDI \85 %, and 14.9 % of
patients with a BSA B 2 m2 received an RDI \85 %.
Similarly, 31.1 % of patients with a BSA [ 2 m2 received
an RDI \ 90 %, and 23.8 % of patients with a
BSA B 2 m2 received an RDI \ 90 %.
Multivariate analysis
To obtain model convergence, HER2 status and patients
with unknown hormone receptor status were excluded.
Covariates associated with RDI \85 % included weight,
hormone receptor status, disease stage, histology, platelet
count, and primary G-CSF prophylaxis (see Table 2).
Increased risk of RDI \85 % was associated with higher
weight and stage IIb–IIIa disease. Reduced risk of
RDI \85 % was associated with ductal or lobular histol-
ogy, higher platelet count, ER? and/or PR? hormone
receptor status, and use of primary G-CSF prophylaxis.
Dose delays and reductions
Overall, 85 patients (16.0 %) had at least one dose delay
C7 days and 111 patients (20.9 %) had at least one dose
reduction C15 % from NCCN standard. Dose delays and
dose reductions were observed in every regimen studied.
Dose delays were most frequently observed in the TCH
regimen, where 15 of 56 patients (26.8 %) receiving TCH
experienced a dose delay. Dose delays were least
Table 1 Baseline disease characteristics and treatment regimens
N = 532 n (%)
Disease stage
I 194 (36.5)
IIa 197 (37.0)
IIb 90 (16.9)
IIIa 51 (9.6)
Histology
Carcinoma, NOS 20 (3.8)
Ductal 453 (85.2)
Lobular 49 (9.2)
Undifferentiated carcinoma 10 (1.9)
Number of positive nodes
0 278 (52.3)
1–3 195 (36.7)
4? 45 (8.5)
Unknown 14 (2.6)
Post-menopausal
No 158 (29.7)
Yes 260 (48.9)
Unknown 114 (21.4)
Tumor hormone receptor positive
ER-/PR- 141 (26.5)
ER? and/or PR? 387 (72.7)
Unknown 4 (0.8)
HER-2 overexpression
No 421 (79.1)
Yes 103 (19.4)
Unknown 8 (1.5)
Treatment regimens
TC 221 (41.5)
AC 58 (10.9)
TCH 56 (10.5)
TAC 34 (6.4)
AC-Tweekly 22 (4.1)
AC-T14 83 (15.6)
AC14-Tweekly 54 (10.2)
AC-T 4 (0.8)
NOS not otherwise specified, ER estrogen receptor, PR progesterone
receptor, HER-2, Human Epidermal Growth Factor Receptor 2, TC
docetaxel ? cyclophosphamide, AC doxorubicin ? cyclophospha-
mide, TCH docetaxel ? carboplatin ? trastuzumab, TAC doce-
taxel ? doxorubicin ? cyclophosphamide, AC-Tweekly 21-day AC
followed by weekly paclitaxel, AC-T14 14-day AC followed by
14-day paclitaxel, AC14-Tweekly 14-day AC followed by weekly
paclitaxel, AC-T 21-day AC followed by 21-day paclitaxel
866 Breast Cancer Res Treat (2013) 139:863–872
123
Overall < 65 years 65 years
0%
20%
40%
60%
80%
100%
TC AC-T14 AC TCH AC14-Tweekly
Mea
n R
DI
Overall N = 221 N = 83 N = 58 N = 56 N = 54 N = 532 < 65 years N = 160 N = 73 N = 49 N = 41 N = 46N = 415 65 years N = 61 N = 10 N = 9 N = 15 N = 8N =117
<
<
Fig. 1 Relative dose intensity
by regimen and age. Mean RDI
and 95 % CIs are plotted for the
five most common
chemotherapy regimens
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Overall N = 532
Cycle 1 N = 532
Cycle 2 N = 527
Cycle 3 N = 522
Cycle 4 N = 516
Cycle 5 N = 287
Cycle 6 N = 278
% o
f Pat
ient
s E
xper
ienc
ing
Eve
nt
Dose Delays Dose Reduction RDI < 85%
Fig. 2 Dose delays, dose
reductions, and RDI \85 % by
cycle. The incidences of dose
delays and dose reductions and
the percentage of patients who
received an RDI \85 % are
plotted with 95 % CIs. Overall
includes data from all cycles of
chemotherapy. Details for
cycles 1–6 are graphed
Table 2 Multivariate analysis
of covariates for RDI \85 %
OR odds ratio, CL confidence
limit, PR progesterone receptor,
G-CSF granulocyte colony-
stimulating factor, NOS not
otherwise specified
Covariate Point estimate
of OR
95 % Wald
CL
Weight 1.006 1.000–1.011
ER? and/or PR? 0.606 0.351–1.045
Stage IIb–IIIa disease 1.924 1.086–3.408
Disease histology: lobular vs carcinoma NOS, paget
disease, or undifferentiated carcinoma
0.297 0.085–1.035
Disease histology: ductal vs carcinoma NOS, paget
disease, or undifferentiated carcinoma
0.244 0.093–0.636
Platelet count C 150 0.250 0.050–1.243
Primary G-CSF prophylaxis 0.367 0.212–0.636
Breast Cancer Res Treat (2013) 139:863–872 867
123
frequently observed in the TC regimen, where 18 of 221
patients (8.1 %) receiving TC experienced a dose delay.
Dose reductions were most frequently observed among
patients receiving AC-Tweekly, where 16 of 22 patients
(72.7 %) had at least one dose reduction; however, inter-
preting this result can be difficult given the small number
of patients receiving AC-Tweekly. The regimen with the
next highest number of observed dose reductions was TCH,
where 17 of 56 patients (30.4 %) experienced at least one
dose reduction. Dose reductions were least frequently
observed among patients receiving AC, where 4 of 58
patients (6.9 %) had at least one dose reduction.
Patients C65 years were more likely to have dose delays
and dose reductions. At least one dose delay occurred in 28
patients (23.9 %) C65 years and 57 patients (13.7 %)
\65 years. Similarly, at least one dose reduction occurred
in 29 patients (24.8 %) C65 years and 82 patients (19.8 %)
\65 years.
The incidences of dose delays and dose reductions were
similar across cycles (Fig. 2). Slightly more dose delays
were seen in cycle 5 (n = 20; 7.0 %), while slightly more
dose reductions were seen in cycle 1 (n = 36; 6.8 %) and
cycle 5 (n = 24; 8.4 %).
Reasons for dose delays were attributed to other reasons
related to chemotherapy (n = 23) or not related to chemo-
therapy (n = 41), personal/patient request (n = 17), neu-
tropenia (n = 8), and other hematological reasons (n = 3).
Reasons for dose reductions were attributed to other reasons
related to chemotherapy (n = 50), weight change (n = 6),
neutropenia (n = 6), thrombocytopenia (n = 4), anemia
(n = 1), and dose administration error (n = 0).
Neutropenia and febrile neutropenia
Across all cycles, 215 patients (40.4 %) had at least one
episode of grade 3/4 neutropenia, while 18 patients (3.4 %)
had at least one episode of grade 3/4 FN. Patients
\65 years were slightly less likely to have grade 3/4
neutropenia (n = 163, 39.3 %) than patients C65 years
(n = 52, 44.4 %). Patients \65 years were equally likely
to experience grade 3/4 FN (n = 14, 3.4 %) as patients
C65 years (n = 4; 3.4 %). The incidence of grade 3/4
neutropenia was the highest in cycle 1 (n = 144; 27.1 %),
was near 20 % for cycles 2–4 (18.4–19.7 %), and lower in
cycles 5–8 (7.9–0.9 %). Grade 3/4 FN was similar across
all cycles, ranging from 0 to 1 % (Supplemental Table 3).
Grade 3/4 neutropenia was relatively common in all che-
motherapy regimens, ranging from 25.0 to 63.6 %
(Table 3). FN was most common with AC chemotherapy;
10.3 % (n = 6) of patients receiving AC experienced grade
3/4 FN and 6.9 % (n = 4) experienced grade 4 FN
(Table 3). Overall, nine patients (1.7 %) were reported to
be hospitalized with FN.
Supportive care
Overall, 481 patients (90.4 %) received G-CSF at some
point, and 75.0 % of chemotherapy cycles administered
were supported with G-CSF. For TC, the most common
chemotherapy regimen in this study, 88.7 % of patients
(n = 196) received G-CSF at some point and 73.5 % of
these patients (n = 144) received primary prophylactic
G-CSF. G-CSF use in additional chemotherapy regimens is
shown in Supplemental Table 4.
Pegfilgrastim was the most common G-CSF used in this
study; 398 patients (74.8 %) received only pegfilgrastim,
34 patients (6.4 %) received only filgrastim, and 49
patients (9.2 %) received both filgrastim and pegfilgrastim
over the course of their chemotherapy. Pegfilgrastim was
administered only as prophylaxis with 90.2 % of patients
(n = 359) receiving primary prophylaxis and 9.8 %
(n = 39) receiving secondary prophylaxis (Table 4).
Table 3 Neutropenia by regimen
Regimen Grade 3/4 neutropenia n (%) Grade 3/4 FN n (%) Grade 4 FN n (%)
TC (N = 221) 73 (33.0) 6 (2.7) 3 (1.4)
AC (N = 58) 34 (58.6) 6 (10.3) 4 (6.9)
TCH (N = 56) 20 (35.7) 2 (3.6) 1 (1.8)
TAC (N = 34) 15 (44.1) 2 (5.9) 2 (5.9)
AC-Tweekly (N = 22) 14 (63.6) 0 (0) 0 (0)
AC-T14 (N = 83) 34 (41.0) 0 (0) 0 (0)
AC14-Tweekly (N = 54) 24 (44.4) 2 (3.7) 2 (3.7)
AC-T (N = 4) 1 (25.0) 0 (0) 0 (0)
FN febrile neutropenia, TC docetaxel ? cyclophosphamide, AC doxorubicin ? cyclophosphamide, TCH docetaxel ? carboplatin ? trast-
uzumab, TAC docetaxel ? doxorubicin ? cyclophosphamide, AC-Tweekly 21-day AC followed by 21-day paclitaxel at 80 mg/m2 given on day 1,
8, and 15, AC-T14 14-day AC followed by 14-day paclitaxel at 175 mg/m2, AC14-Tweekly 14-day AC followed by 21-day paclitaxel at 80 mg/m2
given on day 1, 8, and 15, AC-T 21-day AC followed by 21-day paclitaxel at 175 mg/m2
868 Breast Cancer Res Treat (2013) 139:863–872
123
Filgrastim was administered both as prophylaxis and
treatment with 23.5 % of patients (n = 8) receiving pri-
mary prophylaxis, 38.2 % (n = 13) receiving secondary
prophylaxis, and 38.2 % (n = 13) receiving treatment
(Table 4).
Pegfilgrastim alone was administered to 312 patients
\65 years and 86 patients C65 years. Pegfilgrastim use
was similar among patients \65 years and patients
C65 years for both primary prophylaxis (91.0 vs 87.2 %)
and secondary prophylaxis (9.0 vs 12.8 %). Filgrastim
alone was administered to 25 patients \65 years and nine
patients C65 years. Filgrastim use was also similar among
patients \65 years and patients C65 years for primary
prophylaxis (20.0 vs 33.3 %), secondary prophylaxis (40.0
vs 33.3 %), and treatment (40.0 vs 33.3 %).
Overall, 160 patients (30.1 %) received at least one
antimicrobial agent; and 146 patients (27.4 %) received an
antimicrobial and G-CSF at some point over the chemo-
therapy course. Overall, 130 patients (24.4 %) received
oral agents only, 29 patients (5.5 %) received intravenous
agents with or without oral agents, and one patient received
a topical antimicrobial. Antimicrobial use was initiated
during day 1–5 of any chemotherapy cycle for 44 patients
(8.3 %), during day 6–10 of any chemotherapy cycle for 87
patients (16.4 %), and after day 10 of any chemotherapy
cycle for 76 patients (14.3 %). Antimicrobial use was
similar across cycles 1–3 (9.3–11.1 %) and lower across
subsequent cycles (3.9–7.4 %). Quinolones were the most
common antimicrobial (n = 108, 20.3 %).
Treatment patterns over time
Changes over time between Study 1 and Study 2 can be
described since 79 % of the sites in Study 2 also partici-
pated in Study 1 (Table 5). Baseline patient demographics
and disease characteristics were similar between Study 1
and Study 2, though patients in Study 2 were slightly older
and fewer patients had lymph node-positive disease. Con-
sistent with findings of Giordano et al. [21], we noted a
marked increase in taxane-based regimens, which were
administered to\4 % of patients in Study 1 and to 89.1 %
of patients in Study 2. Relative to Study 1, fewer patients
received an RDI \85 % (16.2 vs 55.5 %), and fewer dose
delays (16.0 vs 24.9 %) and dose reductions (20.9 vs
36.5 %) were seen. In addition, G-CSF use increased from
Table 4 G-CSF use
Pegfilgrastim only (N = 398) Filgrastim only (N = 34) Overalla (N = 481)
Prophylactic use—n (%) 398 (100.0) 21 (61.8) 467 (97.1)
Primary 359 (90.2) 8 (23.5) 404 (84.0)
Secondaryb 39 (9.8) 13 (38.2) 63 (13.1)
Treatment use—n (%) 0 (0) 13 (38.2) 14 (2.9)
51 patients who did not receive either pegfilgrastim or filgrastim are excluded from this tablea Includes 49 patients who received both pegfilgrastim and filgrastimb Includes 23 patients (4.8 %) who initially received treatment G-CSF followed by secondary prophylaxis
Table 5 Key patient and treatment characteristics in Study 1 and
Study 2
Study 1
N = 19,898
Study 2
N = 532
Age, mean 52 55
\65 years 83 % 78 %
BSA, mean 1.83 m2 1.84 m2
Lymph node-positive disease 52.4 % 45.1 %
Chemotherapy regimena
CMFb 43 % N/A
CAFb 19 % N/A
AC 34 % 11 %
AC followed by T \4 % 31 %
TC N/A 42 %
TAC N/A 6 %
TCH N/A 11 %
RDI \85 % 55.5 % 16.2 %
Dose delay C7 days 24.9 % 16.0 %
Dose reduction C15 % 36.5 % 20.9 %
G-CSF administration
Any 26.4 % 90.4 %
Primary prophylactic *3 %c 75.9 %
BSA body surface area, RDI relative dose intensity, CMF cyclophos-
phamide ? methotrexate ? fluorouracil, CAF cyclophosphamide ?
doxorubicin ? fluorouracil, AC doxorubicin ? cyclophosphamide, TC
docetaxel ? cyclophosphamide, TAC docetaxel ? doxorubicin ? cycl-
ophosphamide, TCH docetaxel ? carboplatin ? trastuzumab, N/A not
applicable, G-CSF granulocyte-colony-stimulating factora A small number of patients in Study 1 received doxorubicin fol-
lowed by cyclophosphamide ? methotrexate ? fluorouracil or
doxorubicin followed by paclitaxel followed by cyclophosphamideb Includes both 21- and 28-day dosing schedulesc In Study 1, prophylactic use was defined as use within 3 days of
chemotherapy completion
Breast Cancer Res Treat (2013) 139:863–872 869
123
Study 1 to Study 2. In Study 1, 26.4 % of patients received
G-CSF at some point (vs 90.4 % in Study 2) and *3 %
received primary prophylactic G-CSF (vs 75.9 % in Study
2). Rates of neutropenia, FN, FN-related hospitalization,
and antimicrobial use were not reported in Study 1.
Discussion
Treatment for ESBC has evolved over the past decade, as
reflected in this retrospective analysis of 532 patients
treated with adjuvant chemotherapy in US community- and
hospital-based outpatient oncology practices. Notable
changes include higher mean RDI, greater use of prophy-
lactic G-CSF, and a shift towards taxane-based chemo-
therapy regimens.
In the past decade, a growing body of work has dem-
onstrated that high RDI improves patient outcomes in
ESBC [17–19, 23]. Historically, older patients and obese
patients have been given lower doses of chemotherapy
from the onset of treatment; indeed, both advanced age and
higher BMI were risk factors for RDI \85 % in Study 1. In
this study, mean RDI was high across all regimens exam-
ined. Also, little difference in RDI was seen between
patients\65 years and patients C65 years, and age was not
associated with risk for RDI \85 %. Though most cancer
patients are C65 years, these patients are underrepresented
in clinical trials [24], leading to a paucity of clinical data
on the efficacy and safety of treatments in the elderly.
However, healthy patients C65 years can derive the same
benefits from chemotherapy as younger patients [25].
Finally, in this study, RDI was calculated to be lower
among patients with a BSA [ 2 m2 than among patients
with BSAs B 2 m2. Though BMI was not associated with
risk for RDI \85 %, weight was a risk factor. Full-dose
chemotherapy has been shown to be safe and effective in
overweight patients; however, chemotherapy doses are
routinely ‘‘capped,’’ which can lead to underdosing of
obese patients. Recent ASCO guidelines, which were
released after this study was conducted, recommend that
full weight-based cytotoxic chemotherapy doses can be
used to treat obese patients with cancer, particularly in the
curative setting [26]. The data reported here suggest that
disparities among the treatment of different age groups
have diminished over the past decade, but undertreatment
of obese patients may still persist.
Consistent with higher RDI, greater compliance with
NCCN-standard doses and number of cycles for the treat-
ment of breast cancer [22] was also seen. In Study 1, 24 %
of patients had a planned dose reduction. In this study,
cycle 1 dose reductions, which were likely planned, were
seen in 7 % of patients. Similarly, the median number of
planned cycles was identical to the NCCN-standard
number of cycles for each chemotherapy regimen. Though
compliance has improved, 16.2 % of patients received an
RDI \85 %.
As guidelines for the use of adjuvant chemotherapy in
breast cancer have evolved, chemotherapy has been rec-
ommended for an expanding population of patients [27,
28]. Correspondingly, the rate of use of adjuvant chemo-
therapy appears to have increased over time, at least in
certain populations of patients [29, 30]. Currently, the
NCCN-preferred regimens for adjuvant chemotherapy for
ESBC are AC followed by paclitaxel, TC, and TCH, all
taxane-containing regimens [22]. In Study 1, taxane-based
therapies were just emerging, and \4 % of patients
received a taxane. Study 2 reflects the shift in practice
toward taxane-based regimens, with 89.1 % of patients
receiving a regimen that contained a taxane.
Taxane-based regimens are largely considered the
standard of care for patients with ESBC based on a number
of pivotal trials. In a phase 3 trial comparing TAC with
fluorouracil, doxorubicin, and cyclophosphamide (FAC),
TAC significantly decreased the risk of relapse and death
compared to FAC [9]. However, the incidence of FN was
24.7 % in patients treated with TAC compared to 2.5 % in
patients treated with FAC [9]. In a phase 3 trial that showed
that TC was superior to AC [31], the incidence of FN in the
TC arm was reported as 5 %; however, the use of pro-
phylactic antibiotics was widespread, and the use of G-CSF
was not reported [31]. In recent retrospective studies, the
incidence of FN in patients receiving TC ranged from 0 to
6.3 % in patients who received G-CSF and 25 to 50 % in
patients who did not receive G-CSF [32–34]. Consistent
with studies where G-CSF use was common, we found that
the incidence of FN in patients receiving TC was 2.7 %.
Current guidelines recommend the use of prophylactic
CSFs in patients with a C20 % risk of FN and that the use
of prophylactic CSFs be considered in patients with
10–20 % risk of FN [35–37] when no other equally
effective regimen that does not require CSFs is available
[36]. In the most recent NCCN guidelines on breast cancer,
TC is listed as a preferred regimen for invasive breast
cancer with G-CSF support in all cycles [22]. Therefore,
increased G-CSF use may, in part, be a response to the shift
toward the use of newer, taxane-containing chemotherapy
regimens which may be more myelotoxic, as well as a
greater awareness of the risk of FN associated with these
regimens.
This study has a number of limitations that are inherent
to retrospective analyses where data are collected from
patient charts and electronic medical record (EMR) dat-
abases. Transfer of inpatient data into the EMR is not
always complete; thus some data may be underreported. In
addition, hospitalizations were only captured for patients
who were hospitalized with FN. Hospitalizations for other
870 Breast Cancer Res Treat (2013) 139:863–872
123
causes were not captured. Reasons for dose delays and dose
reductions were captured as broad categories, and deter-
mining underlying causes of dose delays and dose reduc-
tions was difficult. For example, most dose delays and
reductions were attributed to ‘‘other’’ reasons. Apart from
this limitation, 17 patients had a dose delay due to per-
sonal/patient request. Though this category could encom-
pass several underlying reasons, continued physician and
patient education on the importance of maintaining high
RDI may further increase RDI and ultimately improve
patient outcomes.
In summary, this study describes a shift in the past decade
to higher RDI across all patient populations regardless of
age. Though survival outcomes are not available from the
previous study or this study, the data shown here indicates
maintaining full-dose chemotherapy on the planned sche-
dule has become an important goal in clinical practice. In
ESBC, maintaining high RDI is associated with improved
disease-free survival and overall survival [17, 18, 23]. Most
patients in this study received an RDI C85 %, indicating
that patient care has continued to improve in the past decade.
Acknowledgments The authors thank Greg Valin, Sharon Hunter,
Natasha Gicanov, Paul Chang, and Sejal Badre (Amgen Inc.) for their
contributions to this study. Kerri Hebard-Massey, PhD (Amgen Inc.)
provided writing assistance. This study was funded by Amgen Inc.
Conflict of interest GHL is principal investigator of a research
grant to Duke University from Amgen in support of the ANC Study
Group. DCD and JC received research funding from and are on an
advisory board of Amgen Inc. DT and SW are employees of and
stockholders in Amgen Inc.
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