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Breast Cancer Res Treat (2012) 131:483–490

DOI 10.1007/s10549-011-1799-1


Prognostic value of chemotherapy-induced neutropenia

in early-stage breast cancer
Yunwei Han • Zhihao Yu • Shaoyan Wen •

Bin Zhang • Xuchen Cao • Xin Wang

Received: 7 June 2011 / Accepted: 21 September 2011 / Published online: 5 October 2011
Ó Springer Science+Business Media, LLC. 2011

Abstract Neutropenia is one of the most important dose- Introduction

limiting toxicities and often the reason for dose reduction.
In this study we aimed to assess whether chemotherapy- Breast cancer is the most common female cancer [1]. In
induced neutropenia could be a marker of efficacy and early-stage breast cancer, adjuvant chemotherapy has
associate with increased survival. Data from a retrospective become an element of standard therapy and reduces the
survey for early breast cancer patients in our hospital were hazard rate of death by about 15% [2]. Numerous studies
reviewed. Three hundred and thirty-five patients who had have demonstrated benefits of adjuvant chemotherapy in
been treated with six cycles of cyclophosphamide, epiru- early-stage breast cancer and that anthracycline (doxoru-
bicin, and fluorouracil (CEF) were studied. The association bicin or epirubicin)-based regimens are among the most
between chemotherapy-induced neutropenia and overall effective [3]. Moreover, six cycles of fluorouracil, doxo-
survival (OS) was assessed. According to a multivariate rubicin, and cyclophosphamide (FAC), or fluorouracil,
Cox model with time-varying covariates, hazard ratios of epirubicin, and cyclophosphamide (FEC) appear superior
death were 0.434 (95% confidence interval (CI), to six cycles of cyclophosphamide, methotrexate, and flu-
0.298–0.634; P \ 0.001) for patients with mild neutrope- orouracil (CMF) in early-stage breast cancer [4]. Despite
nia, and 0.640 (95% CI, 0.42–0.975; P = 0.038) for those this evidence of benefit with adjuvant chemotherapy,
with severe neutropenia. Neutropenia occurring in early important questions remain to be resolved with regard to
breast cancer patients is an independent predictor of the relative effectiveness and toxicities of chemotherapy
increased survival. These findings suggest that neutropenia regimens.
in patients who receive chemotherapy is strongly associ- Patients receiving adjuvant chemotherapy may experi-
ated with a better prognosis. ence varying levels of toxicity. Neutropenia due to
cytotoxic chemotherapy is a common type of myelosup-
Keywords Breast cancer  Adjuvant chemotherapy  pression. Neutropenia during cytotoxic chemotherapy for
Neutropenia Prognosis  Time-dependent variable several types of cancer has been reported to be associated
favorably with survival [5–7]. Studies of adjuvant chemo-
therapy for breast cancer have shown that patients who
have increased toxic effects during treatment had a better
outcome than those who had no toxic effects. Neutropenia
or leukopenia occurring during adjuvant chemotherapy
regimens using cyclophosphamide, doxorubicin, and oral
ftorafur (CAFt) [8] or cyclophosphamide, methotrexate and
Y. Han  Z. Yu  S. Wen  B. Zhang  X. Cao  X. Wang (&) 5-FU (CMF) [9, 10] was associated with significantly
First Department of Breast Tumor, Tianjin Medical University longer survival. Moreover, Ishitobi et al. [11] examined
Cancer Institute and Hospital; Key Laboratory of Breast Cancer
the patients having a chemotherapy-induced neutropenia
Prevention and Therapy, Tianjin Medical University, Ministry of
Education, Tianjin 300060, China was associated with better prognosis in epirubicin-based
e-mail: neoadjuvant chemotherapy. A possible explanation for

484 Breast Cancer Res Treat (2012) 131:483–490

neutropenia’s favorable impact on survival is that it is a who received radiotherapy were those with positive lymph
surrogate marker for a sufficient antitumor dose of cyto- nodes more than three, or the women who received breast-
toxic chemotherapy. However, the nature of the relation- conserving surgery. The dosage was 45–50 Gy in 18–25
ship between chemotherapy-induced neutropenia and the fractions over 5 weeks after six cycles of chemotherapy.
survival, in particular, remains controversy. In this report, Estrogen receptor (ER) status was determined by immu-
we described a retrospective analysis of patients with early- nohistochemistry and tumors with 10% or more positively
stage breast cancer, who were treated with the first-line stained tumor cells were classified positive for ER. Histo-
chemotherapy of CEF, to evaluate any possible association logical grade was determined according to the modified
between chemotherapy-induced neutropenia occurring Scarff-Bloom-Richardson criteria [12]. Patients with ER-
during chemotherapy and survival. positive or PR-positive tumors were administered hor-
monal therapy. Adjuvant trastuzumab was administered in
17 patients (5%). After treatment, the patients were fol-
Patients and methods lowed up at 3 to 4 month intervals for the first 2 years
and thereafter at 6-month intervals for at least 5 years.
Patients Staging investigations included clinical investigation, liver
enzymes, chest X-ray, liver ultrasound, and bone scintig-
The study population comprised primary breast cancer raphy. The dose intensity was calculated as the total dose
patients in Tianjin Medical University Cancer Institute and administered divided by the duration of time over which it
Hospital between April 2005 and April 2007, 335 patients was given. The relative dose intensity (RDI) was then
with early-stage breast cancer were identified who met calculated as the ratio of the actual dose intensity to the
the inclusion criteria. The inclusion criteria were as fol- ideal value if planned doses were all given on schedule.
lows: sufficient bone marrow function (leukocyte count
4.0 9 109/l, neutrophil count 2.0 9 109/l, platelet count Evaluation of neutropenia and supportive therapy
100 9 109/l, hemoglobin 9.0 g/dl); normal liver and renal
functions; no history of prior chemotherapy for advanced Routine blood counts were taken during every chemo-
disease; and no history of chemotherapy before the com- therapy cycle, day one before treatment and approximately
mencement of CEF treatment. The patients were selected on day 7 and day 14, in all patients during all chemo-
from those who survived beyond 180 days of treatment. therapy cycles. Hematologic toxicity, including neutrope-
Febrile neutropenia patients were excluded from this study. nia, leukopenia, thrombocytopenia and decreased
The patients were followed up until December 2010 to hemoglobin level, was graded according to the National
obtain survival information. Cancer Institute Common Terminology Criteria for
One hundred and eighty patients were stage I breast Adverse Events(NCI-CTCAE), version 3. Chemotherapy
cancer and 155 patients were stage II breast cancer. was delayed until recovery for a neutrophil count of
Estrogen receptor (ER) values were available for 329 1.5 9 109/l or any significant persisting nonhematologic
patients, 66% of whom were positive. Progesterone toxicity. The treatment was discontinued if the patient
receptor (PR) values were available for 329 patients, 60% developed unacceptable toxic effects, refused treatment, or
of whom were positive. The human epidermal growth withdrew consent. Patients with treatment delay due to
factor receptor 2 (HER-2) values were available for 327 toxicity were followed up with weekly or more frequent
patients, 21% of whom were positive. One hundred and blood counts. The most severe grade of neutropenia was
seventy-nine (53%) patients were over 50 years old. The based on the neutrophil count for a given patient between
median follow-up time was 65 month. the first day of CEF administration and 2 weeks after the
last CEF cycle was administered. The grade was according
Treatment delivery to the National Cancer Institute Common Toxicity Criteria
version 3.0. (grade 0 equates to Within normal limits; grade
The patients had received six cycles of intravenous CEF as 1 equates to a neutrophil count of between 1.5 and
adjuvant postoperative chemotherapy for a diagnosis of 2.0 9 109 cells/l; grade 2 equates to a neutrophil count of
invasive breast cancer. All patients had been undergone between 1.0 and 1.5 9 109 cells/l; grade 3 equates to a
surgery with modified radical mastectomy or breast-con- neutrophil count of between 0.5 and 1 9 109 cells/l; and
serving resection and axillary lymph node dissection. grade 4 equates to a neutrophil count of lower than
Patients were treated with adjuvant chemotherapy, which 0.5 9 109 cells/l.) To evaluate neutropenia during che-
consisted of cyclophosphamide (600 mg/m2), epirubicin motherapy, patients were divided into three categories:
(60 mg/m2), and fluorouracil (600 mg/m2) administered neutropenia absent (grade 0), mild (grades 1–2), and severe
intravenously on day 1 at 3-week intervals. The patients (grades 3–4). The indication for using granulocyte-colony-

Breast Cancer Res Treat (2012) 131:483–490 485

stimulating factor (G-CSF) was generally used in grade 4 in 139 (42%) of 335 patients and severe neutropenia
neutropenia or in febrile neutropenia, and no use as pro- (grades 3–4) occurred in 37 (11%). The other 159 patients
phylaxis was allowed. To avoid bias from different fre- (47%) did not experience neutropenia during treatment
quencies of neutrophil counting, the worst grade of with CEF. The relative dose intensity was not significantly
neutropenia was evaluated by the lowest recorded neutrophil different between each group. In 176 patients experiencing
count of six cycles of chemotherapy regimen. neutropenia, the worst grade was seen during the first cycle
in 32 patients, during the second cycle in 38, during the
Statistical analysis third cycle in 32, during the fourth cycle in 31 and during
the fifth cycle 22 or thereafter in 20, indicating that 76% of
The association between neutropenia and various clinico- patients with neutropenia experienced their worst grade
pathological parameters was assessed using the v2 test or within four cycles. On the other hand, 43 of 202 patients
Fisher’s exact test. Overall survival (OS) was the primary (21%) without neutropenia within four cycles experienced
endpoint of the analysis. OS was defined as the time from neutropenia (35 patients with mild neutropenia and 8
surgery to death or follow up. The survival curves of the patients with severe neutropenia) (Fig. 2).
three categories were estimated by the Kaplan–Meier
method and compared by the log-rank test. What is more,
we treated chemotherapy-induced neutropenia as a time- Relationship between neutropenia and prognosis
dependent variable. For each patient, the worst grade of
neutropenia occurring during the CEF treatment was The survival curves of the three categories were estimated
defined as the value of the variable at T. The variable value by the Kaplan–Meier method and compared by the log-
for each patient could change over time according to the rank test. Neutropenia status was significantly associated
worst grade of neutropenia experienced by that time. To with OS. Patients without neutropenia showed a signifi-
quantify the impact of time-dependent neutropenia on cantly lower 5-year OS rate (65%) than those with mild
survival, Clinical and pathological factors were tested by neutropenia (P \ 0.001) (89%) and severe neutropenia
univariate and multivariate analyses according to the worst (P = 0.033) (84%) (Fig. 3). The result of a Cox regression
grade of neutropenia, which was considered to be a time- analysis for the association between overall survival and
dependent variable. All of the statistical tests and P values the worst grade of neutropenia, which was treated as a
were two-tailed, and P \ 0.05 was considered significant. time-dependent variable is showed in Table 2. Univariate
and multivariate analyses including neutropenia and vari-
ous clinicopathological parameters of breast cancer was
Results done. In univariate analysis, the HR for mild (grade 1–2)
neutropenia in comparison with no neutropenia (grade 0)
Incidence of neutropenia was 0.424 (95% CI, 0.280–0.642; P \ 0.001). Similarly,
the HR for severe (grade 3–4) neutropenia in comparison
Figure 1 shows the worst grade of neutropenia recorded at with no neutropenia was 0.579 (95% CI, 0.415–0.807;
each cycle of chemotherapy in the 335 patients. Table 1 P = 0.001). In multivariate analysis, the HR for mild
shows characteristics of patients in the analysis. Relation- (grade 1–2) neutropenia in comparison with no neutropenia
ship between neutropenia and various clinicopathological (grade 0) was 0.434 (95% CI, 0.298–0.634; P \ 0.001),
parameters overall, mild neutropenia (grades 1–2) occurred which translated into a 24% lower risk of death. Similarly,
the HR for severe (grade 3–4) neutropenia in comparison
with no neutropenia was 0. 640 (95% CI, 0.42–0.975;
severe mild absent P = 0.038), which represented a 19% lower risk of
100% death. Therefore, patients who experienced neutropenia
80% had a more favorable prognosis, and the presence of mild
ratio of patientas

70% neutropenia suggested a higher efficacy of the drug than

50% did the presence of either severe neutropenia or no
40% neutropenia. It demonstrated that both mild and severe
20% grade of neutropenia were independently associated with
a better survival. Furthermore, univariate and multivariate
1 2 3 4 5 6 analysis including other clinical features such as tumor
cycle size, nodal status, ER status, HER-2 status, histological
Fig. 1 Worst grade of neutropenia recorded by each cycle of grade were also independent predictive factors for OS
chemotherapy in 335 patients (Table 2).

486 Breast Cancer Res Treat (2012) 131:483–490

Table 1 Baseline demographics and clinical/hematologic characteristics in all patients and in subgroups stratified according to the worst grade
of neutropenia during six cycles
All patients (n = 335) Neutropenia P
Absent (n = 159) Mild (n = 139) Severe (n = 37)

Age, median (range) 50 (28–74) 52 (28–74) 52 (28–74) 52 (32–67) 0.518

BSA, median (range) 1.63 (1.01–2.04) 1.62 (1.15–2.04) 1.66 (1.17–2.03) 1.59 (1.01–1.95) 0.318
Treatment duration, median (range) 156 (124–178) 142 (124–163) 150 (126–168) 164 (128–178) 0.257
RDI, median (range) 0.86 (0.35–1.25) 0.86 (0.35–1.25) 0.88 (0.55–1.25) 0.85 (0.43–1.23) 0.166
leukocytes, median (range) 8.5 (4.0–15.5) 8.0 (4.0–13.2) 8.7 (4.1–14.1) 8.3 (4.0–15.5) 0.433
Neutrophils, median (range) 4.0 (1.95–6.5) 4.0 (1.95–6.4) 4.3 (2.0–6.5) 4.1 (2.0 –6.4) 0.526
Clinical tumor size, n 0.418
T B 50 mm 174 91 65 18
T [ 50 mm 151 68 64 19
Clinical nodal status, n 0.143
N0 180 80 76 24
N1–3 155 79 63 13
ER, n 0.147
Positive 213 101 83 29
Negative 116 55 53 8
PR, n 0.128
Positive 119 104 75 20
Negative 130 52 61 17
HER-2, n 0.120
Positive 69 35 31 3
Negative 258 120 104 34
Use of tamoxifen 0.218
Yes 160 76 63 21
No 161 77 70 14
Histological grade 0.073
I 108 57 45 6
II–III 196 88 81 27
Surgical 0.518
Modified radical mastectomy 296 141 129 26
Breast conservation 39 18 13 8
2 9 9
BSA body surface area; Units age (years), BSA (m ), leukocytes (9 10 /l), neutrophils (9 10 /l), treatment duration (days)

40 Relationship between neutropenia and various

35 clinicopathological parameters
number of patients

25 Both mild and severe neutropenia tended to be associ-
20 ated with improved prognosis in almost all subgroups
15 (Fig. 4). In all subgroups, both mild and severe neu-
10 tropenia were favorable prognostic factors almost to the
5 same degree.
0 Finally, we performed similar analysis for other hema-
1 2 3 4 5 6
tologic manifestations of toxicity, including leukopenia,
hemoglobin decrease, and thrombocytopenia. However,
Fig. 2 The timing of occurrence of neutropenia with worst grade in none of these variables remained as significant factors in
176 patients during six cycles of CEF the multivariate model (data not shown).

Breast Cancer Res Treat (2012) 131:483–490 487

experienced neutropenia during CEF treatment as first-line

chemotherapy for the early-stage breast cancer. The fre-
quencies of neutropenia in this study were comparable to
past clinical study reports where CEF regimens were used
[13–16]. In our study, both the mild and severe chemo-
therapy-induced neutropenia were prognostic for increased
survival. The results indicate that both mild and severe
neutropenia during chemotherapy have a significant impact
on the risk of death (HR = 0.434 in mild neutropenia and
HR = 0.640 in severe neutropenia). To the best of our
knowledge, this is the first report in the early-stage breast
cancer of CEF chemotherapy.
Several findings lend support to the idea that neutrope-
nia might be a surrogate indicator for the biological activity
of drugs [17]. Since the late 1990s, a series of reports have
suggested that those who experienced myelosuppression
Fig. 3 Kaplan–Meier survival curves according to the three groups of
worst grade neutropenia that occurred during six cycles of CEF
had better outcome than those who did not in both post-
operative and neoadjuvant chemotherapies of breast cancer
[8–11, 18]. In all these studies, the hematologic toxic
Discussion effects analyzed with neutropenia or leukocyte nadir had a
significant effect on survival.
Patients receiving adjuvant chemotherapy may experience The prognostic role of chemotherapy-induced neutro-
varying levels of toxicity. It is well known that neutropenia penia also has been investigated in other diseases.
is one of the most important dose-limiting toxicities Recently, Di Maio et al. [5] analyzed the pooled data from
and often the reason for dose reduction. In this study, we three randomized trials of 1265 patients in advanced non-
found significantly improved survival in patients who small-cell lung cancer. They concluded that both mild

Table 2 Univariate and multivariate Cox models for the association between survival and chemotherapy-induced neutropeniaa
Univariate analysis Multivariate analysis
Adjusted hazard ratio (95% CI) P Adjusted hazard ratio (95% CI) P

Mild vs. 0 0.424 (0.280–0.642) \0.001 0.434 (0.298–0.634) \0.001
Severe vs. 0 0.579 (0.415–0.807) 0.001 0.640 (0.42–0.975) 0.038
\50 y vs. C 50 y 0.846 (0.541–1.322) 0.463
[1.50 m2 vs. B 1.50 m2 0.660 (0.419–1.039) 0.072
Clinical tumor size, n
T B 50 mm vs. T [ 50 mm 1.981 (1.365–2.875) \0.001 1.762 (1.118–2.777) 0.015
Clinical nodal status, n
N0 vs. N1–3 2.614 (1.629–4.193) \0.001 1.92 (1.098–3.383) 0.022
ER, n
Positive vs. negative 0.609 (0.388–0.955) 0.031 0.601 (0.37–0.978) 0.04
PR, n
Positive vs. negative 0.657 (0.420–1.028) 0.066
HER-2, n
Positive vs. negative 1.730 (1.376–2.175) \0.001 1.377 (1.067–1.777) 0.014
Histological grade
IvsII–III 1.946 (1.112–3.404) 0.02 1.964 (1.098–3.513) 0.023
BSA body surface area, Neutropenia is treated as a time-dependent variable

488 Breast Cancer Res Treat (2012) 131:483–490

between body surface area and the pharmacokinetics of

most cytotoxic agents have been pointed out [24–29]. A
complex model taken into account not only body surface
area, but also bodyweight, serum creatinine, sex, and
platelet count before treatment are important for the che-
motherapy effect. These results lead us to recognize the
possibility that optimal dosing is not necessarily governed
by the use of BSA-dosing guidelines. Using a tailored
regimen of fluorouracil, epirubicin, and cyclophosphamide
guided by toxic effects in patients with breast cancer
probably would have a better result in many patients
[23, 30]. The fact that severe neutropenia is no better than
mild neutropenia but that both are better than no neutro-
penia at prediction of survival suggests that enough, but not
too much, chemotherapy needs to be given. What is more,
a large randomized study on dose-escalation of doxorubi-
cin failed to show any benefits in the adjuvant setting [31].
Although the methods of dose optimization and calculation
have been criticized repeatedly [32, 33], the doses directed
by BSA are valid for most, in insuring that the majority of
patients receive an effective dose. If not, all the patients
without toxicity such as myelosuppression will continue to
derive substantial benefits from treatment. However, our
study and that of others suggest that the absence of neu-
Fig. 4 Hazard ratios for death and 95% CI. In subgroup analyses,
both mild and severe neutropenia tended to be associated with tropenia may actually be a sign of an inadequate dose of
improved prognosis in almost all subgroup chemotherapy [17]. The cause of this interpatient variation
is unclear. Patients show quite different concentration time
(grade 1–2) and severe (grade 3–4) neutropenia might be a properties for levels of drug in tissue after the adminis-
surrogate marker of an adequate chemotherapy dose and tration of a uniform dose. The explanation might be related
that lack of neutropenia indicates underdosing. Other arti- to genetic predisposition and a large inter-individual
cles reported that chemotherapy-induced neutropenia dur- variation of systemic exposure [34–36].
ing treatment is associated with a higher probability of However, chemotherapy dose reductions and dose
treatment response and better survival in colon and gastric delays, as a result of chemotherapy-induced neutropenia,
cancer patients [6, 7, 19]. These findings prompted us to can lead to reduce patient survival [37–39]. In our study,
perform a rigorous quantification of the prognostic value of between the subgroups of patients with and without neu-
chemotherapy-induced neutropenia with respect to survival tropenia, the RDI and the dose delays did not significantly
outcomes in patients with early-stage breast cancer. differ. Therefore, the better prognosis of patients with
The availability of active antitumor drug at tumor cells neutropenia was not due to a dose reductions and dose
is affected by pharmacokinetic factors, including drug delays in patients with neutropenia. Neutropenia might be
metabolism or elimination which produces a similar effect associated with prognosis as a consequence of selection
in healthy cells. The sensitivity of tumor cells and healthy bias. Patients with occult problems due to disease might be
cells is affected, partly, myelosuppression might represent more prone to toxicity and early failures may receive lower
an index of bodily drug exposure. Several prospective doses because of treatment discontinuation. Since neutro-
randomized studies [20–22] have investigated the dose– penia does not exist before the initiation of chemotherapy,
response relationship in breast carcinoma to assess the patients surviving longer had a greater chance to receive
preference for higher doses than those guided by the body additional cycles. Therefore, a higher incidence of neu-
surface area (BSA) criteria. However, the BSA-based tropenia was expected as the number of cycles of chemo-
dosing system is not appropriate, then the optimal dose of therapy increased. To avoid the bias, we restrict the
chemotherapy for individual patients is relatively unrelated primary analysis to patients who had completed six
to whether the dose is high or low in terms of the BSA- cycles of treatment and who survived after 180 days of
based one [23]. Several previous reports suggest that the treatment [5].
optimal dose defined by an estimated body surface area We further evaluated the impact of neutropenia during
may be insufficient in some cases. A poor correlation the first four cycles of CEF on survival and found that 76%

Breast Cancer Res Treat (2012) 131:483–490 489

of patients with neutropenia (133 of 176 patients) experi- [20090139] and Talented Professionals Scientific Research Funds of
enced their highest grade within four cycles, and those Tianjin Medical University Cancer Institute and Hospital. The authors
would like to thank Yue Li, Hongmeng Zhao, Yanqun Song for their
without neutropenia occurring in the first four cycles rarely help with data collecting.
experienced severe late-onset neutropenia (8 of 202
patients). However, the number of patients who remained Conflict of interest None of the authors has any competing interest
at grade 1–2 neutropenia in the first four cycles but to declare. The authors have no relevant financial interests to disclose.
thereafter developed neutropenia or one of the above
toxicities to a grade 3–4 level was only 43. Taking into
consideration, an early dose increase would not be a prob-
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