Han Et Al. - 2012 - Prognostic Value of Chemotherapy-Induced Neutropenia in Early-stage Breast...

8/11/2019 Han Et Al. - 2012 - Prognostic Value of Chemotherapy-Induced Neutropenia in Early-stage Breast Cancer(2)

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C L I N I C A L T R I A L

Prognostic value of chemotherapy-induced neutropeniain 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

Springer Science+Business Media, LLC. 2011

Abstract Neutropenia is one of the most important dose-

limiting toxicities and often the reason for dose reduction.In this study we aimed to assess whether chemotherapy-

induced neutropenia could be a marker of efficacy and

associate with increased survival. Data from a retrospective

survey for early breast cancer patients in our hospital were

reviewed. Three hundred and thirty-five patients who had

been treated with six cycles of cyclophosphamide, epiru-

bicin, and fluorouracil (CEF) were studied. The association

between chemotherapy-induced neutropenia and overall

survival (OS) was assessed. According to a multivariate

Cox model with time-varying covariates, hazard ratios of

death were 0.434 (95% confidence interval (CI),

0.2980.634; P\ 0.001) for patients with mild neutrope-

nia, and 0.640 (95% CI, 0.420.975; P = 0.038) for those

with severe neutropenia. Neutropenia occurring in early

breast cancer patients is an independent predictor of

increased survival. These findings suggest that neutropenia

in patients who receive chemotherapy is strongly associ-

ated with a better prognosis.

Keywords Breast cancer Adjuvant chemotherapy

Neutropenia Prognosis Time-dependent variable

Introduction

Breast cancer is the most common female cancer [1]. In

early-stage breast cancer, adjuvant chemotherapy has

become an element of standard therapy and reduces the

hazard rate of death by about 15% [2]. Numerous studies

have demonstrated benefits of adjuvant chemotherapy in

early-stage breast cancer and that anthracycline (doxoru-

bicin or epirubicin)-based regimens are among the most

effective [3]. Moreover, six cycles of fluorouracil, doxo-

rubicin, and cyclophosphamide (FAC), or fluorouracil,

epirubicin, and cyclophosphamide (FEC) appear superior

to six cycles of cyclophosphamide, methotrexate, and flu-

orouracil (CMF) in early-stage breast cancer [4]. Despite

this evidence of benefit with adjuvant chemotherapy,

important questions remain to be resolved with regard to

the relative effectiveness and toxicities of chemotherapy

regimens.

Patients receiving adjuvant chemotherapy may experi-

ence varying levels of toxicity. Neutropenia due to

cytotoxic chemotherapy is a common type of myelosup-

pression. Neutropenia during cytotoxic chemotherapy for

several types of cancer has been reported to be associated

favorably with survival [57]. 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

5-FU (CMF) [9, 10] was associated with significantly

longer survival. Moreover, Ishitobi et al. [11] examined

the patients having a chemotherapy-induced neutropenia

was associated with better prognosis in epirubicin-based

neoadjuvant chemotherapy. A possible explanation for

Y. Han Z. Yu S. Wen B. Zhang X. Cao X. Wang (&)

First Department of Breast Tumor, Tianjin Medical University

Cancer Institute and Hospital; Key Laboratory of Breast Cancer

Prevention and Therapy, Tianjin Medical University, Ministry of

Education, Tianjin 300060, China

e-mail: [email protected]

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Breast Cancer Res Treat (2012) 131:483490

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neutropenias favorable impact on survival is that it is a

surrogate marker for a sufficient antitumor dose of cyto-

toxic chemotherapy. However, the nature of the relation-

ship between chemotherapy-induced neutropenia and the

survival, in particular, remains controversy. In this report,

we described a retrospective analysis of patients with early-

stage breast cancer, who were treated with the first-line

chemotherapy of CEF, to evaluate any possible associationbetween chemotherapy-induced neutropenia occurring

during chemotherapy and survival.

Patients and methods

Patients

The study population comprised primary breast cancer

patients in Tianjin Medical University Cancer Institute and

Hospital between April 2005 and April 2007, 335 patients

with early-stage breast cancer were identified who metthe inclusion criteria. The inclusion criteria were as fol-

lows: sufficient bone marrow function (leukocyte count

4.0 9 109/l, neutrophil count 2.0 9 109/l, platelet count

100 9 109/l, hemoglobin 9.0 g/dl); normal liver and renal

functions; no history of prior chemotherapy for advanced

disease; and no history of chemotherapy before the com-

mencement of CEF treatment. The patients were selected

from those who survived beyond 180 days of treatment.

Febrile neutropenia patients were excluded from this study.

The patients were followed up until December 2010 to

obtain survival information.

One hundred and eighty patients were stage I breast

cancer and 155 patients were stage II breast cancer.

Estrogen receptor (ER) values were available for 329

patients, 66% of whom were positive. Progesterone

receptor (PR) values were available for 329 patients, 60%

of whom were positive. The human epidermal growth

factor receptor 2 (HER-2) values were available for 327

patients, 21% of whom were positive. One hundred and

seventy-nine (53%) patients were over 50 years old. The

median follow-up time was 65 month.

Treatment delivery

The patients had received six cycles of intravenous CEF as

adjuvant postoperative chemotherapy for a diagnosis of

invasive breast cancer. All patients had been undergone

surgery with modified radical mastectomy or breast-con-

serving resection and axillary lymph node dissection.

Patients were treated with adjuvant chemotherapy, which

consisted of cyclophosphamide (600 mg/m2), epirubicin

(60 mg/m2), and fluorouracil (600 mg/m2) administered

intravenously on day 1 at 3-week intervals. The patients

who received radiotherapy were those with positive lymph

nodes more than three, or the women who received breast-

conserving surgery. The dosage was 4550 Gy in 1825

fractions over 5 weeks after six cycles of chemotherapy.

Estrogen receptor (ER) status was determined by immu-

nohistochemistry and tumors with 10% or more positively

stained tumor cells were classified positive for ER. Histo-

logical grade was determined according to the modifiedScarff-Bloom-Richardson criteria [12]. Patients with ER-

positive or PR-positive tumors were administered hor-

monal therapy. Adjuvant trastuzumab was administered in

17 patients (5%). After treatment, the patients were fol-

lowed up at 3 to 4 month intervals for the first 2 years

and thereafter at 6-month intervals for at least 5 years.

Staging investigations included clinical investigation, liver

enzymes, chest X-ray, liver ultrasound, and bone scintig-

raphy. The dose intensity was calculated as the total dose

administered divided by the duration of time over which it

was given. The relative dose intensity (RDI) was then

calculated as the ratio of the actual dose intensity to theideal value if planned doses were all given on schedule.

Evaluation of neutropenia and supportive therapy

Routine blood counts were taken during every chemo-

therapy cycle, day one before treatment and approximately

on day 7 and day 14, in all patients during all chemo-

therapy cycles. Hematologic toxicity, including neutrope-

nia, leukopenia, thrombocytopenia and decreased

hemoglobin level, was graded according to the National

Cancer Institute Common Terminology Criteria for

Adverse Events(NCI-CTCAE), version 3. Chemotherapy

was delayed until recovery for a neutrophil count of

1.5 9 109/l or any significant persisting nonhematologic

toxicity. The treatment was discontinued if the patient

developed unacceptable toxic effects, refused treatment, or

withdrew consent. Patients with treatment delay due to

toxicity were followed up with weekly or more frequent

blood counts. The most severe grade of neutropenia was

based on the neutrophil count for a given patient between

the first day of CEF administration and 2 weeks after the

last CEF cycle was administered. The grade was according

to the National Cancer Institute Common Toxicity Criteria

version 3.0. (grade 0 equates to Within normal limits; grade

1 equates to a neutrophil count of between 1.5 and

2.0 9 109 cells/l; grade 2 equates to a neutrophil count of

between 1.0 and 1.5 9 109 cells/l; grade 3 equates to a

neutrophil count of between 0.5 and 1 9 109 cells/l; and

grade 4 equates to a neutrophil count of lower than

0.5 9 109 cells/l.) To evaluate neutropenia during che-

motherapy, patients were divided into three categories:

neutropenia absent (grade 0), mild (grades 12), and severe

(grades 34). The indication for using granulocyte-colony-

484 Breast Cancer Res Treat (2012) 131:483490

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stimulating factor (G-CSF) was generally used in grade 4

neutropenia or in febrile neutropenia, and no use as pro-

phylaxis was allowed. To avoid bias from different fre-

quencies of neutrophil counting, the worst grade of

neutropenia was evaluated by the lowest recorded neutrophil

count of six cycles of chemotherapy regimen.

Statistical analysis

The association between neutropenia and various clinico-

pathological parameters was assessed using the v2 test or

Fishers exact test. Overall survival (OS) was the primary

endpoint of the analysis. OS was defined as the time from

surgery to death or follow up. The survival curves of the

three categories were estimated by the KaplanMeier

method and compared by the log-rank test. What is more,

we treated chemotherapy-induced neutropenia as a time-

dependent variable. For each patient, the worst grade of

neutropenia occurring during the CEF treatment was

defined as the value of the variable at T. The variable valuefor each patient could change over time according to the

worst grade of neutropenia experienced by that time. To

quantify the impact of time-dependent neutropenia on

survival, Clinical and pathological factors were tested by

univariate and multivariate analyses according to the worst

grade of neutropenia, which was considered to be a time-

dependent variable. All of the statistical tests and P values

were two-tailed, and P\ 0.05 was considered significant.

Results

Incidence of neutropenia

Figure1shows the worst grade of neutropenia recorded at

each cycle of chemotherapy in the 335 patients. Table 1

shows characteristics of patients in the analysis. Relation-

ship between neutropenia and various clinicopathological

parameters overall, mild neutropenia (grades 12) occurred

in 139 (42%) of 335 patients and severe neutropenia

(grades 34) occurred in 37 (11%). The other 159 patients

(47%) did not experience neutropenia during treatment

with CEF. The relative dose intensity was not significantly

different between each group. In 176 patients experiencing

neutropenia, the worst grade was seen during the first cycle

in 32 patients, during the second cycle in 38, during the

third cycle in 32, during the fourth cycle in 31 and duringthe fifth cycle 22 or thereafter in 20, indicating that 76% of

patients with neutropenia experienced their worst grade

within four cycles. On the other hand, 43 of 202 patients

(21%) without neutropenia within four cycles experienced

neutropenia (35 patients with mild neutropenia and 8

patients with severe neutropenia) (Fig. 2).

Relationship between neutropenia and prognosis

The survival curves of the three categories were estimated

by the KaplanMeier method and compared by the log-rank test. Neutropenia status was significantly associated

with OS. Patients without neutropenia showed a signifi-

cantly lower 5-year OS rate (65%) than those with mild

neutropenia (P\ 0.001) (89%) and severe neutropenia

(P = 0.033) (84%) (Fig. 3). The result of a Cox regression

analysis for the association between overall survival and

the worst grade of neutropenia, which was treated as a

time-dependent variable is showed in Table 2. Univariate

and multivariate analyses including neutropenia and vari-

ous clinicopathological parameters of breast cancer was

done. In univariate analysis, the HR for mild (grade 12)

neutropenia in comparison with no neutropenia (grade 0)was 0.424 (95% CI, 0.2800.642; P\ 0.001). Similarly,

the HR for severe (grade 34) neutropenia in comparison

with no neutropenia was 0.579 (95% CI, 0.4150.807;

P = 0.001). In multivariate analysis, the HR for mild

(grade 12) neutropenia in comparison with no neutropenia

(grade 0) was 0.434 (95% CI, 0.2980.634; P\ 0.001),

which translated into a 24% lower risk of death. Similarly,

the HR for severe (grade 34) neutropenia in comparison

with no neutropenia was 0. 640 (95% CI, 0.420.975;

P = 0.038), which represented a 19% lower risk of

death. Therefore, patients who experienced neutropenia

had a more favorable prognosis, and the presence of mild

neutropenia suggested a higher efficacy of the drug than

did the presence of either severe neutropenia or no

neutropenia. It demonstrated that both mild and severe

grade of neutropenia were independently associated with

a better survival. Furthermore, univariate and multivariate

analysis including other clinical features such as tumor

size, nodal status, ER status, HER-2 status, histological

grade were also independent predictive factors for OS

(Table2).

0%

10%

20%

30%

40%

50%

60%

70%

80%90%

100%

1 2 3 4 5 6

cycle

ratioofpatientas

severe mild absent

Fig. 1 Worst grade of neutropenia recorded by each cycle of

chemotherapy in 335 patients

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Relationship between neutropenia and various

clinicopathological parameters

Both mild and severe neutropenia tended to be associ-

ated with improved prognosis in almost all subgroups

(Fig.4). In all subgroups, both mild and severe neu-

tropenia were favorable prognostic factors almost to the

same degree.

Finally, we performed similar analysis for other hema-

tologic manifestations of toxicity, including leukopenia,

hemoglobin decrease, and thrombocytopenia. However,

none of these variables remained as significant factors in

the multivariate model (data not shown).

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 (2874) 52 (2874) 52 (2874) 52 (3267) 0.518

BSA, median (range) 1.63 (1.012.04) 1.62 (1.152.04) 1.66 (1.172.03) 1.59 (1.011.95) 0.318

Treatment duration, median (range) 156 (124178) 142 (124163) 150 (126168) 164 (128178) 0.257

RDI, median (range) 0.86 (0.351.25) 0.86 (0.351.25) 0.88 (0.551.25) 0.85 (0.431.23) 0.166

leukocytes, median (range) 8.5 (4.015.5) 8.0 (4.013.2) 8.7 (4.114.1) 8.3 (4.015.5) 0.433

Neutrophils, median (range) 4.0 (1.956.5) 4.0 (1.956.4) 4.3 (2.06.5) 4.1 (2.0 6.4) 0.526

Clinical tumor size, n 0.418

TB 50 mm 174 91 65 18

T[ 50 mm 151 68 64 19

Clinical nodal status, n 0.143

N0 180 80 76 24

N13 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 6IIIII 196 88 81 27

Surgical 0.518

Modified radical mastectomy 296 141 129 26

Breast conservation 39 18 13 8

BSA body surface area; Units age (years), BSA (m2), leukocytes (9 109/l), neutrophils (9 109/l), treatment duration (days)

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6

cycle

number

ofpatients

Fig. 2 The timing of occurrence of neutropenia with worst grade in

176 patients during six cycles of CEF


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Discussion

Patients receiving adjuvant chemotherapy may experience

varying levels of toxicity. It is well known that neutropenia

is one of the most important dose-limiting toxicities

and often the reason for dose reduction. In this study, we

found significantly improved survival in patients who

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

[1316]. 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 impacton 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

had better outcome than those who did not in both post-

operative and neoadjuvant chemotherapies of breast cancer

[811, 18]. In all these studies, the hematologic toxic

effects analyzed with neutropenia or leukocyte nadir had asignificant effect on survival.

The prognostic role of chemotherapy-induced neutro-

penia also has been investigated in other diseases.

Recently, Di Maio et al. [5] analyzed the pooled data from

three randomized trials of 1265 patients in advanced non-

small-cell lung cancer. They concluded that both mild

Fig. 3 KaplanMeier survival curves according to the three groups of

worst grade neutropenia that occurred during six cycles of CEF

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

Neutropeniaa

Mild vs. 0 0.424 (0.2800.642) \0.001 0.434 (0.2980.634) \0.001

Severe vs. 0 0.579 (0.4150.807) 0.001 0.640 (0.420.975) 0.038

Age

\50 y vs. C 50 y 0.846 (0.5411.322) 0.463

BSA

[1.50 m2 vs. B 1.50 m2 0.660 (0.4191.039) 0.072

Clinical tumor size, n

T B 50 mm vs. T[50 mm 1.981 (1.3652.875) \0.001 1.762 (1.1182.777) 0.015

Clinical nodal status, n

N0 vs. N13 2.614 (1.6294.193) \0.001 1.92 (1.0983.383) 0.022

ER, n

Positive vs. negative 0.609 (0.3880.955) 0.031 0.601 (0.370.978) 0.04

PR, n

Positive vs. negative 0.657 (0.4201.028) 0.066

HER-2, n

Positive vs. negative 1.730 (1.3762.175) \0.001 1.377 (1.0671.777) 0.014

Histological grade

IvsIIIII 1.946 (1.1123.404) 0.02 1.964 (1.0983.513) 0.023

BSA body surface area, Neutropeniaa is treated as a time-dependent variable

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(grade 12) and severe (grade 34) neutropenia might be a

surrogate marker of an adequate chemotherapy dose and

that lack of neutropenia indicates underdosing. Other arti-

cles reported that chemotherapy-induced neutropenia dur-

ing treatment is associated with a higher probability of

treatment response and better survival in colon and gastric

cancer patients [6, 7, 19]. These findings prompted us to

perform a rigorous quantification of the prognostic value of

chemotherapy-induced neutropenia with respect to survival

outcomes in patients with early-stage breast cancer.

The availability of active antitumor drug at tumor cells

is affected by pharmacokinetic factors, including drug

metabolism or elimination which produces a similar effect

in healthy cells. The sensitivity of tumor cells and healthy

cells is affected, partly, myelosuppression might represent

an index of bodily drug exposure. Several prospective

randomized studies [2022] have investigated the dose

response relationship in breast carcinoma to assess the

preference for higher doses than those guided by the body

surface area (BSA) criteria. However, the BSA-based

dosing system is not appropriate, then the optimal dose of

chemotherapy for individual patients is relatively unrelated

to whether the dose is high or low in terms of the BSA-

based one [23]. Several previous reports suggest that the

optimal dose defined by an estimated body surface area

may be insufficient in some cases. A poor correlation

between body surface area and the pharmacokinetics of

most cytotoxic agents have been pointed out [2429]. 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 tailoredregimen 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 ofpatients 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-

tropenia may actually be a sign of an inadequate dose of

chemotherapy [17]. The cause of this interpatient variation

is unclear. Patients show quite different concentration time

properties for levels of drug in tissue after the adminis-

tration of a uniform dose. The explanation might be related

to genetic predisposition and a large inter-individual

variation of systemic exposure [3436].

However, chemotherapy dose reductions and dose

delays, as a result of chemotherapy-induced neutropenia,

can lead to reduce patient survival [3739]. In our study,

between the subgroups of patients with and without neu-

tropenia, the RDI and the dose delays did not significantly

differ. Therefore, the better prognosis of patients with

neutropenia was not due to a dose reductions and dose

delays in patients with neutropenia. Neutropenia might be

associated with prognosis as a consequence of selection

bias. Patients with occult problems due to disease might be

more prone to toxicity and early failures may receive lower

doses because of treatment discontinuation. Since neutro-

penia does not exist before the initiation of chemotherapy,

patients surviving longer had a greater chance to receive

additional cycles. Therefore, a higher incidence of neu-

tropenia was expected as the number of cycles of chemo-

therapy increased. To avoid the bias, we restrict the

primary analysis to patients who had completed six

cycles of treatment and who survived after 180 days of

treatment [5].

We further evaluated the impact of neutropenia during

the first four cycles of CEF on survival and found that 76%

Fig. 4 Hazard ratios for death and 95% CI. In subgroup analyses,

both mild and severe neutropenia tended to be associated with

improved prognosis in almost all subgroup


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