




































CMI 04 (02), 378−386 
CMI JOURNAL 378 

 

 
 

Clinical Medicine Insights 
 

DOI:https://doi.org/10.52845/CMI/2023-4-2-1 

    CMI 04 (02), 378-386 (2023)                                                                                                                                                   
ISSN (O) 2694-4626

 

RESEARCH ARTICLE                                                                                                    

Efficacy and Safety of Neoadjuvant Chemotherapy with Dose De-Escalation 

Tri-Weekly Nanoparticle Albumin-Bound Paclitaxel and FEC for Human 

Epidermal Growth Factor Receptor 2-Positive Breast Cancer 

Kazumi Kawase
1,*

, Kazuhiko Yoshida
1
, Keigo Hara

1
, Suguru Hidaka

1
, and Hiroshi 

Takeyama
2 

1
Department of Surgery, The Jikei University School of Medicine Katsushika Medical Center, Tokyo, 

Japan 

2
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan 

*Corresponding author: Kazumi Kawase 

  

Introduction

Neoadjuvant chemotherapy (NAC) is the standard 

treatment for early and locally advanced breast 

cancer because it enables less extensive surgery 

and provides information on treatment effects. 

Currently, the standard treatment for breast cancer 

is NAC consisting of an anthracycline and taxane-

based regimens. The most frequently used drugs 

are the solvent-based paclitaxel (sb-PTX) and 

Abstract 

Introduction: Neoadjuvant chemotherapy (NAC) is widely used for human epidermal growth factor 

receptor 2-positive (HER2
+
) breast cancer. The standard NAC regimen for HER2

+
 breast cancer is an 

anthracycline, followed by taxane in combination with anti-HER2 drugs. However, the risk of toxicities 

such as cardiac dysfunction and peripheral neuropathy occasionally requires dose reduction. Nanoparticle 

albumin-bound paclitaxel (nab-PTX) is a new taxane used in NAC. The aim of this study was to examine 

the effects of tri-weekly low-dose nab-PTX with anti-HER2 drugs followed by fluorouracil, epirubicin, 

and cyclophosphamide (FEC) as NAC in patients with HER2
+
 breast cancer. 

Methods: Patients with operable primary HER2
+
 breast cancer in clinical stages I–III were enrolled in 

this study. The NAC regimen included four courses of nab-PTX (220 mg/m
2
) concurrently with 

trastuzumab (6 mg/kg) tri-weekly, followed by four courses of FEC75 (5-fluorouracil: 500 mg/m
2
, 

epirubicin: 75 mg/m
2
, and cyclophosphamide: 500 mg/m

2
). Pathological responses, adverse events, and 

follow-up data at 36 months were evaluated.  

Results: Among the 20 patients enrolled, 15 completed the treatment protocol. The pathological complete 

response (pCR) rates were 60.0% overall and 85.7% in hormone receptor-negative/HER2
+
 patients. At 36 

months, one secondary malignancy was observed. The most frequent adverse event was peripheral 

sensory neuropathy (25/42, 59.5%), which persisted in four (16%) patients at 36-month follow-up. 

Conclusions: NAC with low-dose tri-weekly nab-PTX followed by FEC demonstrated favorable pCR and 

disease-free survival. Peripheral sensory neuropathy remains a concerning long-term adverse effect in 

some patients, even after reducing the nab-PTX dosage. 

Keywords: albumin-bound paclitaxel, human epidermal growth factor receptor 2, neoadjuvant 

chemotherapy, breast cancer, peripheral neuropathy 

Copyright : © 2021 The Authors. Published by Medical Editor and Educational Research Publishers Ltd. 

This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/lic enses/by-

nc-nd/4.0/). 

https://doi.org/10.52845/CMI/2023-4-2-1
https://creativecommons.org/lic%20enses/by-nc-nd/4.0/
https://creativecommons.org/lic%20enses/by-nc-nd/4.0/


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docetaxel
1
;
 
however, their adverse effects (e.g., 

peripheral neuropathy and allergic reactions) are 

associated with the vehicles such as polyethylated 

castor oil and ethanol which are used in the 

formulation of these drugs that limits their long-

term efficacy. Nanoparticle albumin-bound PTX 

(nab-PTX) is a solvent-free, 130 nm particle form 

of PTX bound to albumin, which was developed 

to avoid such adverse effects. Although nab-PTX 

has been utilized as a NAC in breast cancer, 

toxicities such as peripheral neuropathy are still 

observed, necessitating dose reduction to complete 

the treatment.
2
 In addition, the long-term adverse 

events of nab-PTX have not been widely 

examined, and thus further research is required. 

In 2014, we conducted a single-institution phase II 

clinical study (nab-PTX220 study) with reduced 

doses of tri-weekly q3w nab-PTX and FEC (5-

fluorouracil: 500 mg/m
2
, epirubicin: 75 mg/m

2
, 

and cyclophosphamide: 500 mg/m
2
) to assess the 

efficacy and safety of dose-reduced nab-PTX as 

an NAC. Herein, we report these results, along 

with the long-term outcomes, including the 

adverse effects.  

Material and methods 

Nab-PTX220 study design 

Women aged ≥20 years with histologically 

confirmed breast cancer were included in this 

study. The inclusion criteria were as follows: 

Eastern Cooperative Oncology Group 

performance status of 0–1; clinical stage T1c-3, 

N0/M0 or T1-3, N1/M0; adequate bone marrow, 

liver, and kidney function; estrogen receptor (ER), 

progesterone receptor (PgR) and human epidermal 

growth factor receptor-2 (HER2) expression status 

confirmed using core needle biopsy specimens; 

curative surgery were performed following 

neoadjuvant treatment. Primary lesion and lymph 

nodes were detected using ultrasonography, 

computed tomography, or magnetic resonance 

imaging. No history of therapy, including 

chemotherapy, radiotherapy, hormonal therapy, 

and immunotherapy and malignancy. The written 

informed consent were obtained from all the 

participants. The HER2 was defined as positive 

according to an immunohistochemical HER2 

protein staining score of 3+ in >10% of tumor 

cells, or HER2 gene was regarded as amplified 

when the HER2/chromosome enumeration probe 

17 (CEP17) ratio was >2.0 in a dual-probe assay 

by fluorescence in situ hybridization. ER and PgR 

were considered as positive when 

immunohistochemical staining showed at least 1% 

positivity. Cancer was considered as hormone 

receptor (HR)-positive when either ER or PgR 

was positive.  

The patients were administered four cycles of nab-

PTX (220 mg/m
2
 q3w), followed by four cycles of 

q3w FEC without using prophylactic granulocyte 

colony-stimulating factor. For anti-HER2 

treatment, q3w trastuzumab at 6 mg/kg (8 mg/kg 

as the loading dose) was administered 

concurrently with nab-PTX for four cycles. In 

addition, 13 cycles of trastuzumab were 

administered following the surgery. Toxicities 

were evaluated according to the National Cancer 

Institute Common Terminology Criteria for 

Adverse Events (CTCAE) version 4.0. The 

protocol treatment was discontinued upon 

observation of any adverse events such as grade 4 

non-hematologic toxicity, progression of the 

primary tumor, or lymph node metastasis. 

Adjuvant systemic or radiation therapy was 

administered as needed. This study was approved 

by the institutional review board of the Jikei 

University School of Medicine [25-305(7440)]. 

Assessment 

The primary endpoint of the nab-PTX220 study 

was the pathological complete response (pCR) 

rate, which is defined as the absence of 

histological evidence of residual invasive tumor 

cells in the breast and axillary lymph nodes 

(ypT0/TisypN0). The secondary endpoint was 

toxicity.  

Follow-up 

All patients were followed up for at least 36 

months; those who completed the treatment 

protocol and underwent surgery (n = 15) were 

analyzed for long-term follow-up. Relapse-free 

survival (RFS) was calculated as the time interval 

(in months) between the date of enrollment and 

the first observation of tumor recurrence 

(metastatic recurrence, local, or regional relapse), 

death, or last follow-up. Disease-free survival 

(DFS) was calculated as the time interval (in 

months) between the date of enrollment and the 

first observation of tumor recurrence (metastatic 



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recurrence and local or regional relapse), any 

second malignancy, death, or last follow-up. 

Overall survival (OS) was calculated as the time 

interval between the date of enrollment and death 

or last follow-up. This part was approved 

separately as observational study by the 

institutional review board of the Jikei University 

School of Medicine [ 32-484(10577)]. 

Statistical analysis 

The pCR rates of previous neoadjuvant trials with 

anthracycline/taxane were 31.3%–65.2%.
3, 4

 We 

estimated the required sample size of 17 by setting 

an efficacy of 60%, threshold efficacy of 35%, 

power of 80%, and the alpha value of 0.1% (one-

sided) using the binomial test. All analyses were 

performed using SPSS statistical software version 

24.0 (SPSS, Inc., Chicago, IL, USA), and the 

significance level for a two-sided test was set at 

0.05. RFS and OS were assessed using Kaplan–

Meier estimates, and sub-groups were analyzed 

using the log-rank test. 

Results 

Patient characteristics 

Twenty patients were enrolled in this study. The 

patient and tumor characteristics are presented in 

Table 1. 

 

Table 1. Patient and tumor characteristics 

Characteristic N (%) 

Number of patients 20 (100.0) 

Median age (range), years 61.5 (36–77) 

PS 

0 

1 

 

13 (65.0) 

7 (35.0) 

cT  

1 

2 

3 

 

2 (10.0) 

15 (75.0) 

3 (15.0) 

cN  

0 

1 

2 

 

8 (40.0) 

9 (45.0) 

3 (15.0) 

Stage 

I 

II 

III 

 

1 (5.0) 

15 (75.0) 

4 (20.0) 

Histology 

Invasive ductal carcinoma 

 

20 (100.0) 

ER 

Negative (<1%) 

Positive (≥1%) 

 

8 (40.0) 

12 (60.0) 

PgR 

Negative (<1%) 

Positive (≥1%) 

 

12 (60.0) 

8 (40.0) 

Subtype 

   HR
+
 

HR
–
 

 

9 (45.0) 

11 (55.0) 

PS, performance status; cT, clinical T stage; cN, clinical N stage; ER, estrogen receptor; PgR, progesterone 

receptor; HR, hormone receptor 

 



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The median age was 61.5 (36–77) years. Most 

patients had stage II or III disease, 60.0% of 

patients had clinically positive nodes at the 

initiation of chemotherapy, and 45% were HR
+
. 

Regarding histology, all patients presented with 

invasive ductal carcinoma. 

Outcomes 

During the study, four patients discontinued the 

treatment protocol (patient decision, n = 3; liver 

dysfunction, n = 1). In total, 16 patients completed 

the protocol treatment, one of whom violated the 

protocol (use of prophylactic granulocyte colony-

stimulating factor). Therefore, we assessed all 

patients who underwent surgery (n = 20) as the 

intention-to-treat group and those who completed 

the protocol (n = 15) as the completed protocol 

treatment group (Fig. 1). 

 

 
Figure 1. Study flow chart. ER, estrogen receptor; PgR, progesterone receptor; HER2, human 

epidermal growth factor receptor 2; HBV, hepatitis B virus infection; PTX, paclitaxel; Nab-PTX, 

nanoparticle albumin-bound paclitaxel; FEC, fluorouracil, epirubicin, and cyclophosphamide; GCSF, 

granulocyte colony-stimulating factor. 

 

Operative procedures and pathological responses among patients who underwent surgery following 

completion of the treatment protocol are presented in Table 2.  



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CMI  JOURNAL                                                                                              Kazumi Kawase et al. 

 

 
 

Table 2. Surgical procedure and pathological response 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CPT, completed protocol treatment; ITT, intention-to-treat; Bp, partial mastectomy; Bt, total mastectomy; 

SN, sentinel lymph node biopsy; Ax, axillary lymph node dissection 

 

In total, 60.0% of the patients achieved pCR, with 37.5% of HR
+
 patients and 85.7% of HR

–
 patients 

achieving pCR (Table 3).  

 

Table 3. Tumor subtype and pathological response 

pCR,pathological complete response; HR, hormone receptor 

 

At 36 months following study enrollment, there 

was only one secondary malignancy in a patient 

who developed acute myeloid leukemia at 30 

months after enrollment. The patient was treated 

with chemotherapy and hematopoietic stem cell 

transplantation and was disease-free with pCR at 

60 months of follow-up. There were two 

locoregional recurrences at a median follow-up of 

61.5 months, one secondary malignancy, no 

systemic recurrence, and no death from any 

disease. Therefore, at the 61.6-month follow-up 

point, RFS, DFS, and OS were 90%, 85%, and 

100%, respectively. Achieving the pCR or HR 

status did not affect the RFS of DFS. 

Toxicity 

Overall, 95.0% (19/20) of patients experienced at 

least one adverse effect. The toxicity profiles are 

listed in Table 4. 

 

    CPT 

N (%) 

ITT 

N (%) 

Total number of patients 15 (100.0) 20 (100.0) 

Procedure (breast)     

Bp 

   Bt 

 

9 (65.0) 

6 (35.0) 

 

13 (65.0) 

7 (35.0) 

Procedure (lymph node)  

SN 

   Ax 

 

9 (60.0) 

6 (40.0) 

 

12 (60.0) 

8 (40.0) 

Pathological response     

ypT0ypN0  

ypTisypN0 

    Other 

 

5 (33.3) 

4 (26.7) 

6 (40.0) 

 

6 (30.0) 

5 (25.0) 

9 (45.0) 

Pathological response among N1 patients 

    ypN+ 

     ypN0  

 

2 (22.2) 

7 (77.8) 

 

3 (25.0) 

9 (75.0) 

Subtype ypT+ or N+ ypTisN0 ypT0N0 % pCR  P  

HR
+
 

HR
–
 

5 

1 

1 

3 

2 

3 

37.5 

85.7 

0.06 



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Table 4. Toxicity 

Adverse event All grades, N (%) Grade 3,N (%) 

Arthralgia/myalgia 13 (65.0)  

Peripheral neuropathy 11 (55.0)  1 (5.0) 

Constipation 6 (30.0)  

Fatigue 5 (25.0)  

Nausea/vomiting 4 (20.0)  

Mucositis 4 (20.0)  

Skin rash 3 (15.0)  

Neutropenic fever 2 (10.0) 2 (10.0) 

Anorexia 2 (10.0)  

Dose reduction 4 (20.0)  

Treatment postponement 5 (25.0)  

Treatment discontinuation 4 (20.0)  

 

The most frequent adverse event was peripheral 

sensory neuropathy (PSN) (11/20, 55.0%), 

including grade-3 neuropathy in one patient 

(5.0%). Among patients who experienced PSN, 

18.2% (2/11) complained of numbness and/or 

paresthesia in the foot following a median time of 

61.5 (37–86) months of follow-up. Two patients 

had Grade 3 neutropenic fever during the FEC 

treatment. 

Discussion 

The aim of this study was to examine the effects 

of q3w low-dose nab-PTX (220 mg/m
2
) followed 

by FEC75 (5-fluorouracil: 500 mg/m
2
, epirubicin: 

75 mg/m
2
, and cyclophosphamide: 500 mg/m

2
) as 

a neoadjuvant treatment for HER2
+
 breast cancer. 

The results revealed an overall pCR rate of 60.0% 

and excellent 3-year RFS and DFS.  

Various studies have demonstrated the efficacy of 

nab-PTX in metastatic or advanced breast 

cancer.
5–8

 In the metastatic setting, q3w nab-PTX 

(260 mg/m
2
) showed a superior response than sb-

PTX 175 mg/m
2
.
7
 In addition, a randomized phase 

II study in which patients with previously 

untreated metastatic breast cancer were 

administered nab-PTX 300 mg/m
2
 q3w, 100 

mg/m
2 

weekly, 150 mg/m
2
 weekly, or docetaxel 

100 mg/m
2
 q3w, weekly nab-PTX at 150 mg/m

2 

demonstrated superior efficacy and safety over 

docetaxel.
10

 Subsequently, the nab-PTX dose, and 

schedule in neoadjuvant settings have been 

evaluated in several studies. In studies on nab-

PTX combined with anthracycline therapy, the 

pCR rate for breast cancer including all subtypes 

(HR
+
/HER2

+
, HR

–
/HER2

+
, HR

+
HER2

–
, 

HR
+
HER2

–
) has been 20%–40%.

11–15
 In most 

studies, the dose of nab-PTX used has been 260 

mg/m
2
 q3w or 125 mg/m

2
 weekly. The pCR rates 

varied according to the HR and HER2 status, with 

a high pCR rate (60%–75%) observed in HER2
+
 

patients, particularly in HR
–
/HER2

+
 patients.

11,12,16
 

Initially, we used nab-PTX 260mg/m
2
 q3w, 

however, as many patients were required nab-PTX 

dose reduction to 220mg, which is recommended 

usage as one step dose reduction in reference to 

the product document, we intended to proceed this 

study. We found a pCR rate of 85.7% in HR
–

/HER2
+
 patients, which is comparable to that in 

previous studies, although we used a low dose of 

q3w nab-PTX (220 mg/m
2
) and FEC75.  

 The GeparSepto trial was performed to compare 

the effectiveness of weekly nab-PTX 150 mg/m
2
 

(reduced to 125 mg/m
2
 following study 

amendment) with weekly sb-PTX 80 mg/m
2
 

followed by EC demonstrated that patients treated 

with nab-PTX had a significantly better DFS than 

patients treated with sb-PTX.
17

 In this trial, a 

significantly higher pCR rate was associated with 

a significantly improved invasive DFS, and the 

estimated 36-month DFS was 91.8% in the HR
–

/HER2
+
 subgroup. We observed comparable 

results with 36-month RFS, DFS, and OS of 90%, 

85%, and 100%, respectively. There was no 

survival difference depending on the HR status or 

pCR status, possibly because of our small number 

of patients. 

Other studies utilized more aggressive therapeutic 

regimens for more aggressive tumors. The 



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CMI  JOURNAL                                                                                              Kazumi Kawase et al. 

 

 
 

addition of pertuzumab to trastuzumab in 

combination chemotherapy significantly improved 

the survival of patients with high-risk HER2
+
 

breast cancer.
18 

The study which compared dose-

dense chemotherapy (either AC or FEC) with 

standard chemotherapy in conjunction with 

paclitaxel and trastuzumab showed little benefit in 

patients with HER2
+
 breast cancer.

19
 

 However, dose de-escalation therapy has also 

been suggested as a means of reducing adverse 

events. Hence, dose de-escalation therapies were 

explored to reduce the adverse effects of 

chemotherapy. Cardiac toxicity is the most serious 

adverse event following anthracycline and anti-

HER2 treatment. The risk of anthracycline-

induced cardiotoxicity is dose-dependent and 

increases with the cumulative dose. To avoid 

cardiac toxicity, several studies have utilized 

FEC75,
3, 20

 which was also applied in our study. 

In addition, anthracycline-free regimens have been 

tested for the treatment of selected low-risk 

tumors. In the neoadjuvant setting, a Japanese trial 

that included patients with low-risk HR
–
/HER2

+
 

tumors reported a pCR rate of 66.7% using an 

anthracycline-free regimen of nab-PTX 260 

mg/m
2
 with q3w trastuzumab for four cycles.

21
  

Most studies have reported acceptable toxicity 

profiles in terms of adverse events associated with 

nab-PTX.
7,15

 However, according to the drug use 

survey for nab-PTX conducted in Japan based on 

the criteria for approval during 2010–2011, 

numerous adverse events were observed. In this 

survey, 934 patients were evaluated to determine 

the safety profiles of a q3w nab-PTX dose of 260 

mg/m
2
, with adverse events observed in 92.8% of 

patients, the most common of which were 

myelosuppression and PSN.
22

 Both these adverse 

events occurred frequently following the second 

course of treatment and were the primary reason 

for discontinuation. In terms of treatment 

schedule, grade-3 or higher adverse events were 

more frequently observed with weekly 

administration
15

 and higher drug doses.
5,11,14

 In the 

GeparSepto trial, long-term follow-up of 

treatment-related PSN led to a significant decrease 

in the median time to resolve PSN following nab-

PTX 125 mg/m
2
 as compared to nab-PTX 150 

mg/m
2
. Nab-PTX combination therapy with other 

agents such as bevacizumab or atezolizumab 

resulted in a higher rate of discontinuation or 

reduction.
23,24

 In our study, despite the low-dose 

administration of nab-PTX, 55.0% of patients 

reported PSN, and 18.5% continued to be 

symptomatic at 36 months following 

chemotherapy. Most studies have reported PSN as 

reversible, whereas in our study, even low-dose 

PTX caused prolonged PSN. Although this 

analysis was conducted as a phase II study, the 

results reflected real-world data.  

De-escalation treatment has also been assessed to 

reduce adverse events resulting from nab-PTX. In 

the metastatic setting, a randomized phase II trial 

in Japan was performed to compare three different 

doses of q3w nab-PTX (260 vs. 220 vs. 180 

mg/m
2
) in patients with HER2

–
 metastatic breast 

cancer; the results showed that the optimal 

treatment dose was 180 mg/m
2
.
25

 However, to 

date, no study of de-escalation nab-PTX has been 

conducted in the neoadjuvant setting. In our study, 

the pCR rates were 37.5% (HR
+
/HER2

+
) and 

85.7% (HR
–
/HER2

+
) with concurrent 

administration of nab-PTX 220 mg/m
2
 and 

trastuzumab, respectively, which is comparable or 

even better than those reported in other studies 

using the standard dose of anthracycline and nab-

PTX. Because of the expected improved 

outcomes, low-dose nab-PTX can be considered 

an effective chemotherapeutic agent. 

Our study had some limitations. First, this was a 

single-institution study with a limited number of 

patients. Hence, there was likely some bias. On 

the basis of our results, more number of patients 

need to be assessed. Second, PSN was diagnosed 

based on subjective assessment by patients and 

physicians. The extent of toxicity was assessed 

using the CTCAE criteria; however, the toxicity 

estimation may have changed according to each 

assessor. 

In conclusion, NAC with low-dose q3w nab-PTX 

followed by FEC demonstrated favorable pCR 

rates and DFS, particularly in patients with HR
–

/HER2
+
 breast cancer. PSN remains a concerning 

long-term adverse effect in some patients, even 

after reducing the nab-PTX administration dose.  

Acknowledgments: We gratefully acknowledge 

all patients for their participation and 

contributions.  

 



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CMI  JOURNAL                                                                                              Kazumi Kawase et al. 

 

 
 

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