The Breast 56 (2021) 70e77

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The Breast
journal homepage: www.elsevier.com/brst

Original article

Prospective cohort study of febrile neutropenia in breast cancer
patients administered with neoadjuvant and adjuvant
chemotherapies: CSPOR-BC FN study
Takashi Ishikawa a, *, Kentaro Sakamaki b, Kazutaka Narui c, Hideki Nishimura d,
Takafumi Sangai e, Kentaro Tamaki f, Yoshie Hasegawa g, Ken-ichi Watanabe h,Nobuyasu Suganuma i, Shintaro Michishita j, Sadatoshi Sugae k, Tomohiko Aihara l,
Koichiro Tsugawa m, Hirose Kaise a, Naruto Taira n, Hirofumi Mukai o, for Comprehensive
Support Project for Oncological Research of Breast CanceraDepartment of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
Department of Biostatistics, Yokohama City University, Yokohama, Japan
Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japand
Department of Breast Surgery, Nagano Municipal Hospital, Nagano, Japane
Department of Breast and Thyroid Surgery, Chiba University, Chiba, Japanf
Naha-Nishi Clinic, Okinawa, Japang
Department of Breast Surgery, Hirosaki Municipal Hospital, Aomori, Japanh
Department of Breast Surgery, Hokkaido Cancer Center, Hokkaido, Japani
Department of Breast and Thyroid Surgery, Kanagawa Cancer Center, Kanagawa, Japanj
Department of Breast Surgery, Yao Municipal Hospital, Osaka, Japank
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japanl
Breast Center, Aihara Hospital, Osaka, Japanm
Department of Breast and Thyroid Surgery, St. Marianna University, Kawasaki, Japann
Department of Breast and Endocrinology Surgery, Okayama University Graduate School of Medicine, Okayama, JapanoDivision of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japanbca r t i c l e i n f o

a b s t r a c t

Article history:
Received 13 October 2020
Received in revised form
14 January 2021
Accepted 27 January 2021
Available online 16 February 2021

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of
FN incidence and risk factors in Asians are important for the appropriate use of primary pegﬁlgrastim(PEG-G).
Patients and methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were
prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2
treatment policies: true FN (T-FN): 37.5  C, grade 4 neutropenia, mandatory hospital visit (visiting);surrogate FN (S-FN): 37.5  C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at thephysicians’ discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic
regression analysis was performed to identify T-FN risk factors.
Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN
incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively.
Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more
frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was 0.85 in bothgroups. In the analysis of risk factors, TC (odds ratio ¼ 2.67), age  65 years (2.24), and pretreatment
absolute neutrophil count (ANC)/1000 ml (0.8) remained signiﬁcant.

Keywords:
Breast cancer
Febrile neutropenia
Adjuvant chemotherapy
Risk factors
Prospective study* Corresponding author. Department of Breast Surgery and Oncology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
E-mail address: tishik@tokyo-med.ac.jp (T. Ishikawa).
https://doi.org/10.1016/j.breast.2021.01.005
0960-9776/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

T. Ishikawa, K. Sakamaki, K. Narui et al.

The Breast 56 (2021) 70e77

Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was
maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age
and pretreatment ANC.
© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

blood tests at the time the nadir is expected. With the current
empirical prescription of oral antibiotics, it is practically important
to know whether this method is safe in the short and long terms,
and in terms of excessive use of antibiotics for prophylaxis.
These backgrounds indicate the importance of evaluating FN in
breast cancer patients in Asian countries. The purpose of this cohort
study is to evaluate the incidences and risk factors of FN in Japanese
breast cancer patients who received 3 mainstream adjuvant regimens according to 2 treatment policies for FN.

1. Introduction
Febrile neutropenia (FN) is a major hematologic side effectassociated with chemotherapy, and results in dose reduction anddelayed treatment [1]. Both conditions are directly linked to a
reduction in relative dose intensity (RDI), which impedes cure ofpatients with early breast cancer [2,3]. In addition, FN is a potentially life-threatening toxicity similarly to sepsis, and may require
emergency admission and hospitalization [4,5]. For patients with ahigh risk of FN, primary pegﬁlgrastim (PEG-G) prophylaxis is recommended in clinical practice guidelines [6e8]. A meta-analysis
showed that primary PEG-G support improved the overall survival of breast cancer patients with FN undergoing intensiﬁed
chemotherapy [9]. However, primary PEG-G is associated with ahigher risk for secondary malignancies in solid tumor or malignant
lymphoma treatment [9]. The toxicities and also costs associatedwith PEG-G deserve a careful and systematic study. Therefore,
identifying the risk factors and predictors of FN is clinicallyimportant to determine the appropriate indication of primary PEGG.
The incidence of FN is associated with the myelosuppressive
effect of chemotherapy regimens and individual patient risk factors. Regimens are categorized into 3 groups according to the risk of
FN. Primary PEG-G is recommended for patients when using highrisk regimens with an FN incidence of >20%, whereas primary PEGG is required for patients with risk factors for moderate-risk regimens with an FN incidence of 10%e20% [6e8].
As for patient-related risk factors of FN, advanced age (>65
years) is listed in all guidelines [6e8]. Except for age, slightly
different factors appear in various guidelines. Advanced disease,previous chemotherapy or radiation therapy, pre-existing neutropenia, bone marrow involvement with the tumor, infection,
open wounds, poor performance or nutritional status, poor renal
function, liver dysfunction, and multiple comorbid conditions arelisted as risk factors of FN [6e8].
Ethnic origin may be related to the incidence of FN, with Asians
reported to be more vulnerable to FN than Caucasians [10e13]. In a
study comparing hematologic toxicity during neoadjuvant andadjuvant FEC treatments in breast cancer patients of 4 races, Asians
had a signiﬁcantly higher rate of grade 3 hematologic toxicity than
Caucasians, African-Americans, and Hispanics [12]. This ethnic
difference is partly due to differences in physical constitutions, suchas the activity of metabolic enzymes [12]. Another possible reason
is that calculation of the therapeutic dose practically tends to be
based on the ideal weight and not on the actual weight in obese
patients, who are less common in Asians [14]. However, only a few
studies have examined the incidences and risk factors of FN in
Asian patients with breast cancer [12,13]. Examination of theseincidences and risk factors may help clarify the indication of primary PEG-G based on race.
For the prevention or early treatment of FN, prophylactic ortherapeutic oral antibiotic administration is an alternative to primary PEG-G prophylaxis. In daily clinical practice, some physiciansprescribe antibiotics and instruct patients to take these drugs ifthey have a fever, instead of using primary PEG-G or performing

2. Patients and methods
2.1. Study design
A multicenter, prospective observational study was performedin female patients who were diagnosed with clinical stages I to III
breast ductal or lobular carcinoma and were scheduled for adjuvant
or neoadjuvant chemotherapy using the following 6 regimens [15]:(1) 4 cycles of 5-ﬂuorouracil 500 mg/m2 þ epirubicin 100 mg/
m2 þ cyclophosphamide 500 mg/m2 (FEC), (2) 4 cycles of epirubicin
90 mg/m2 (doxorubicin 60 mg/m2) þ cyclophosphamide 600 mg/
m2 (E(A)C), (3) 4 cycles of docetaxel 60e100 mg/m2 (DOC), (4) 6cycles of docetaxel 75 mg/m2 þ doxorubicin 50 mg/
m2 þ cyclophosphamide 500 mg/m2 (TAC), (5) 4 cycles of docetaxel
75 mg/m2 þ cyclophosphamide 600 mg/m2 (TC), and (6) 6 cycles of
docetaxel 75 mg/m2 þ carboplatin AUC6 þ trastuzumab 8 mg/kg(TCbH). There was no provision regarding the administration of
PEG-G, and it was used at the discretion of physicians. Early
monitoring after the study initiation showed that only few patients
received the TAC, TCbH, and DOC regimens, and identifying theincidence of FN for these regimens would be difﬁcult. Therefore, theprotocol was revised in July 2016 to limit the regimens that would
be evaluated to FEC, E(A)C, and TC.
Patients were consecutively enrolled from August 2015 to July
2017 from 44 institutions. The number of patients varied from 1 to
98 in various institutions. Written informed consent was obtained
from all patients. The study was approved by the protocol review
committee of the Comprehensive Support Project for OncologicalResearch of Breast Cancer on February 10, 2015 and by the institutional review board of Tokyo Medical University on April 28, 2015
(No. 3044). This trial was registered at the UMIN Clinical Trials
Registry as UMIN 000017857.

2.2. Baseline assessment
After enrollment, the following information was collected asbaseline data: date of birth; site of breast cancer (left or right);
pathological stage; status of lymph node metastasis; expression
status of estrogen receptor (ER), progesterone receptor (PgR) andhuman epidermal growth factor receptor type 2 (HER2); nuclear
grade; histological grade; performance status (PS); previous treatment for breast cancer (endocrine, radiation and surgical treatments); comorbidity (renal disorder, liver disorder, neutropenia
before treatment); and height and weight.
71

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The Breast 56 (2021) 70e77

summarized by proportions and were compared between thevisiting and non-visiting groups in each regimen. RDI was calculated as the number and proportion of patients in which 85% ormore of the standard dose could be administered. The data show
the proportion of cases with an RDI of 85% or higher for each cycleand for all cycles. Grade 4 neutropenia was summarized only in thevisiting group.
To evaluate the risk factors of FN, we predeﬁned regimens, age,PS, stage, history of chemotherapy or radiotherapy, infectious
wounds, open wounds, ANC, and renal and liver dysfunctions as
possible risk factors using the following categorization: age: < 65vs  65 years; PS: 0 vs  1; stage: I or II vs III; prior chemotherapy:
positive vs negative; radiotherapy: positive vs negative; infectious
wound: positive vs negative; open wound: positive vs negative;
ANC: < 1500 vs  1500/ml; renal dysfunction: Cr < 1.5 vs  1.5; andliver dysfunction: AST/ALT or total bilirubin >3 or 1.5 times theinstitutional normal range. Risk factors were evaluated in thevisiting group. Multiple logistic regression analysis was used toassess the risk factors of T-FN, and the odds ratio (OR) and 95%
conﬁdence interval (CI) were calculated using T-FN in the visiting
group as the outcome measure.
The target sample size was calculated based on interval estimation, as described in detail previously [15]. From the clinicalperspective, the admissible 95% CIs were the estimated incidence
proportion ±5%. If the true incidence proportion is 10% or 20%, therequired number of cases was 165 or 264 to achieve an admissible
95% CI. In this sample size calculation, the incidence proportions in
all the enrolled patients were considered based on the speculationthat these incidence proportions were similar between the visiting
and non-visiting groups. Considering that the number of patients
who use TAC, TCbH, and DOC is not very large, we set the target
sample size to 1000 for the 6 regimens. Initially, 200 patients wereplanned for the 3 major regimens of E(A)C, FEC, TC and DOC toachieve 95% CI. For TAC and TCbH, 50 patients were planned forthese regimens in consideration of feasibility rather than 95% CI.
However, early monitoring after the study initiation showed that
only few patients received these regimens, and identifying theincidence of FN for these regimens would be difﬁcult. Thus, theprotocol was revised in July 2016 to limit the regimens to beevaluated to FEC, E(A)C, and TC with 330 cases each.

2.3. Data collection during treatment
The following items were investigated on day 1 of each treatment cycle: PS; type and dose of chemotherapeutic agent; and dateof administration. Body temperature, laboratory values (whiteblood cell count, neutrophil count), and adverse event (AE)s were
investigated at regular visits (or on admission) for chemotherapy
and at unscheduled visits for fever and AEs. Information on theadministration of primary PEG-G or therapeutic granulocytecolony-stimulating factor (G-CSF) and antibiotics was investigatedin each treatment cycle.
2.4. Patient diary
During the chemotherapy period, patients measured their bodytemperature in the morning and evening, and when they felt afever, and recorded the data in a diary.
2.5. Evaluation and deﬁnition of FN
Preliminary survey prior to this study revealed that each institution had different policies for responding to a fever in patients
undergoing chemotherapy. These policies were broadly divided
into 2 types. Some facilities instructed patients to visit the hospitalif they developed a fever and to undergo a blood test for FN diagnosis. Other facilities asked patients to immediately take a prespeciﬁed antibiotic if they developed a fever during chemotherapy without visiting the hospital, and only to visit if their fever
persisted.
The present study used an observational design based on dailyclinical practice. Thus, if patients developed an axillary temperature37.5  C, 2 procedures were used to manage the fever: (1) undergoa hematologic test with a hospital visit (visiting group) or (2) take aprescribed oral antibiotic without a hospital visit (non-visiting
group).
We deﬁned FN in 2 ways in accordance with the abovementioned procedures (visiting and non-visiting groups) for
managing fever during chemotherapy, namely, True-FN (T-FN) andSurrogate-FN (S-FN). T-FN was deﬁned as an axillary temperature37.5  C and an absolute neutrophil count (ANC) of <500/ml(visiting group). S-FN was deﬁned as an axillary temperature37.5  C and oral antibiotic/antipyretic intake according to the
instructions of each hospital (non-visiting group). Each facility was
required to clarify which policy was used to manage FN at the timeof the study.

3. Results
From August 2015 to July 2017, a total of 1005 patients withstages I to III breast cancer were consecutively enrolled in thepresent study. Of these 1005 patients, 489 patients were registeredin the visiting group. Among these 489 patients, 11 were excluded
because of chemotherapy interruption and 1 was excluded owing
to being lost to follow-up. The reasons for chemotherapy interruption in the 11 patients were refusal of study enrollment in 4
patients, refusal of chemotherapy in 2 patients, change of hospitalin 3 patients, change of treatment regimen in 1 patient, anddetection of metastatic disease in 1 patient. A total of 516 patientswere registered in the non-visiting group. Among these 516 patients, 3 were excluded because of consent withdrawal and 10 were
excluded owing to being lost to follow-up. Finally, 980 patients,
namely, 477 (48.7%) in the visiting group and 503 (51.3%) in the
non-visiting group, were analyzed in the present study (Fig. 1).
The patient demographics and background factors of the regimens are shown in Table 1. The chemotherapy regimens administered in the visiting and non-visiting groups were FEC in 170 (36%)
and 168 (33%), E(A)C in 165 (35%) and 170 (34%), and TC in 142(30%) and 165 (33%), respectively. The TC regimen was mainly used
for patients with earlier stages and ER-positive disease at the
adjuvant treatment setting in contrast to the FEC and E(A)C

2.6. Endpoints
The primary endpoint was the incidence of FN for the whole 4cycles of treatment. The patient was used as an analysis unit. The
secondary endpoints were (1) FN incidence in the 1st cycle, (2)grade 4 neutropenia, (3) hospitalization, (4) use of therapeutic GCSF, (5) use of therapeutic antibiotics, (6) AEs due to FN, (7) RDI, and(8) serious AEs.
2.7. Statistical analysis
In the analysis of the primary endpoint, the incidence proportions of FN for each regimen were estimated. To evaluate thedifference between the 2 treatment policies, we calculated 3 typesof proportions: (1) number of T-FN and S-FN cases/total number ofpatients in the entire population, (2) number of T-FN cases/numberof patients in the visiting group, and (3) number of S-FN cases/
number of patients in the non-visiting group.
In the analyses of the secondary endpoints, the endpoints were72

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The Breast 56 (2021) 70e77

Fig. 1. Flow diagram of patient enrollment and selection. In this study, 1005 patients with stages I to III breast cancer were consecutively enrolled from August 2015 to July 2017. Of
these 1005 patients, 489 patients were registered in the visiting group. Among these 489 patients, 11 were excluded because of chemotherapy interruption and 1 was excluded
owing to being lost to follow-up. A total of 516 patients were registered in the non-visiting group. Among these 516 patients, 3 were excluded because of consent withdrawal and 10
were excluded owing to being lost to follow-up. Finally, 980 patients, namely, 477 (48.7%) in the visiting group and 503 (51.3%) in the non-visiting group, were analyzed in thepresent study.

regimens. The FEC regimen tended to be given to younger patientsat the neoadjuvant treatment setting. The proportion of primary
PEG-G was higher in the patients receiving the TC regimen than in
the patients receiving the FEC or E(A)C regimen, and in the nonvisiting group than in the visiting group (Table 1, Fig. 2, andSupplementary Table 1). Very few patients had a history of radiation therapy, current wound infections, open wounds, renal
dysfunction, and hepatic dysfunction, which were possible risk
factors of FN.

found more frequently in the visiting group than in the non-visiting
group (30.1% vs 16.5% in FEC, 42.0% vs 29.2% in TC). Therapeutic
antibiotics were used for these regimens more often in the visiting
group (46.1% vs 37.6% in FEC, 56.9% vs 46.2% in TC). In addition, therate of therapeutic G-CSF usage was higher in the visiting group in
all the 3 regimens. FN-related severe AEs were rarely found at only
0.2% for stomatitis and 0.1% for sore throat. In all the 3 regimens, thepercentage of cases with an RDI 0.85 was high at approximately
90% in both groups.

3.1. Incidence of febrile neutropenia

3.3. Risk factors

The estimated incidence proportions and 95% CIs of FN during 4cycles of treatment were 22.5% (18.1%e27.3%) for FEC, 27.5%(22.8%e32.6%) for E(A)C, and 33.9% (28.6%e39.5%) for TC in theentire study population; 27.7% (21.1%e35.0%) for FEC, 22.4%(16.3%e29.6%) for E(A)C, and 36.6% (28.7%e45.1%) for TC in thevisiting group; and 17.3% (11.8%e23.8%) for FEC, 32.4% (25.4%e39.9%) for E(A)C, and 31.5% (24.5%e39.2%) for TC in the non-visiting
group (Table 2). These results did not consider whether PEG-G was
administered.
The incidence proportion of T-FN was approximately 10% higher
than that of S-FN with the FEC regimen, whereas that of S-FN was
approximately 10% higher with the E(A)C regimen, with noconsistent trend. The proportions of FN incidence and PEG-G during each treatment cycle are shown in Fig. 2 and Supplementary
Table 1. The Incidence proportion of FN in the 1st cycle was thehighest at approximately 20%, and decreased to 3%e8% after thesecond cycle. The proportion of primary PEG-G in the 1st cycle washigher in the non-visiting group at 20%e30%, with the highest at
52% for the TC regimen. The PEG-G rate was gradually increased
after the 2nd cycle in the visiting group.

Risk factors were evaluated in the visiting group. In the logistic
regression analysis, we reconsidered which possible risk factors
were used because few patients had a low PS, prior chemotherapy,
radiation therapy, infected wounds, open wounds, renal dysfunction, and hepatic dysfunction. We used regimen (FEC vs E(A)C vsTC), age (<65 vs  65), ANC, stage (I vs II vs III), treatment setting(adjuvant vs neoadjuvant), primary PEG-G administration (yes vsno) in the logistic regression models for exploratory evaluation ofrisk factors. As the ANC of most patients was >1500/ml, ANC wasused as a continuous variable. Risk factors were evaluated in thevisiting group, with T-FN used for event data.
Logistic regression analysis revealed that the TC regimen(OR ¼ 2.62, 95% CI: 1.34e5.12), age  65 (OR ¼ 2.24, 95% CI:
1.34e3.75), and ANC/1000 ml (OR ¼ 0.8, 95% CI: 0.67e0.95) weresigniﬁcant risk factors of FN. Adjuvant treatment setting (OR ¼ 0.51,
95% CI: 0.29e0.88) and primary PEG-G administration (OR ¼ 0.04,
95% CI: 0.01e0.34) were signiﬁcant protective factors against FN(Table 4).
To search for risk factors as a decision tool for PEG-G usage,
another multivariate analysis was conducted in the patients
without PEG-G at the 1st cycle (Supplementary Table 3). The results
were not signiﬁcantly different from those shown in Table 4.

3.2. Secondary endpoints
The results of the analysis of the secondary endpoints are
summarized in Table 3. Hospitalization occurred most often in the
E(A)C regimen in the visiting group at 10.6%. Grade 3 or 4 AEs were

4. Discussion
This study set out to evaluate the incidences and risk factors of73

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Table 1
Patient demographics and background factors of regimens.
FEC

E(A)C

TC

All patients(N ¼ 338)

Visiting(N ¼ 170)

Non-visiting(N ¼ 168)

All patients(N ¼ 335)

Visiting(N ¼ 165

Non-visiting(N ¼ 170)

All patients(N ¼ 307)

Visiting(N ¼ 142)

Non-visiting(N ¼ 165)

Age; YearsMedian(range)<6550.5 (22e78)

50 (25e78)

52 (22e74)

54 (27e77)

55 (27e76)

53 (30e77)

53 (30e80)

52 (30e80)

53 (31e76)292 (86.4%)

150 (88.2%)

142 (84.5%)

251 (74.9%)

120 (72.7%)

131 (77.1%)

236 (76.9%)

111 (78.2%)

125 (75.8%)

65

46 (13.6%)

20 (11.8%)

26 (15.5%)

84 (25.1%)

45 (27.3%)

39 (22.9%)

71 (23.1%)

31 (21.8%)

40 (24.2%)

ECOG PS0337 (99.7%)

169 (99.4%)

168 (100%)

334 (99.7%)

164 (99.4%)

170 (100%)

305 (99.3%)

142 (100%)

163 (98.8%)

1

1 (0.3%)1 (0.6%)0 (0%)

1 (0.3%)1 (0.6%)0 (0%)

2 (0.7%)0 (0%)

2 (1.2%)

StageI

35 (10.4%)

10 (5.9%)25 (14.9%)

82 (24.5%)

47 (28.5%)

35 (20.6%)

115 (37.5%)

46 (32.4%)

69 (41.8%)

IIA

99 (29.3%)

51 (30%)48 (28.6%)

97 (29.0%)

48 (29.1%)

49 (28.8%)

116 (37.8%)

57 (40.1%)

59 (35.8%)

IIB

106 (31.4%)

55 (32.4%)

51 (30.4%)

80 (23.8%)

36 (21.8%)

44 (25.9%)

64 (20.8%)32 (22.5%)

32 (19.4%)

IIIA

41 (12.1%)

24 (14.1%)

17 (10.1%)

39 (11.6%)

19 (11.5%)

20 (11.8%)

7 (2.3%)4 (2.8%)3 (1.8%)IIIB

21 (6.2%)

7 (4.1%)14 (8.3%)

15 (4.5%)

10 (6.1%)

5 (2.9%)5 (1.6%)3 (2.1%)2 (1.2%)

IIIC

36 (10.6%)

23 (13.5%)

13 (7.7%)

22 (6.6%)5 (3.0%)17 (10.0%)

0 (0%)

0 (0%)

0 (0%)

Status of estrogen receptor
Positive
204 (60.4%)

112 (65.9%)

92 (54.8%)

207 (61.8%)102 (61.8%)

105 (61.8%)251 (81.8%)

123 (86.6%)

128 (77.6%)

Negative

134 (39.6%)

58 (34.1%)

76 (45.2%)

128 (38.2%)

63 (38.2%)

65 (38.2%)

56 (18.2%)

19 (13.4%)

37 (22.4%)

Status of HER20、1þ166 (49.1%)

84 (49.4%)

82 (48.8%)

162 (48.4%)

66 (40.0%)

96 (56.5%)

199 (64.8%)

104 (73.2%)

95 (57.6%)

2þ/FISH()42 (12.4%)

20 (11.8%)

22 (13.1%)

44 (13.1%)

28 (17.0%)

16 (9.4%)

48 (15.6%)

20 (14.1%)

28 (17.0%)

3þ/FISH()129 (38.2%)

66 (38.8%)

63 (37.5%)

128 (38.2%)

71 (43.0%)

57 (33.5%)

60 (19.5%)

18 (12.7%)

42 (25.4%)

Unknown

1 (0.3%)0 (0%)

1 (0.6%)

1 (0.3%)0 (0%)

1 (0.6%)0 (0%)

0 (0%)

0 (0%)

Treatment setting
Neoadjuvant 237 (70.1%)

122 (71.8%)

115 (68.5%)

145 (43.3%)

83 (50.3%)

62 (46.5%)

24 (7.8%)

6 (4.2%)18 (10.9%)

Adjuvant

48 (28.2%)

53 (31.5%)

190 (56.7%)

82 (49.7%)

108 (63.5%)283 (92.2%)

136 (95.8%)

147 (89.1%)

Use of PEG-G for 1st cycle
Yes
73 (21.6%)

8 (4.7%)65 (38.7%)

23 (6.9%)

3 (1.8%)20 (11.8%)

106 (34.5%)

20 (14.1%)

86 (52.1%)

No

162 (95.3%)

103 (61.3%)

312 (93.1%)

162 (98.2%)

150 (88.2%)

201 (65.5%)

122 (85.9%)

79 (47.9%)3047.5 (1364e7740)

3198 (638e9314)

3030 (1092e6578)

3322 (638e9314)

3485 (1023e19,890)3261 (1453
e19,890)3570 (1023e18,110)101 (29.9%)

265 (78.4%)

Absolute neutropenia countMedian3126.5 (1360
3311 (1360(range)e8215)
e8215)

FEC, ﬂuorouracil þ epirubicin þ cyclophosphamide.
E(A)C, epirubicin (doxorubicin) þ cyclophosphamide.
TC, docetaxel þ cyclophosphamide.
FISH, Fluorescence in situ hybridization.

low patient rates particularly for the latter (Table 2, Supplementary
Table 1). Although the patient characteristics were different in the 3
regimens (Table 1), it is clear that TC is the regimen that mostfrequently induces the development of FN. In all the regimens, theFN proportions decreased at the 2nd cycle with the increasing usage of PEG-G (Fig. 2) or antibiotics (data not shown) in the secondand subsequent cycles, which is deﬁned as secondary prophylaxis
in response to the low neutrophil counts or FN-related events
observed in the ﬁrst cycle. In previous reports in which FN without
primary PEG-G at the 1st cycle was investigated in Caucasian

FN in breast cancer patients who received 3 adjuvant regimens
according to 2 treatment policies for FN. To our knowledge, this is
the ﬁrst prospective study directly comparing FN incidences between 3 mainstream regimens. The FN proportions of these 3
regimens were above 20%. The FN proportion of TC could be higher
than 40% because the T-FN proportion of TC was 36.6% when primary PEG-G was used at the 1st cycle in 14.1% of the patients(Table 2, Supplementary Table 1). The T-FN proportions of FEC andE(A)C were 27.7% and 22.4% when primary PEG-G was respectively
used at the 1st cycle in 4.7% and 1.8% of the patients, which are very74

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Fig. 2. Proportions of FN incidence and primary PEG-G during each treatment cycle. In all the regimens, the FN proportions (solid lines) were the highest in the 1st cycle anddecreased after the second cycle in response to the increasing usage of primary PEG-G (dotted lines). The proportions of primary PEG-G (dotted lines) were higher in the nonvisiting group (triangles) than in the visiting group (circles) in the FEC and TC regimens, with the highest at more than 50% in the non-visiting group for the TC regimen.

Table 2
Incidence proportions of FN during all courses of chemotherapy.
All patients

T-FN(Visiting Group)

S-FN(Non-Visiting Group)N

Proportion (95%Cl)N

Proportion (95%Cl)N

Proportion (95%Cl)

FEC

338

22.5% (18.1%e27.3%)

170

27.7% (21.1%e35.0%)

168

17.3% (11.8%e23.8%)

E(A)C

335

27.5% (22.8%e32.6%)

165

22.4% (16.3%e29.6%)

170

32.4% (25.4%e39.9%)

TC

307

33.9% (28.6%e39.5%)142

36.6% (28.7%e45.1%)

165

31.5% (24.5%e39.2%)
F

FEC, ﬂuorouracil þ epirubicin þ cyclophosphamide.
E(A)C, epirubicin (doxorubicin) þ cyclophosphamide.
TC, docetaxel þ cyclophosphamide.

Table 3Results of analysis of secondary endpoints.
FEC
All patients

E(A)C
Visiting

FN incidence in the ﬁrst course
62 (18.3%)
42 (24.7%)
Grade 4 neutropeniaー
46 (27.1%)
Hospitalization
21 (6.5%)
12 (7.3%)
Use of therapeutic G-CSF (all cycles)
52 (16.2%)
43 (26.2%)
Use of therapeutic antibiotics (all cycles) 135 (41.9%) 76 (46.1%)
Grade 3 or 4 adverse events76 (23.5%)
50 (30.1%)
FN-related adverse events (grade 3 or above, all cycles)
Stomatitis
0 (0%)
0 (0%)
sore throat
0 (0%)
0 (0%)aRelative dose intensity
307 (90.8%) 155 (91.2%)
RDI (0.85)
1st cycle
337 (99.7%) 170 (100%)
2nd cycle
326 (98.2%) 165 (98.8%)
3rd cycle
317 (97.5%) 159 (98.2%)
4th cycle
309 (96.9%) 157 (97.5%)

TC

Non-visiting

All patients

Visiting

Non-visiting

All patients

Visiting

Non-visiting

20 (11.9%)ー
9 (5.7%)9 (5.7%)59 (37.6%)
26 (16.5%)

64 (19.1%)ー
24 (7.4%)
55 (16.9%)
143 (44.0%)
82 (24.9%)

27 (16.4%)
42 (25.5%)
17 (10.6%)
42 (26.3%)
60 (37.7%)
39 (24.4%)

37 (21.8%)ー
7 (4.2%)13 (7.8%)
83 (50.0%)43 (25.4%)

66 (21.5%)ー
22 (7.7%)
62 (21.5%)
150 (51.2%)
103 (35.3%)

36 (25.4%)
30 (21.1%)
11 (8.2%)
49 (35.3%)
78 (56.9%)
58 (42.0%)30 (18.2%)ー
11 (7.2%)
13 (8.7%)
72 (46.2%)
45 (29.2%)

0 (0%)
0 (0%)
152 (90.5%)

0 (0%)
1 (0.3%)311 (92.8%)

0 (0%)
1 (0.61%)150 (90.9%)

0 (0%)
0 (0%)
161 (94.7%)

2 (0.65%)
0 (0%)
272 (88.9%)

2 (1.41%)0 (0%)
129 (90.9%)

0 (0%)
0 (0%)
143 (87.2%)

167 (99.4%)
161 (97.6%)
158 (96.9%)
152 (96.2%)

332 (99.1%)
321 (97.0%)
312 (95.1%)
305 (93.9%)

162 (98.2%)
154 (94.5%)
150 (93.2%)
145 (90.6%)

170 (100%)
167 (99.4%)
162 (97.0%)
160 (97.0%)

305 (99.7%)
291 (98.3%)
281 (96.9%)273 (97.2%)

142 (100%)
134 (97.1%)
130 (96.3%)
129 (96.3%)

163 (99.4%)
157 (99.4%)
151 (97.4%)
144 (98.0%)

FEC, ﬂuorouracil þ epirubicin þ cyclophosphamide E(A)C, epirubicin (doxorubicin) þ cyclophosphamide TC, docetaxel þ cyclophosphamide.
G-CSF, granulocyte colony-stimulating factor RDI, relative dose intensity.
a
For all 4 courses  0.85.

generally well managed with a few severe events, low rates of
hospitalization, and no fatal cases. It is not reasonable to compare
these FN-related events between the non-visiting and visiting
groups because of many differences in their baseline characteristics. However, grade 3 or 4 AEs and hospitalization more frequently

countries, the FN proportions in E(A)C ranged from 5.4% to 10.0%[16e21]. The comparison of these with 22.4% in E(A)C of this study
revealed that an ethnic difference may exist and that the Japanese
population may be vulnerable to FN.
In the analysis of secondary endpoints, FN-related events were75

T. Ishikawa, K. Sakamaki, K. Narui et al.

The Breast 56 (2021) 70e77

No regulation was established for antibiotic usage. These might
have underestimated the FN frequency in the visiting group. Second, the neoadjuvant setting remained as one of the risk factors of
FN. It may be unreasonable to make a comparison between neoadjuvant chemotherapy and adjuvant chemotherapy because thesesettings were diametrically related with the patient characteristics
and regimens. The relationship of the neoadjuvant setting with FN
may be biased owing to multicollinearity in the multivariate analysis. Third, the managements of FN in the visiting and non-visiting
groups were dependent on the institutions, which may result indifferent characteristics between these 2 groups.

Table 4Multivariate analysis for exploring the risk factors of FN.

RegimenAge
Neutrophils (continuous)Stage

Treatment setting
Primary PEG-G

Parameter

Odds ratio

95% CIp -value

TC
E(A)C
FEC
>65
/1000 mLIII
II
I
Adjuvant
Neoadjuvant
Yes
No

2.67
0.66

1.36e5.26
0.38e1.14
ref1.34e3.75
0.67e0.95
0.48e1.99
0.47e1.44
ref0.29e0.88
ref0.01e0.34
ref

0.005
0.137

2.24
0.8
0.98
0.82
0.51
0.04

0.002
0.012
0.961
0.492
0.017
0.003

5. Conclusion

FEC, ﬂuorouracil þ epirubicin þ cyclophosphamide.
E(A)C, epirubicin (doxorubicin) þ cyclophosphamide.
TC, docetaxel þ cyclophosphamide.
PEG-G, pegﬁlgrastim.

The FN proportions in the FEC, E(A)C, and TC regimens wereabove 20%, with the TC regimen showing the highest proportion.
However, regarding the present status, the RDI was maintained at ahigh level and FN-related events were all well managed in both thevisiting and non-visiting groups. Thus, it remains clinically meaningful to select patients with a high risk of FN with the adequate useof primary PEG-G. Age and pretreatment ANC were found to bepatient-related risk factors of FN development. The thresholds ofthese 2 factors, which might be different from the current guidelines, warrant further investigation.

occurred in the visiting group than in the non-visiting group.
Possibly related to these increased events, therapeutic G-CSF andantibiotics were used more frequently in the visiting group(Table 3). These trends were preserved in limited cases with primary PEG-G not used at the 1st cycle (data not shown). Importantly,
the RDIs in all the 3 regimens were maintained at sufﬁciently highlevels in both groups (Table 3).
As for FN risk factors, we analyzed the entire cohort with PEG-G
as one of the confounding factors. As for patient-related FN risk
factors, advanced age and low pretreatment ANC remained significant in the multivariate analysis (Table 4). We also performed
another multivariate analysis in the patients without PEG-G used at
the 1st cycle (Supplementary Table 3). It is possible that the baseline characteristics were different between the patients with andwithout PEG-G at the 1st cycle. However, the results of the othermultivariate analysis were not signiﬁcantly different from the results of the multivariate analysis shown in Table 4.
Notably, age has been identiﬁed as a risk factor of FN in any
guidelines [6e8]. The age of 65 years has been used as a thresholdestablished from analyses including hematologic malignancies in
Caucasian countries [22,23]. By comparing the FN proportion ofE(A)C in Caucasians with that in Asians in this study, it clearlysuggests that an ethnic difference in the vulnerability to FN may
exist. Thus, it is necessary to determine the threshold of the age for
FN in Japanese patients.
The guidelines of The American Society of Clinical Oncology andNational Comprehensive Cancer Network have listed pre-existingneutropenia as a risk factor of FN. However, the threshold has notbeen ﬁxed for prophylaxis. The present prospective study revealed
a signiﬁcant association of pretreatment ANC with FN (Table 4). The
categorical analysis on ANC showed a consistent increase in theodds ratio on FN (Supplementary Table 2). Thus, the pretreatment
ANC could be a reliable marker for FN development. Previously,
there were retrospective studies identifying ANC as a predictive
factor of FN [24,25]. These studies investigated 741 patientsadministered with FEC retrospectively [24] and validated theirﬁndings with another set of 263 patients administered with TAC[25]. The combination of ANC and absolute lymphocyte count wasreported to be valuable in predicting neutropenic events including
FN, in which the association between ANC and FN appears to be
most signiﬁcant [24]. However, the threshold of ANC was notinvestigated in these studies. Thus, plans are underway for a further
study to establish the ANC threshold for predicting FN.
There are several limitations in this study. First, in the visiting
group, 47 of the 477 cases (9.8%) did not visit hospitals for a blood
test and 12 cases (2.5%) did a blood test 3 days after having a fever.

Declaration of competing interest
The authors declare the following ﬁnancial interests/personal
relationships which may be considered as potential competinginterests: TI has received honoraria from AstraZeneca, Eisai, Daiichi
Sankyo, Pﬁzer, Taiho, Lilly, Nippon Kayaku and Takeda. His institution has received research grants from Taiho, Eisai, Daiichi Sankyo, Nippon Kayaku, and Takeda. KT has received honoraria from
AstraZeneca, Eisai, Daiichi Sankyo, Pﬁzer, Taiho, Lilly, Nippon
Kayaku, Chugai, and Takeda. His institution has received research
grants from AstraZeneca, Chugai, Taiho, Eisai, Nippon Kayaku, MSD,
and Takeda. HM has received honoraria from AstraZeneca, Eisai,
Daiichi Sankyo, Pﬁzer, Taiho, and Takeda. His institution hasreceived research grants from the Japanese government, Eisai,
Daiichi Sankyo, Nippon Kayaku, and Pﬁzer. All remaining authors
have declared no conﬂicts of interest associated with this study.
Acknowledgement
We greatly appreciate Dr. Edward Barroga (http://orcid.org/
0000-0002-8920-2607), Medical Editor and Professor of Academic Writing at St. Luke’s International University, Tokyo, Japanfor reviewing and editing the article.
Appendix A. Supplementary data
Supplementary data to this article can be found online athttps://doi.org/10.1016/j.breast.2021.01.005.
Author contributions
Conceptualization of study: T. Ishikawa, H. Mukai. Conception
and design of study: T. Ishikawa, K. Narui, N. Suganuma, H. Kaise, K.
Tsugawa, H. Mukai. Funding acquisition: T. Aihara, H. Mukai. Project
administration: T. Aihara, H. Mukai. Analysis of data: T. Ishikawa, K.
Sakamaki, K. Narui. Statistical analysis: K. Sakamaki. Contributionof patient accrual: T. Ishikawa, K. Narui, H. Nishimura, T. Sangai, K.
Tamaki, Y. Hasegawa, K. Watanabe, N. Suganuma, S. Michishita, S.
Sugae, K. Tsugawa. Manuscript writing (original draft, interpretation, and revisions): T. Ishikawa, K. Sakamaki, K. Narui. Manuscript76

T. Ishikawa, K. Sakamaki, K. Narui et al.

The Breast 56 (2021) 70e77

writing (review/revisions for intellectual content): N. Taira, H.
Mukai.

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Final approval
All authors.
Ethics approval and consent to participate
The study was approved by the protocol review committee of
the Comprehensive Support Project for Oncological Research of
Breast Cancer on February 10, 2015 and by the institutional review
board of Tokyo Medical University on April 28, 2015 (No. 3044).
This trial was registered at the UMIN Clinical Trials Registry as
UMIN 000017857. The study was performed in accordance with the
Declaration of Helsinki. The manuscript is in line with the Recommendations for the Conduct, Reporting, Editing and Publication of
Scholarly Work in Medical Journals. Informed consent was obtained
and the privacy rights of the subjects was always observed.
Funding
This research was funded by Kyowa Kirin. All decisions concerning the planning, implementation, and publication of thisstudy were made by the executive committee of CSPOR-BC.
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