The Breast 55 (2021) 63e68

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

Original article

Randomized phase II study to determine the optimal dose of 3-weekcycle nab-paclitaxel in patients with metastatic breast cancer
Junji Tsurutani a, *, Fumikata Hara b, Masahiro Kitada c, Masato Takahashi d,Yuichiro Kikawa e, Hiroaki Kato f, Eiko Sakata g, Yoichi Naito h, Yoshie Hasegawa i,
Tsuyoshi Saito j, Tsutomu Iwasa k, Naruto Taira l, Tsutomu Takashima m,
Kosuke Kashiwabara n, Tomohiko Aihara o, Hirofumi Mukai paAdvanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
Department of Breast Medical Oncology, Cancer Institute Hospital of JFCR, Koto, Tokyo, Japanc
Department of Breast Disease Center, Asahikawa Medical University Hospital, Asahikawa, JapandNHO Hokkaido Cancer Center, Sapporo, Japane
Department of Breast Surgery, Kobe City Medical Center General Hospital, Kobe, JapanfTeine Keijinkai Hospital, Sapporo, Japang
Niigata City General Hospital, Niigata, Japanh
Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japani
Department of Breast Surgery, Hirosaki Municipal Hospital, Hirosaki, JapanjJapanese Red Cross Saitama Hospital, Saitama, Japank
Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japanl
Okayama University Hospital, Okayama, Japanm
Osaka City University Graduate School of Medicine, Osaka, Japann
Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, JapanoBreast Center, Aihara Hospital, Minoh, Japanp
National Cancer Center Hospital East, Kashiwa, Chiba, Japanba r t i c l e i n f o

a b s t r a c t

Article history:
Received 18 September 2020
Received in revised form
4 December 2020
Accepted 7 December 2020
Available online 9 December 2020

Background: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treatedwith nanoparticle albuminebound paclitaxel (nab-PTX). We conducted a multicenter randomized
controlled study to evaluate the optimal dose of nab-PTX.
Methods: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic
breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates
in the three doses were estimated using the logistic regression model. The optimal dose was selected in
two steps. Initially, if the hazard ratio (HR) for PFS was <0.75 or >1.33, the inferior dose was excluded,
and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4
neurotoxicity exceeded 10%, that dose was also excluded.
Results: One hundred forty-one patients were randomly assigned to SD260 (n ¼ 47), MD220 (n ¼ 46),
and LD180 (n ¼ 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs
were 0.73 (95% conﬁdence interval [CI]: 0.42e1.28) in MD220 vs SD260, 0.77 (95% CI 0.47e1.28) in LD180
vs SD260, and 0.96 (95% CI 0.56e1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was
excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220,
and 5.9% in LD180. The ﬁnal selected dose was LD180.

Keywords:
Nab-paclitaxel
Nanoparticle albuminebound paclitaxel
Metastatic breast cancer
Solvent-base paclitaxel
Chemotherapy-induced peripheral
neuropathy

Abbreviations: CI, conﬁdence interval; CIPN, chemotherapy-induced peripheral neuropathy; CR, complete remission; DCR, disease control rate; DFI, disease-free interval;
ECOG, Eastern Cooperative Oncology Group performance; HR, hazard ratio; MBC, metastatic breast cancer; Nab-PTX, nanoparticle albuminebound paclitaxel; ORR, overall
response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PROs/HRQoL, patient-reported outcomes/health-related quality-of-life; QoL, qualityof-life; RDI, relative dose intensity; RECIST, response evaluation criteria in solid tumors; sb-PTX, comparing solvent-based paclitaxel; TNBC, triple-negative breast cancer; TTF,
time-to-treatment failure.
* Corresponding author.
E-mail address: tsurutaj@med.showa-u.ac.jp (J. Tsurutani).
https://doi.org/10.1016/j.breast.2020.12.002
0960-9776/© 2020 The Authors. 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/).

J. Tsurutani, F. Hara, M. Kitada et al.

The Breast 55 (2021) 63e68

Conclusions: Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal
therapy with meaningful efﬁcacy and favorable toxicity in patients with MBC.
© 2020 The Authors. 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/).

1. Introduction

2. Materials and methods

The primary goal of patient care in metastatic breast cancer(MBC) is palliation and maintaining good quality-of-life (QoL)
throughout the disease course, along with prolonging survival.
Chemotherapy remains the mainstay of patient care, and choosing
an appropriate drug and optimizing the required dose are keys toachieving this goal.
Nab-paclitaxel (nab-PTX) is an albumin-stabilized nanoparticle
formulation of paclitaxel and can be administered without ethanolor steroid premedication [1]. Currently, nab-PTX is approved fortreating breast, gastric, lung, and pancreatic cancers, and intravenous administration at 260 mg/m2 every 3 weeks (q3w) is the only
indication for treating breast cancer with nab-PTX in Japan, US, andEU.
A Phase III study, CA012, comparing solvent-based paclitaxel(sb-PTX) (175 mg/m2, q3w) with nab-PTX (260 mg/m2, q3w) was
conducted in patients with MBC [2]. The overall response rates(ORR) and progression-free survival (PFS) were signiﬁcantly superior in the nab-PTX arm than in the sb-PTX arm. However,chemotherapy-induced peripheral neuropathy (CIPN) at grade 3 orhigher occurred more frequently in the nab-PTX arm than in the sbPTX arm (10.5% vs 2.2%, respectively).
Another Phase III trial, CALGB 40502, compared three regimens:
weekly sb-PTX (90 mg/m2), weekly nab-PTX at 150 mg/m2, andixabepilone (16 mg/m2) with bevacizumab (10 mg/kg) every 2
weeks as ﬁrst-line chemotherapy for MBC [3]. Compared with sbPTX, nab-PTX did not improve PFS in the study, and CIPN was
signiﬁcantly higher in the nab-PTX arm than in the sb-PTX arm(25% vs 16%).
According to the post-marketing surveillance of nab-PTX use inJapanese breast cancer patients, one-third of patients required dose
reductions after receiving an initial dose [4]. Although the recommended dosage of nab-paclitaxel by the Pharmaceuticals andMedical Devices Agency, the US Food and Drug Administration, andEuropean Medicines Agency is 260 mg/m2 intravenously over
30 min every 3 weeks, for MBC, 27.3% of patients starting at thisdose required subsequent reductions. Grade 2/3 CIPN was
frequently observed (42.5% and 10.8%, respectively). Therefore,
further studies are required to ﬁnd the optimal dose of q3w nabPTX in Japanese patients.
Nab-PTX promptly collapses in the blood to yield albuminbound PTX and is efﬁciently delivered to tumor cells [5]. Nab-PTX
is more efﬁcient than sb-PTX even at similar doses. Several
studies have demonstrated the safety and efﬁcacy of nab-PTX q3w
at reduced doses [6e8]. In a single arm Phase II trial, CA002-0LD,
nab-PTX was administered at 175 mg/m2 q3w. The resulting ORR
was 39.5% and no grade 3/4 CIPN was observed [6]. Thus, theeffectiveness of lower-dose nab-PTX may be similar to that ofstandard-dose nab-PTX. Here, we conducted a randomized Phase II
study to optimize the nab-PTX dose comparing three different
doses of nab-PTX (180 mg/m2 vs 220 mg/m2 vs 260 mg/m2) q3w, inpatients with MBC.

2.1. Patients
Patients between 20 and 75 years of age with pathologicallyconﬁrmed stage IV breast adenocarcinoma, an Eastern Cooperative
Oncology Group performance status (ECOG) of 0 or 1, and up to one
chemotherapy regimen for MBC were eligible for the study. If
sensory neuropathy was present, it was restricted to grade 1 forinclusion. Neoadjuvant or adjuvant chemotherapy followed by one
line of chemotherapy for MBC was allowed if 6 or more months had
elapsed from the end of neo- or adjuvant chemotherapy to thediagnosis of recurrence. Patients were excluded if they werereceiving concurrent immunotherapy or hormonal therapy forbreast cancer or had parenchymal brain metastases (unless stable),a history of class II to IV congestive heart failure, or other malignancy within the last 5 years that could affect the diagnosis orassessment of breast cancer.
2.2. Study design
The study was approved by an appropriate institutional review
board and all patients provided informed consent for participation.
The CSPOR Data Centre conﬁrmed patient eligibility, and treatment
was assigned using a minimization method with the allocation
factors for eligible patients. The allocation factors were as follows:
institution, hormone sensitivity, prior chemotherapy, taxane, anddisease-free interval (DFI) from surgery.
2.3. Study end points
The primary endpoint was PFS, which was deﬁned as the timefrom the date of randomization to that of disease progression ordeath, whichever occurred ﬁrst. Secondary endpoints included
time-to-treatment failure (TTF), overall survival (OS), ORR, disease
control rate (DCR), adverse events, and patient-reported outcomes/
health-related quality-of-life (PROs/HRQoL). QoL was assessed inthis trial and the results has been submitted separately to anotherjournal.
2.4. Tumor assessments
Tumor responses were assessed every 6 weeks for the ﬁrst 18
weeks and every 9 weeks thereafter (regardless of treatment
schedule). Patients with measurable disease were evaluated forcomplete remission (CR), partial response (PR), stable disease, or
progressive disease per the Response evaluation criteria in solid
tumors (RECIST) guidelines.
For safety or tolerability evaluations, investigator-assessed
incidence of adverse events was reported. Laboratory abnormalities and incidence of dose modiﬁcations or interruptions, withpremature discontinuation of the study drug, were recorded. All
toxicities were graded according to the National Cancer Institute64J. Tsurutani, F. Hara, M. Kitada et al.

The Breast 55 (2021) 63e68

probability of the three arms; not based on their conﬁdence intervals. In this respect, this selection design is different from theordinary non-inferiority and superiority trials, and the deﬁnition of
non-inferiority on PFS is also different as described above.
According to the selection design, the required sample size wascalculated based on the probability that the true optimal dose iscorrectly chosen by the above two-step procedure. The study wasplanned to ensure the selection of an MD220 with a probability of
70%, when the one-year PFSs of all three doses were 30% and thegrade 3 neurotoxicity rates of SD260, MD220, and LD180 were 15%,8%, and 0.1%, respectively. This required 40 patients per group withexpected registration periods of two years and follow-up periods of
two years. Eventually, we chose 42 patients per group. Other simulations are provided in the Supplementary Table S1.
The protocol was registered at the website of the University
Hospital Medical Information Network (UMIN), Japan (protocol ID
UMIN000012429), on November 1, 2014. The details are available atthe following web address: http://www.umin.ac.jp/ctr/.

Common Terminology Criteria for Adverse Events (version 4.0).
2.5. Statistical methods
The purpose of the main analysis was to select the optimal dosethat conferred reasonable PFS and tolerable neurotoxicity proﬁle,from the three tested dose levels [9]. We deﬁned the optimal doseas that where the PFS was not inferior to PFS of SD260, and where
the grade 3 neurotoxicity rate was less than 10%. The selection
consisted of two steps. First, pairwise comparison of PFS was conducted using three Cox regressions, each of which included two
dose groups of the three tested doses. If the HR was outside therange of 0.75 and 1.33, the inferior dose group was excluded and we
proceeded with the non-inferior doses. Second, we chose thegreatest dose level from the dose groups whose estimated incidence probability of grade 3/4 neurotoxicity was less than 10%. The
neurotoxicity probabilities in the three dose groups were estimatedby the single logistic regression including the doses as a continuous
variable, because the dose-dependent increase in neurotoxicity was
regarded as a reasonable assumption. Regardless of the result of theﬁrst dose-selection step, the logistic regression included all dosegroups to precisely estimate the dose-toxicity curve. If the estimated neurotoxicity incidence exceeded 10% at any non-inferior
dose levels, we chose the lowest dose level. This design, called
the selection design [9], selects the optimal dose worthy of further
investigation in a subsequent phase III trial based on the HR estimates of the PFS and the estimates of neurotoxicity incidence

3. Results
3.1. Enrolment
Between February 2015 and February 2017, 141 patients wereenrolled and randomly assigned to different dose groups. One patient did not start treatment in the MD220 arm (Fig. 1). Overall, 47
patients were treated with SD260 of nab-PTX; 46, with MD220; and48, with LD180. At the time of reporting, all patients had stopped
the study therapy. The median follow-up time was 25 months.
Patient characteristics were well-balanced between the study
arms except with performance status 1a, which was a little higher
in LD (Table 1). Median age was 57 years. Seventy-four percent ofpatients had visceral metastases and an ECOG of zero; 78% had
hormone receptor-positive disease; and 22% triple-negative BC(TNBC) tumors. Among treated patients, 55% had a DFI from thediagnosis of primary tumor to diagnosis of metastatic disease of
more than 2 years, 26% received chemotherapy for MBC, and 38%
received prior taxanes.
3.2. Dose selection

Fig. 1. Consort diagram. One hundred forty-one patients were enrolled in the study
and randomized into one of three groups: SD260 or MD220 or LD180, where thesubjects were treated with 260 mg/m2 or 220 mg/m2 or 180 mg/m2 of nab-PTX,
respectively, every 3 weeks until either disease progression or unacceptable toxicity.

Median PFS was 6.66 (95% CI 4.82e8.82), 7.34 (95% CI
4.59e8.92), and 6.82 months (95% CI 4.43e9.15) in the SD260,
MD220, and LD180 groups, respectively (Fig. 2). The HRs were 0.73

Table 1
Characteristics of patients.

Median age, years (range)
PS (ECOG)
01
ER-positive
PgR-positive
Disease-free interval
De novo2 years<2 years
Chemotherapy for MBC
Yes
No
Prior taxane therapy
Yes
No

SD260

MD220

LD180

(n ¼ 47)(n ¼ 45)(n ¼ 48)59.0 (36e75)61.0 (34e74)

58.5 (35e74)

38 (80.9%)9 (19.1%)
38 (80.9%)
29 (61.7%)

34 (75.6%)
10 (22.2%)
34 (75.6%)
22 (48.9%)

31 (64.6%)
17 (35.4%)
37 (77.1%)
27 (56.3%)

13 (27.7%)
27 (57.4%)
13 (27.7%)

12 (26.7%)
24 (53.3%)
9 (20.0%)

11 (22.9%)
27 (56.3%)
10 (20.8%)

12 (25.5%)
35 (74.5%)

11 (24.4%)
34 (75.6%)

13 (27.1%)
35 (72.9%)

19 (40.4%)
28 (59.6%)

17 (37.8%)
28 (62.2%)

17 (35.4%)
31 (64.6%)

P-value

0.82
0.22

0.88
0.53
0.93

0.96

0.88

65

J. Tsurutani, F. Hara, M. Kitada et al.

The Breast 55 (2021) 63e68

these groups (5.31, 5.11, and 5.28 months, respectively).
3.4. Toxicity
The common adverse events were sensory neuropathy, fatigue,
arthralgia, myalgia, and leukopenia (Table 3). Grade3/4 sensory
neuropathy and myalgia were more commonly observed in patients
who received SD260 and MD220 than in those who received LD180(Table 3: 31.9, 8.9 vs 8.3% and 12.8, 6.7 vs 0%, respectively,
Supplementary Figure S1). Notably, sensory neuropathy of grade 2
or higher was more common, and rapidly occurred in the SD260
group than in the MD220 or LD180 groups (Fig. 3).
Grade 3/4 neutropenia events were more common in SD260 or
MD220 than in LD180 groups (Table 3: 25.4, 37.7 vs 14.7%,
respectively). The dose reduction rate during treatment wassigniﬁcantly higher in SD260 group than in the other groups(Table 4).

Fig. 2. Progression-free survival by treatment groups. Curves were drawn using
Kaplan-Meier estimation by the assigned groups. Events were deﬁned as diseaseprogression or death by any causes.

(95% conﬁdence interval [CI]: 0.42e1.28) in MD220 vs SD260, 0.77
(95% CI 0.47e1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56e1.66)
in LD180 vs MD220. SD260 was inferior to MD220 and was
excluded (Table 2). In the second stage, the frequencies estimatedby logistic regression for CIPN G3/4 were 14.0% and 5.9% for MD220
and LD180, respectively (Table 2), and MD220 exceeding 10% were
excluded. Resultantly, LD180 was selected as the most optimal dose.

3.5. Relative dose intensity (RDI)The RDI in each group to the planned SD260 regimen were 0.87,
0.77, and 0.63 in SD260, MD220, and LD180, respectively (Table 5).
4. Discussion
This is the ﬁrst randomized control study that has compared the
reduced doses of nab-PTX with the standard dose (260 mg/m2)
q3w, in patients with MBC, and evaluated the non-inferiority (withthe intention of selecting the optimal dose) of the reduced initial
doses to the standard dose, in terms of PFS and the adverse events,
including CIPN. We found that LD180 was not inferior to SD260 or
MD220 and selected this dose because it had less than 10% of the

3.3. Efﬁcacy
ORRs were 48.7%, 44.1%, and 37.8% in SD260, MD220, and LD180,
respectively. The OS events occurred at 77/140 (55%) at the time ofanalysis, and the median OS was 2.1, 2.8, and 2.5 years for SD260,
MD220, and LD180, respectively There were no signiﬁcant differences between treatment groups. The TTFs were similar between

Table 2
Selection of the optimal dose.
Cox regression

Hazard ratio (HR) of PFS

MD220 vs SD260
LD180 vs SD260
LD180 vs MD220

Estimate
0.73
0.77
0.96

Selectiona
95% CI(0.42, 1.28)(0.47, 1.28)(0.56, 1.66)

Drop SD260 due to HR < 0.75
Equivalent
Equivalent

Logistic regression

Incidence (%) of CIPN ¼ /> Gr3
Estimate
95% CI

Selectionb

SD260
MD220
LD180

29.5
14
5.9

Not candidate for 2nd selection
Drop MD220 due to estimated incidence rate exceeding 10%
Retain LD180(18.7, 43.2)(8.8, 21.6)(2.3, 14.6)

CI, conﬁdence interval.
a
If HR<0.75 or >1.33, the inferior one was excluded.
b
The dose with its estimated incidence rate exceeding 10% was excluded.

Table 3Adverse events.
EventsSD260: n, (%)

MD220: n, (%)

Any Grade3

Any Grade3

Any Grade3No. of patientsn ¼ 47n ¼ 45n ¼ 48

Leukopenia
Neutropenia
Hemoglobin
ALT elevation
Fatigue
Sensory neuropathy
Arthralgia
Myalgia
Rash
Anorexia

31 (66.0)
27 (57.4)
27 (57.4)
26 (55.3)
38 (80.9)
43 (91.5)
35 (74.5)
34 (72.3)
16 (34.1)
24 (51.1)

9 (19.1)
12 (25.4)
1 (2.1)1 (2.1)1 (2.1)15 (31.9)
4 (8.5)6 (12.8)
0 (0.0)1 (2.1)35 (77.8)
33 (73.3)
22 (48.9)
20 (44.4)
35 (77.8)
38 (84.4)
30 (66.7)
26 (57.8)
14 (31.1)
23 (51.1)
66

LD180: n, (%)

12 (26.6)
17 (37.7)
1 (2.2)2 (4.4)0 (0.0)4 (8.9)5 (11.1)
3 (6.7)0 (0.0)0 (0.0)29 (60.4)
24 (50.0)28 (58.3)
18 (37.5)
34 (70.8)
39 (81.3)
27 (56.3)
19 (39.6)
12 (25.0)
20 (41.7)

7 (14.6)
7 (14.6)
2 (4.2)0 (0.0)0 (0.0)4 (8.3)0 (0.0)0 (0.0)0 (0.0)1 (2.1)

J. Tsurutani, F. Hara, M. Kitada et al.

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Table 5
Relative dose intensity (RDI).

LD180
MD220
SD260

n

RDI

95% CI

48
45
46

0.63
0.77
0.87

0.61
0.75
0.84

0.65
0.8
0.91

CI, conﬁdence interval.

Notably, the current study is the only one to randomize patients
according to standard or low-dose regimens, to clarify the differences in therapeutic indices of the variable doses [6e8]. Interestingly, all three of these studies showed uncompromising PFS with
the LD180 regimen, implying that the dose-PFS relationship, but
not the dose-toxicity one, had plateaued at 180 mg/m2 of nab-PTX
q3w, and the therapeutic index of nab-PTX was higher than that ofsb-PTX, due to its better delivery to the tumor [1]. Therefore, the LD
regimen is sufﬁcient to achieve the most efﬁcacy.
One limitation of this study was the tri-weekly treatment
schedule of nab-PTX q3w employed for patients with MBC. Previously, several studies have demonstrated that a weekly sb-PTX
might be more effective and less toxic than q3w administrationfor early or MBC [11,12]. Seidman and colleagues also compared
weekly sb-PTX (80 mg/m2) with q3w sb-PTX (175 mg/m2) regimens
in patients with MBC and have shown that the weekly PTX wassuperior to q3w administration: ORR, time-to-progression, and OS[11]. Further, Sparano and colleagues enrolled 4950 patients withearly breast cancer and randomized sb-PTX either q3w or every
week following doxorubicin and cyclophosphamide, and found thatdisease-free survival and OS were signiﬁcantly improved [12].
Furthermore, weekly nab-PTX was superior to the q3w regimen, in
terms of efﬁcacy and toxicity [13]. The weekly schedule of sb- or
nab-PTX is more commonly used to treat patients with breast
cancer, and the signiﬁcance of our ﬁndings with the reduced doseof q3w nab-PTX may be limited. Nab-PTX at 100 mg/m2 can beadministered weekly to reduce the incidence and degree of
myalgia. Nonetheless, it was not until recently that the weekly nabPTX regimen was adopted in Japan to treat patients with MBC due
to previous failures to demonstrate its superiority to q3w docetaxel[14]. Moreover, there must be room for less frequent and toxic
regimens, especially for patients with limited access to clinics or
those who may beneﬁt from minimizing the risk of coronavirus
infection during the COVID-19 pandemic.
The second limitation of the current study was that this was an
exploratory trial with small sample sizes in each treatment group,and 28 patients included in the study withdrew their consent. Thiscan have a major impact on PFS and neurotoxicity data. Neurotoxicity is cumulative, and patients who withdrew their consent
would not contribute to disease events. Moreover, patients in theFig. 3. Accumulated incidences of G2/3/4 neuropathy are shown by the treatmentgroups.

grade3/4 CIPN.
Gradishar and colleagues have reported that the administrationof nab-PTX at 260 mg/m2 q3w improved clinical outcomes, such as
ORR and PFS, and had a more favorable safety proﬁle, whencompared to administration of sb-PTX at 175 mg/m2, in previously
untreated patients with MBC [2]. Nonetheless, compared to theresults of the pivotal study [2], the incidence of grade 3/4 neuropathy was higher in the group with the SD260 (10.4 vs 31.9%,
respectively), and the grade 3/4 myalgia was not trivial in thecurrent study (12.8%) unlike in the pivotal study. The cause of thisinconsistency between the studies, in terms of the incidence of
CIPN and myalgia is not clear, but may be attributed it to the differences in ethnicity between the subjects enrolled in both studies.
Another study reported that the incidence and degree of CIPN were
extremely high and severe, respectively, among Japanese patientswith the SD regimen (84% grade 3/4) [10]. The common and severe
CIPN and myalgia requiring interruption or reduction of the dosewould rationalize further modiﬁcation of the SD260 regimen in
Japanese patients to ensure a good QoL.
To this end, multiple studies, including the current one, haveevaluated the lower dose of nab-PTX, q3w to establish modiﬁed
doses that can alleviate the CIPN and myalgia [6e8]. These havereported that the regimen of 180 mg/m2 of nab-PTX achieved
23e41% of ORRs and 23e26 weeks of PFS with 0e6% of grade3/4
CINP. Their results are consistent with those of the current study,
with regard to the efﬁcacy and toxicity of the LD180 regimen
compared to the SD260 treatment, highlighting the increased
tolerability of this treatment without compromising the efﬁcacy.

Table 4
Dose reductions.
Treatment Arm
SD260 (n ¼ 47)
Dose reduction
Yes
No. of dose reduction
1
2
By treatment course
By 1st course
By 2nd course
By 3rd course

MD220 (n ¼ 45)

LD180 (n ¼ 48)

n
19

%
40.4

95% CI(26.4, 55.7)

n
11

%
24.4

95% CI(12.9, 39.5)

n
7

%
14.6

95% CI(6.1, 27.8)

14
5

29.8
10.6

(17.3, 44.9)(3.5, 23.1)

8
3

17.8
6.7

(8, 32.1)(1.4, 18.3)

6
1

12.5
2.1

(4.7, 25.2)(0.1, 11.1)

0
3
5

0
6.4
8.5

(0, 7.5)(1.3, 17.5)(2.4, 20.4)

0
1
2

0
2.2
4.4

(0, 7.9)(0.1, 11.8)(0.5, 15.1)

0
0
0

0
0
0

(0, 7.4)(0, 7.4)(0, 7.4)

CI, conﬁdence interval.
67

J. Tsurutani, F. Hara, M. Kitada et al.

The Breast 55 (2021) 63e68

Kosuke Kashiwabara, Tomohiko Aihara and Hirofumi Mukai haveno conﬂict of interest.

medium-dose arm had both the highest withdrawal rate and thebest PFS results. Therefore, the results of such analysis should beinterpreted with caution. Further studies are required to afﬁrm
whether all patients should receive the reduced dose of nab-PTX
from the ﬁrst cycle; however, a reduced-dose regimen is a treatment option without compromising efﬁcacy before the patients
experience severe toxicities, such as grade 3/4 neurotoxicity or
myalgia. The reduced initial dose is endorsed by the consistentefﬁcacy observed with favorable toxicity proﬁles in Japanese patients, although larger studies may be warranted to conﬁrm theseﬁndings [7,8].
Finally, we considered only the grade of neurotoxicity todetermine the optimal dose; however, the length and reversibilityof neurotoxicity are the two very important parameters that should
be considered to interpret the results.

Acknowledgements
We thank all the patients who participated in ABROAD and theirfamilies and the investigators and research coordinators at the 41
institutions and the CSPOR-BC.
The research fund was provided to CSPOR-BC by Taiho Pharmaceutical Co., Ltd under the study contract. All decisions concerning the planning, implementation and publication of this study
were made by the executive committee of this study.
Appendix A. Supplementary data
Supplementary data to this article can be found online athttps://doi.org/10.1016/j.breast.2020.12.002.

5. Conclusion
Intravenous administration of low-dose nab-PTX at 180 mg/m2
q3w may improve tolerability without compromising PFS in patients with MBC, and further evaluation is warranted to conﬁrm
these ﬁndings in a larger trial.

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Author contributions
Junji Tsurutani: Data analysis and interpretation, Manuscript
preparation, Manuscript editing; Fumikata Hara: Study Concepts,
Data analysis and interpretation, Statistical analysis, Manuscript
preparation; Masahiro Kitada: Data acquisition; Masato Takahashi:
Data acquisition; Yuichiro Kikawa: Data acquisition, Statisticalanalysis; Hiroaki Kato: Data acquisition; Eiko Sakata: Data acquisition; Yoichi Naito: Data acquisition; Yoshie Hasegawa: Dataacquisition; Tsuyoshi Saito: Quality Control of data and algorithms;
Tsutomu Iwasa: Quality Control of data and algorithms; Naruto
Taira: Study Concepts; Tsutomu Takashima: Manuscript review;
Kosuke Kashiwabara: Study Design, Formal analysis and interpretation, Statistical analysis, Manuscript preparation; Tomohiko
Aihara: Quality Control of data and algorithms; Hirofumi Mukai:
Quality Control of data and algorithms
Ethics approval
This study was approved by the Institutional Review Board of
Kindai University and conformed to the guidelines of the Declaration of Helsinki.
Funding
This work was supported by the Comprehensive Support Project
for Oncology Research in Breast Cancer. The research fund wasprovided to the Comprehensive Support Project for Oncology
Research in Breast Cancer by Taiho Pharmaceutical under the study
contract. Taiho Pharmaceutical took no part in this study other thanproviding information relevant to proper use of the study drug.
Declaration of competing interest
Junji Tsurutani received preclinical research funds from Daiichi
Sankyo during this study; and outside the submitted work, received
honorarium from Novartis, Taiho, Eisai, Chugai, and Kyowa Kirin;
personal fees for participating in advisory boards for Eisai and Asahi
Kasei; and support for travel expenses from Daiichi Sankyo. Authors Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro
Kikawa, Hiroaki Kato, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa,
Tsuyoshi Saito, Tsutomu Iwasa, Naruto Taira, Tsutomu Takashima,
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