Breast Cancer
https://doi.org/10.1007/s12282-021-01290-5

ORIGINAL ARTICLE

Quality of life in a randomized phase II study to determine the optimaldose of 3‑week cycle nab‑paclitaxel in patients with metastatic breast
cancerNaruto Taira1 · Kosuke Kashiwabara2 · Junji Tsurutani3 · Masahiro Kitada4 · Masato Takahashi5 · Hiroaki Kato6 ·Yuichiro Kikawa7 · Eiko Sakata8 · Yoichi Naito9 · Yoshie Hasegawa10 · Tsuyoshi Saito11 · Tsutomu Iwasa12 ·Tsutomu Takashima13 · Tomohiko Aihara14 · Hirofumi Mukai9 · Fumikata Hara15
Received: 5 June 2021 / Accepted: 25 August 2021
© The Japanese Breast Cancer Society 2021, corrected publication 2021

Abstract
Background To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal doseof 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC).
Methods Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/
m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth coursesof treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and
EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM).
Results A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD
groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial
outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and
LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) andthose for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001).
Conclusion QoL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patientstreated with 260 mg/m2.
Trial registration The protocol was registered at the website of the University Hospital Medical Information Network(UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://​upload.​umin.​ac.​jp/​cgi-​open-​bin/​ctr_e/​ctr_​view.​cgi?​recpt​no=​R0000​17916
Keywords Metastatic breast cancer · Chemotherapy · Nab-paclitaxel · QoL · CIPN · Fatigue
Abbreviations
QoL	Quality of life
q3w nab-PTX	3-Week cycle nab-paclitaxel
MBC	Metastatic breast cancer
FACT-Taxane	Functional Assessment of Cancer
Therapy-Taxane
CFS	Cancer fatigue scale
EQ-5D	EuroQol 5-dimension
MMRM	Mixed-model repeated measures* Naruto Tairantaira@md.okayama-u.ac.jp
Extended author information available on the last page of the article

UMIN	University Hospital Medical Information
Network
PTX	Paclitaxel
so-PTX	Solvent-based PTX
q3w	Every 3 weeks
RR	Response rate
PFS	Progression-free survival
CIPN	Chemotherapy-induced peripheral
neuropathy
HER2	Human epidermal growth factor receptor
type2
HR	Hazard ratio
RCT​	Randomized controlled trial
PS	Performance status
SD	Standard dose

13Vol.:(0123456789)

Breast Cancer

MD	Medium doseLD	Low dose
PWB	Physical well-being
SFWB	Social and family well-being
EWB	Emotional well-being
FWB	Functional well-being
TOI	Trial outcome index
95% CI	95% Confidence interval
BMIs	Body mass indexes
PROs	Patients reported outcomesBackgroundNab-paclitaxel (PTX) is a chemotherapeutic agent for metastatic breast cancer that is administered as a nanoparticulate
preparation of PTX bound to human serum albumin. Unlike
conventional, solvent-based PTX (so-PTX), polyoxyethylene castor oil or absolute ethanol are not used as a solvent.
For this reason, pre-medication with steroid hormones is
not needed and a high dose of PTX can be administeredin a short time. In patients with metastatic breast cancer,
nab-PTX 260 mg/m2 every 3 weeks (q3w) was found to besuperior for response rate (RR) and progression-free survival(PFS) compared to q3w so-PTX 175 mg/m2 [1]. However,in the nab-PTX group, the dose of PTX was approximately
1.5 times higher and the frequency of chemotherapy-induced
peripheral neuropathy (CIPN) was significantly higher.
In Japan, nab-PTX was approved in 2010 for treatment ofmetastatic breast cancer. The recommended dosage of nabPTX by the Pharmaceuticals and Medical Devices Agency
is 260 mg/m2 intravenously over 30 min every 3 weeks formetastatic breast cancer. However, a survey on actual use
started after release of nab-PTX found that about one-thirdof cases were treated with a reduced initial dose [2]. In addition, about 30% of cases that started with the standard dose
required dose reduction, mainly due to myelosuppression
and CIPN. In particular, the rate of CIPN of Grade ≥ 2 was
as high as about 40%. Based on these real-world findings,
the current standard dose of nab-PTX is highly toxic andmay be problematic over time. Thus, the current study wasplanned to investigate the optimal dose of nab-PTX.
This study compared three different doses of q3w nabPTX (SD 260 mg/m2 vs. MD 220 mg/m2 vs. LD 180 mg/m2) in patients with human epidermal growth factor receptor type2 (HER2) negative metastatic breast cancer [3]. The
primary endpoint was PFS. Grade 3/4 neuropathy rates at
the three doses were estimated by logistic regression. The
optimal dose was defined by 2-step selection. First, if thehazard ratio (HR) for PFS was < 0.75 or > 1.33, the inferior dose was dropped. Then, if the estimated incidence
rate of grade 3/4 neuropathy was > 10%, the other dose was
dropped. Primary analysis showed that low-dose nab-PTX at

13

180 mg/m2 q3w may be the optimal therapy with meaningful
efficacy and favorable toxicity in patients with metastatic
breast cancer [4].
In general, the frequency and severity of adverse events
caused by chemotherapy are dose-dependent, so a potential
benefit of using low-dose nab-PTX is reduction of adverse
events. The frequency or severity of CIPN is likely to be
reduced with a low-dose nab-PTX regimen, and this dose
may also reduce symptoms such as fatigue caused by cancer
chemotherapy. Based on the hypothesis that low-dose nabPTX treatment will result in better quality of life (QoL) thanstandard dose nab-PTX, the purpose of this QoL substudy is
to show the superiority of low-dose PTX in terms of QoL.

Methods
Study design
This study is a multicenter, open-label, phase 2 randomized
controlled trial (RCT) conducted in Japan. Details ofstudy protocols have been reported elsewhere [3]. Briefly,
the inclusion criteria were histologically diagnosed invasive breast cancer; incurable metastatic disease; aged
20–75 years; an Eastern Cooperative Oncology Group performance status (PS) score of 0 or 1; and chemotherapy
for metastatic breast cancer allowed up to one regimen.
The exclusion criteria were HER2-positive breast cancer;
patients with CIPN of grade ≥ 2; and brain metastases withsymptoms or requiring treatment.
Eligible patients were randomly assigned by dynamic
allocation in a 1:1:1 ratio to receive any of 3 doses of nabPTX: standard dose (SD) 260 mg/m2, medium dose (MD)
220 mg/m2, and low dose (LD) 180 mg/m2. Stratification
factors were a history of chemotherapy for metastatic disease(yes vs. no), hormone receptor status (positive vs. negative),
history of taxane treatment including perioperative use (yesvs. no), relapse-free interval (< 2 vs. ≥ 2 years), and participating institution.
The patient received the assigned dose of nab-PTX
once every 3 weeks for 30 min until disease progression or
adverse events prevented continued treatment. After starting
the protocol treatment, if a patient developed grade 4 thrombocytopenia, grade 3 thrombocytopenia requiring bloodtransfusion, neutrophils < 500/mm3 lasting for ≥ 7 days, or
grade ≥ 3 non-hematological toxicity (excluding nausea,
vomiting, and diarrhea), the dose in the next course was
reduced by one step to 220, 180 and 140 mg/m2 for the SD,
MD and LD groups, respectively. The target number of registrations was 138 [3].
All subjects gave written informed consent before
enrollment in the study. The study was approved by theBreast Cancer

institutional ethics committee on human research at all participating medical institutions.

QoL assessment
QoL of the study population was assessed using the Japanese version of the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane) scale [5]. FACT-Taxane wasdeveloped to measure adverse events and QoL in patients
undergoing taxane treatment. It consists of a 27-item generalcancer QoL measure (FACT-General) [7 for physical wellbeing (PWB), 7 for social and family well-being (SFWB), 6
for emotional well-being (EWB), and 7 for functional wellbeing (FWB)] and a 16-item taxane subscale, including an
11-item neurotoxicity subscale and 5 questions on symptoms
related to arthralgia, myalgia, and skin discoloration. Each
FACT-Taxane item or question has response choices from0 (“not at all”) to 4 (“very much”). Scores range from 0 to
172 and a higher score indicates better QoL. The Japaneseversion of EuroQol 5-dimension (EQ-5D)-3L was used forpreference-based measures of QoL, and was scored using a
conversion table for the Japanese population [6, 7].
Fatigue in cancer patients was assessed using the Cancer
Fatigue Scale (CFS) [8]. The CFS was developed to measure fatigue in cancer patients in Japan, with 15 items in 3
subscales: 7 for physical (score range 0–28), 4 for affective(0–16), and 4 for cognitive (0–16) subscales. Comprehensive fatigue in cancer patients is calculated as the sum of
the three domains. The score is 0–60, and a higher scoreindicates that fatigue is noticeable.
All patients in the parent trial were invited to be a partof the QoL substudy. Self-administered questionnaires were
distributed by medical staff to subjects and returned to theComprehensive Support Project for Oncological Researchdata center by mail. The date of the investigation and theallowed survey period were at registration (study entry to thestart of protocol treatment), and during the 2nd, 4th and 6thcourses of protocol treatment. If treatment was discontinued
due to disease progression, complications, exacerbations, oradverse events, QoL evaluation was discontinued.

Analysis
The target group for the QoL substudy analysis included
all registered cases except those that 1) did not meet theeligibility criteria. 2) for whom no protocol treatment was
performed, or 3) QoL evaluation was not performed before
the start of protocol treatment. The response rate was definedas the number of responses collected/the number of expected
responses. All questionnaires were quantified using a scoring
manual, and basic statistics for each group and each survey
point were calculated.

The hypothesis for QoL evaluation was that QoL at MD
or LD would be better than at SD. The primary outcomeof the QoL substudy was the FACT-Taxane Trial Outcome
Index (TOI) in the second, fourth, and sixth courses of protocol treatment. FACT-Taxane TOI is a 40-item aggregateof the PWB, FWB, and taxane subscale, and is often used
as a single clinical trial outcome index.
For comparison of scores calculated as continuous variables, analysis was performed using a mixed effects model
for repeated measures (MMRM). The model used the scoresobtained at each survey point, except baseline, as an outcome, and the baseline value, group, survey point, andinteraction terms of group and survey point as explanatory
variables. The least-squares mean square value at each survey point for each group with the 95% confidence interval(CI), the intergroup difference at each survey point with the
95% CI, and the P value were calculated. The P value ofthe group-by-survey-point interaction was also calculated totest the overall treatment effect among the three treatmentgroups.
Missing data were not imputed. There were no multiple-comparison adjustments. All tests were two-sided, andP < 0.05 was considered to be significant. SAS v. 9.3 wasused for analysis.

Results
Patients and characteristics
From February 2015 through June 2018, a total of 141 eligible patients were enrolled in the parent study, and 136
patients (96%) (44, 45 and 47 in the SD, MD, and LD
groups, respectively) were included in QoL analysis (Fig. 1).
The characteristics of the patients in the QoL substudy
are shown in Table 1. In the SD, MD and LD groups, themean ages were 57.9, 58.4 and 57.6 years, and the mean
body mass indexes (BMIs) were 25.2, 23.6 and 22.3 kg/
m2, respectively, with significant differences among BMIs
(P = 0.03). There was no significant difference in PS, estrogen receptor status, pre-treatment by chemotherapy, pretreatment by taxane, and comorbidities.
The response rates of questionnaire in the 2nd, 4th, and6th courses of protocol treatment were 98, 95 and 97% in
the SD group, 98, 100 and 97% in the MD group, and 91, 97
and 94% in the LD group, respectively. Reasons for missing
surveys are listed in Appendix Table A1.

Taxane‑related QoL
Mean scores and standard deviations for FACT-Taxane,
EQ-5D and CFS at each survey point are shown in Table 2.
The baseline scores did not differ significantly among the13

Breast Cancer
Fig. 1  CONSORT diagram.
SD, 260 mg/m2 of 3-week cycle
nab-paclitaxel; MD, 220 mg/m2
of 3-week cycle nab-paclitaxel;
LD, 180 mg/m2 of 3-week cycle
nab-paclitaxel

Enrolled (n=141)

Randomly assigned (n=141)

Allocated to SD (n=47)

Full analysis set (n=47)

Quality of life analysis(n=44)

Allocated to MD (n=46)

Allocated to LD (n=48)

Full analysis set (n=45)

Full analysis set (n=48)

Quality of life analysis(n=45)

Quality of life analysis(n=47)• No initiation of
nab-paclitaxel (n=1)

Reason for missing (n=3)

Reason for missing (n=1)• Doctor forgot to survey(n=1)• Other (n=1)• Unknown (n=1)

Table 1  Characteristics ofpatients in the quality of life
substudy

Characteristic

Age (years)
Mean (SD)
Body mass index (kg/m2)
Mean (SD)ECOG performance status, n (%)
01Missing
Estrogen receptor, n (%)
Negative
Positive
Unknown
Pre-treatment by chemotherapy, n (%)
No
YesPre-treatment by taxane, n (%)
No
YesComorbidity, n (%)
No
Yes• Doctor forgot to survey(n=1)

Treatment

P value

SD 260

MD 220LD 180(n = 44)(n = 45)(n = 47)

57.9 (9.1)

58.4 (10.4)

57.6 (10.3)

25.2 (4.9)

23.6 (3.9)

22.3 (3.5)

36 (82)8 (18)–

34 (76)
10 (22)1 (2)31(66)
16 (34)–8 (18)
36 (82)–10 (22)34 (76)1 (2)

10 (21)36 (77)1 (2)

13 (30)31 (71)16 (36)29 (64)17(36)
30 (64)26 (59)18 (41)28 (62)17 (38)30 (64)17 (36)24 (55)20 (46)22 (49)23 (51)29 (62)18 (38)

0.82*
0.03*
0.26†

0.86†

0.77†

0.89†

0.46†

SD 260 260 mg/m2 of 3-week cycle nab-paclitaxel, MD 220 220 mg/m2 of 3-week cycle nab-paclitaxel, LD
180 180 mg/m2 of 3-week cycle nab-paclitaxel, SD standard deviation, ECOG Eastern Cooperative Oncology Group

*
†

13

Kruskal–Wallis test
χ2 testBreast Cancer
Table 2  Meanscores at each survey point

Questionnaire

Survey point Treatment group

P value*

Number of responses, mean score (SD)SD 260

MD 220LD 180(n = 44)(n = 45)(n = 47)

Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course

44
42
34
28
43
42
34
28
44
42
34
29
44
42
35
29
44
42
35
28
44
42
34
29
44
42
34
29

124.7 (19.8)
111.4 (21.0)
104.4 (22.8)
106.6 (23.1)
68.7 (15.9)
64.7 (15.4)
62.1 (13.6)
64.8 (13.3)
93.4 (14.6)
79.4 (17.7)
73.3 (19.3)
72.3 (22.4)
20.2 (4.9)
18.2 (5.2)
16.5 (4.9)
16.4 (5.7)
16.4 (6.2)
16.2 (6.1)
15.5 (6.1)
16.3 (5.2)
14.9 (5.6)
15.8 (5.0)
15.6 (4.7)
15.9 (5.0)
16.7 (6.8)
14.5 (6.7)
14.5 (5.76)
15.0 (5.9)

44
42
36
30
44
42
36
30
44
42
36
30
44
43
36
30
44
42
36
30
45
42
36
30
45
42
36
30

121.6 (18.4)
117.4 (22.3)
115.6 (20.9)
117.5 (19.8)
67.0 (13.6)
66.5 (15.0)
66.5 (13.9)
68.4 (15.0)
90.6 (15.19)
86.2 (18.9)
83.7 (17.7)
85.2 (16.0)
19.3 (5.4)
20.0 (5.8)
19.4 (5.9)
19.6 (5.3)
18.9 (5.4)
17.0 (6.3)
16.4 (6.0)
16.9 (6.7)
12.0 (5.0)
14.2 (5.6)
15.44 (5.0)
15.4 (5.1)
16.70 (5.1)
15.5 (5.9)
15.3 (5.2)
16.5 (6.1)

47
42
37
31
47
42
37
31
47
42
37
31
47
42
37
31
47
42
37
31
47
42
37
31
47
42
37
31

122.8 (20.6)
121.1 (20.6)
119.3 (20.8)
117.2 (24.0)
67.5 (15.9)
67.3 (15.1)
69.5 (13.7)
69.2 (15.6)
91.4 (15.7)
89.4 (16.4)
86.9 (17.6)
84.6 (18.3)
18.6 (6.4)
18.6 (5.7)
19.8 (5.3)
19.1 (6.1)
18.29 (6.1)
17.4 (6.1)
16.3 (6.6)
16.9 (6.1)
13.1 (6.0)
14.3 (4.7)
16.2 (4.6)
15.7 (4.4)
17.5 (5.4)
17.0 (6.2)
17.3 (5.4)
17.5 (5.3)

0.75

Taxane subscale Baseline
2nd course
4th course
6th course
EQ-5D Utility
Baseline
2nd course
4th course
6th course
CFS
Total
Baseline
2nd course
4th course
6th course
PhysicalBaseline
2nd course
4th course
6th course

44
42
34
29

56.5 (7.3)
46.7 (10.2)
42.3 (12.3)
40.8 (13.6)

45
43
36
30

54.4 (9.0)
51.1 (10.4)
49.1 (10.0)
49.1 (8.5)

47
42
37
31

55.3 (8.2)
53.9 (9.5)
49.8 (10.9)
48.0 (10.2)

0.47

44
42
34
29

0.75 (0.17)
0.67 (0.15)
0.64 (0.15)
0.67 (0.15)

45
43
36
30

0.74 (0.17)
0.76 (0.18)
0.73 (0.18)
0.72 (0.16)

46
42
37
31

0.69 (0.15)
0.72 (0.17)
0.72 (0.17)
0.72 (0.16)

0.24

43
42
34
29
43
42
34
29

28.4 (6.2)
31.5 (8.0)
30.4 (5.6)
31.4 (6.3)
6.8 (5.4)
9.0 (6.6)
9.2 (5.9)
10.2 (6.3)

44
43
36
30
44
43
36
30

28.1 (5.3)
29.7 (5.6)
28.6 (5.3)
29.5 (5.2)
6.2 (4.5)
7.6 (5.3)
7.8 (4.6)
8.1 (5.1)

46
42
37
31
46
42
37
31

28.7 (6.2)
28.7 (5.9)
28.1 (5.5)
28.7 (6.6)
8.1 (5.9)
8.6 (6.0)
7.9 (5.8)
8.6 (5.6)

0.89

FACT-Taxane
Taxane total

General total

Taxane TOI

PWB

SFWB

EWB

FWB

0.86

0.68

0.38

0.13

0.05

0.74

0.19

13

Breast Cancer
Table 2  (continued)

Questionnaire

Survey point Treatment group

P value*

Number of responses, mean score (SD)

Affective

Cognitive

Baseline
2nd course
4th course
6th course
Baseline
2nd course
4th course
6th course

SD 260

MD 220LD 180(n = 44)(n = 45)(n = 47)

43
42
34
29
43
42
34
29

44
43
36
30
44
43
36
30

8.7 (3.1)
9.2 (3.3)
9.0 (2.3)
8.9 (2.5)
13.0 (2.7)
13.3 (2.3)
12.2 (3.3)
12.4 (3.6)

8.6 (3.1)
8.9 (2.8)
8.4 (3.4)
9.0 (2.9)
13.3 (2.2)
13.2 (2.6)
12.5 (3.1)
12.3 (3.3)

46
42
37
31
46
42
37
31

8.3 (3.7)
8.0 (3.9)
8.1 (3.6)
8.1 (3.5)
12.2 (2.9)
12.1 (3.8)
12.1 (3.6)
12.0 (3.2)

0.86

0.14

SD standard deviation, SD 260 260 mg/m2 of 3-week cycle nab-paclitaxel, MD 220 220 mg/m2 of 3-week cycle
nab-paclitaxel, LD 180 18 0 mg/m2 of 3-week cycle nab-paclitaxel, FACT-Taxane Functional Assessment of Cancer
Therapy-Taxane, Taxane TOI Taxane trial outcome index, PWB physical well-being, SFWB social and family wellbeing, EWB emotional well-being, FWB functional well-being, EQ-5D EuroQol 5-dimension, CFS Cancer Fatigue
Scale.
*Baseline scores were compared by t test

groups. The mean change from baseline and 95% CI for eachdose are shown in Appendix Figure A1.
In comparison of baseline-adjusted means by MMRM analysis between SD and MD, there were significant differencesin FACT-Taxane TOI (overall treatment effect, P < 0.001)(Fig. 2). The estimated mean differences and 95% CI between
SD and MD in the FACT-Taxane TOI score change from baseline in the 2nd, 4th, and 6th course of treatment were 9.8 (3.9,
15.6), 12.1 (5.9, 18.4), and 16.2 (9.7, 22.8), and the taxanerelated QoL for MD was significantly better than that for SD
during all observation periods. For other summary and domainscores, the estimated difference in the score change from baseline for MD was significantly higher for FACT-Taxane total(P < 0.001), taxane subscale (P < 0.001), PWB (P = 0.002), andEWB (P = 0.024). On the other hand, the SFWB score wassignificantly lower for MD than for SD (P = 0.037) (Fig. 2).
Significant differences between the groups were noted, especially for the PWB and taxane subscale.
In comparison of baseline-adjusted means by MMRM analysis between SD and LD, there were significant differences in
FACT-Taxane TOI (overall treatment effect, P < 0.001) (Fig. 2.).
The estimated mean differences and 95% CI between SD and LD
for the FACT-Taxane TOI score change from baseline to the 2nd,
4th, and 6th courses of treatment were 11.6 (5.8, 17.4), 15.3 (9.1,
21.4), and 16.5 (10.0, 23.0), and taxane-related QoL for LD wassignificantly better than that for SD during all observation periods. For other summary and domain scores, the estimated difference of the score change from baseline for LD was significantly
higher for FACT-Taxane total (P < 0.001), FACT-General total(P < 0.011), taxane subscale (P < 0.001), PWB (P < 0.001), andEWB (P = 0.004) (Fig. 2). Significant differences between thegroups were noted, especially for the PWB and taxane subscale.

13

In a comparison of baseline-adjusted means by MMRM
analysis, there were significant differences in EQ-5D utility
scores between SD and MD (P = 0.011), and SD and LD(P < 0.001) (Fig. 3). This reveals that preference-based QoL
for MD and LD was also significantly better than that for SD
during all observation periods.

Cancer fatigue
The mean change from baseline and 95% CI for each dose areshown in Appendix Figure A2. In comparison of baselineadjusted means by MMRM analysis, these variables showedno significant differences at SD and MD (Fig. 4). However,there were significant differences between SD and LD for CFS
total score (P = 0.013), and physical (P = 0.001) and cognitive(P = 0.033) subscores (Fig. 4). The estimated mean differences
and 95% CI between SD and LD in the CFS total score change
from baseline to the second, fourth, and sixth courses of treatment were −3.0 (−5.3, −0.8), −2.9 (−5.2, −0.5), and −3.5 (−6.0,−1.0). These data revealed that cancer fatigue for LD was significantly milder than that for SD during all observation periods.

Discussion
This is the first study comparing QoL with 260 mg/m2 of q3w
nab-PTX to that with 220 mg/m2 or 180 mg/m2 of q3w nab-PTX
in patients with metastatic breast cancer. PROs in the clinical
trial were assessed using FACT-Taxane as a taxane-related QoL
scale, CFS as a cancer-related fatigue scale, and EQ-5D as apreference-based comprehensive health assessment scale.

Breast Cancer

A FACT-Taxane TOI
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
9.8
12.1
16.2
11.6
15.3
16.5

P value
0.001<0.001<0.001<0.001(5.8, 17.4) <0.001(9.1, 21.4) <0.001(10.0, 23.0) <0.001<0.001
95%CI(3.9, 15.6)(5.9, 18.4)(9.7, 22.8)

-5

0

5

Favors SD

10

15

20

25

Favors MD or LD

B FACT-Taxane total
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
8.8
12.2
15.1

95%CI
(2.0, 15.6)(5.0, 19.5)(7.5, 22.8)

11.2
16.4
16.8

(4.5, 18.0)(9.3, 23.6)(9.2, 24.4)

P value
0.012<0.001<0.001<0.0010.001<0.001<0.001<0.001-5

0

5Favors SD

10

15

20

25

Favors MD or LD

C FACT-General total
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
95%CI
P value
1.8(-3.0, 6.7) 0.457
2.7(-2.5, 7.9) 0.305
5.1(-0.3, 10.6) 0.065
0.321
2.3
(-2.5, 7.1) 0.346
7.0(1.9, 12.1) 0.007
7.6(2.2, 13.0) 0.006
0.011
-5

0

Favors SD

5

10

15

10

15

Favors MD or LD

D Taxane subscale
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
7.0
9.2
10.4

95%CI
(3.5, 10.6)(5.4, 13.0)(6.4, 14.4)

8.7
9.0
9.4

(5.2, 12.3)(5.3, 12.8)(5.4, 13.4)

P value<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001-5Favors SD

Fig. 2  Estimates of mean differences and 95% confidence intervals
for changes in A Functional Assessment of Cancer Therapy-Taxane
trial outcome index (FACT-Taxane TOI), B FACT-Taxane total, C
FACT-General total, and D Taxane subscale, E physical well-being(PWB), F social and family well-being (SFWB), G emotional well-

05Favors MD or LD

being (EWB), H functional well-being (FWB) scores, compared toSD (260 mg/m2 of 3-week cycle nab-paclitaxel) in a mixed effects
model for repeated measures. MD, 220 mg/m2 of 3-week cycle nabpaclitaxel; LD, 180 mg/m2 of 3-week cycle nab-paclitaxel

13

Breast Cancer

E PWB
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
2.5
3.2
4.3

95%CI
(0.3, 4.6)
(1.0, 5.5)
(2.0, 6.7)

1.7
4.5
4.8

(-0.4, 3.8)
(2.2, 6.7)
(2.5, 7.2)

P value
0.023
0.005<0.001
0.002
0.121<0.001<0.001<0.001-5

0

5Favors SD

10

Favors MD or LD

F SFWBSD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
95%CI
P value-2.1(-4.1, -0.1) 0.037-2.3(-4.4, -0.1) 0.037-3.0(-5.2, -0.7) 0.009
0.037
-1.0
(-3.0, 0.9)
0.301
-1.5
(-3.6, 0.6)
0.153
-2.1
(-4.3, 0.1)
0.063
0.266
-10

-5

0

5

Favors SD

Favors MD or LD

0

5

G EWB
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
1.3
2.4
2.4

95%CI
(-0.4, 3.0)
(0.6, 4.1)
(0.6, 4.3)

0.6
2.5
2.8

(-1.0, 2.3)
(0.8, 4.3)
(0.9, 4.6)

P value
0.123
0.009
0.011
0.024
0.471
0.005
0.003
0.004
-5
Favors SD

Favors MD or LD

H FWB
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
0.3
-0.1
1.5

95%CI
(-1.7, 2.3)(-2.2, 2.0)(-0.8, 3.7)

1.3
1.9
2.3

(-0.6, 3.3)(-0.2, 4.0)
(0.1, 4.5)

P value
0.776
0.914
0.193
0.523
0.186
0.077
0.044
0.165
-5

0
Favors SD

Fig. 2  (continued)

13

5
Favors MD or LD

Breast Cancer

SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
95%CI
P value
0.10(0.04, 0.16) 0.003
0.09(0.02, 0.16) 0.009
0.07(0.00, 0.15) 0.045
0.011
0.11
(0.05, 0.18) <0.001
0.14(0.07, 0.20) <0.001
0.14(0.06, 0.21) <0.001<0.001-0.1
Favors SD

0

0.1

0.2

0.3

Favors MD or LD

Fig. 3  Estimates of mean differences and 95% confidence intervals
for changes in EuroQol 5-Dimension (EQ-5D) scores, compared toSD (260 mg/m2 of 3-week cycle nab-paclitaxel) in a mixed effects

model for repeated measures. MD, 220 mg/m2 of 3-week cycle nabpaclitaxel; LD, 180 mg/m2 of 3-week cycle nab-paclitaxel

We found that the initial dose of q3w nab-PTX had a significant effect on taxane-related QoL and cancer fatigue. QoL
of patients with metastatic breast cancer treated with 260 mg/
m2 of q3w nab-PTX was significantly worse compared tothose treated with 220 or 180 mg/m2 of q3w nab-PTX, andsignificant differences between the groups were noted, especially for the PWB and taxane subscale. Many of the QoL
constituent domains showed a positive trend with low-dose
nab-PTX, but SFWB showed the opposite trend, for unknown
reasons. Primary endpoint analysis showed that intravenous
administration of low-dose nab-PTX at 180 mg/m2 q3w may
be the optimal therapy with meaningful efficacy and favorable
toxicity for patients with metastatic breast cancer [4]. The
QoL substudy also showed that low-dose nab-PTX at 180 mg/
m2 q3w is optimal in terms of QoL and cancer-related fatigue.
Standard doses of chemotherapeutic agents should bedetermined based on risk and benefit balance. However, interms of dose intensity, the standard dose is often determined by acute toxicities such as hematologic toxicity,
diarrhea, and vomiting during development of the drug.
Regarding the cumulative toxicity of chemotherapy, a strategy of continuing treatment by short-term drug withdrawal
or reducing the dose is used based on observation of adverse
events. However, some adverse effects of chemotherapy are
not easily improved by withdrawing or reducing the dose of
chemotherapy, and CIPN is an example. In a discussion at
the start of the study, treatment with nab-PTX using drug
reduction and withdrawal was suggested to be optimal. However, we obtained a result that overturned this opinion, since
we found that the initial dose of nab-PTX has a significant
effect on subsequent patient QoL.
CIPN is a major clinical challenge due to lack of effective treatment and impact on QoL [9]. There are no drugs
for preventing or ameliorating CIPN in a long-term course,
and chemotherapy schedule modification is often required
to limit its severity; however, this also may limit the efficacyof the cancer treatment. Moreover, symptomatic therapy isoften ineffective in reducing CIPN symptoms [10]. Taxanes

are representative chemotherapeutic agents that induce
CIPN. Taxanes inhibit depolymerization of microtubules[11, 12], and CIPN may be caused by the resulting abnormal
aggregation of microtubules in neuronal cells. Polyoxyethylated castor oil, which is used as a vehicle for taxanes, mayalso increase the risk for prolonged peripheral neuropathy[13]. Animal studies have shown that the time to recovery
from CIPN depends on the drug, and that the morphologicaleffect on axons in PTX-treated animals is long lasting [14].
Nab-PTX is an albumin-bound, nanoparticle formulation of PTX that was developed to reduce the incidence of
CIPN compared to that with conventional taxanes [15, 16].
However, in the CA012-0 trial, a phase III study comparing 3-week cycles of nab-PTX (260 mg/m2) and so-PTX(175 mg/m2) in patients with metastatic breast cancer, CIPN
occurred more frequently with nab-PTX, despite nab-PTX
showing greater efficacy in terms of RR [1]. In contrast,
superiority of nab-PTX over so-PTX in PFS was not found inpatients with metastatic breast cancer in the CALGB40502
phase III trial, and hematologic toxicity of grade ≥ 3 andCIPN occurred more frequently with nab-PTX [17]. Dose
reduction was more common and occurred earlier with nabPTX, and discontinuation rates were also higher. Therefore,
it was concluded that the dose of nab-PTX used in the study(150 mg/m2/week) was not appropriate and resulted in significant toxicity. These studies indicate that the initial doseof nab-PTX can cause adverse events that may have a long
recovery time and a significant effect on patient outcomes,
consistent with the findings obtained in this study.
Cancer-related fatigue causes disruption of all aspectsof QoL and may be a risk factor for reduced survival [18].
Fatigue may be elevated before treatment onset and typically increases during cancer treatment, including that withradiation, chemotherapy, hormonal, and/or biological therapies. The rate of cancer-related fatigue ranges from 4 to
91%, depending on the population studied and the methods of assessment [19]. In a RCT comparing taxanes andS-1 in patients with metastatic breast cancer in Japan, the13

Breast Cancer

A CFS total
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
-1.4
-1.4
-2.2
-3.0
-2.9
-3.5

P value
0.220
0.237
0.083
0.338
(-5.3, -0.8) 0.008(-5.2, -0.5) 0.019(-6.0, -1.0) 0.006
0.013
-10
95%CI
(-3.6, 0.8)(-3.8, 1.0)(-4.8, 0.3)

-50Favors MD or LD

5
Favors SD

B CFS physicalSD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
95%CI
P value-0.9(-3.0, 1.1)
0.366
-1.4
(-3.6, 0.7) 0.195-2.6(-4.9, -0.3) 0.026
0.160
-1.8
(-3.8, 0.2)
0.082
-3.2
(-5.4, -1.1) 0.004-4.3(-6.6, -2.1) <0.001
0.001
-10

-5

0

Favors MD or LD

5
Favors SD

C CFS affective
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
-0.2
-0.5
-0.1

95%CI
(-1.4, 1.1)(-1.8, 0.9)(-1.5, 1.3)

-0.8
-0.5
-0.2

(-2.1, 0.5)(-1.8, 0.8)(-1.6, 1.2)

P value
0.809
0.480
0.880
0.912
0.210
0.460
0.823
0.618
-3

-2

-1

0

Favors MD or LD

1

2

Favors SD

D CFS cognitive
SD vs. MD 2nd course
4th course
6th course
overall treatment effect
SD vs. LD 2nd course
4th course
6th course
overall treatment effect

Estimated value
-0.3
0.5
0.5

95%CI
(-1.3, 0.7)(-0.6, 1.5)(-0.6, 1.6)

-0.4
0.9
1.0

(-1.4, 0.6)(-0.2, 1.9)(-0.1, 2.1)

P value
0.530
0.377
0.373
0.384
0.384
0.111
0.088
0.033
-2

-1

Favors MD or LD

Fig. 4  Estimates of mean changes and 95% confidence interval for A
Cancer Fatigue Scale (CFS) total, B physical, C affective, and D cognitive scores, compared to SD (260 mg/m2 of 3-week cycle nab-pacli-

13

0

1

2

3

Favors SD

taxel) by mixed effects model for repeated measures. MD, 220 mg/
m2 of 3-week cycle nab-paclitaxel; LD, 180 mg/m2 of 3-week cycle
nab-paclitaxel

Breast Cancer

frequency of fatigue in the taxane group was approximately
50% in all grades [20]. However, these data are based on
physician’s assessments, which may be underreported, andthe actual rate of fatigue in taxane-based chemotherapy formetastatic breast cancer is likely to be higher [21]. Fatigue
in cancer patients is multifactorial and may be influenced bydemographic, medical, psychosocial, behavioral, and biological factors [18]. Nevertheless, the initial dose of nab-PTX
had a significant effect on subjective fatigue in this study,
especially for physical fatigue. At the current standard doseof 260 mg/m2, physical fatigue worsened over the course oftreatment, but no worsening tendency was observed at 220
or 180 mg/m2. Cancer fatigue in metastatic breast cancer
patients treated with low-dose nab-PTX at 180 mg/m2 q3w
was significantly milder than that in patients treated withstandard dose nab-PTX.
Both CIPN and fatigue are symptoms that are difficult forphysicians to evaluate accurately, and in clinical trials, thediscrepancy between physicians’ assessments and patients
reported outcomes (PROs) can be a problem [21]. In a RCTof adjuvant chemotherapy with taxanes for breast cancer, asubstudy of the agreement between physician and patient
assessments for CIPN gave kappa coefficients for sensory
and motor symptoms of 0.16 and 0.22, which are extremely
low [22]. In a comparative study of clinician and patient
assessment of symptoms in lung cancer patients, 41% ofclinicians underreported symptoms of fatigue compared topatient reports [23]. Therefore, as the results of this study
indicate, there is a limit to the therapeutic strategy of monitoring the cumulative toxicity associated with chemotherapy
by physician assessment and reducing the dose or withdrawing the drug when this toxicity becomes significant. If atreatment strategy is to truly maintain and improve QoL, it
is essential to monitor PROs in daily clinical practice [24]. It
is also important to verify the dose that achieves the optimalrisk and benefit balance after marketing of a new chemotherapeutic agent, particularly for drugs with cumulative
toxicity.
A limitation of this study is that it is based on a secondary endpoint of a small randomized phase 2 trial, with noadjustment for multiple tests. Also, a relatively short-term
evaluation up to the sixth cycle was used, and long-term
effects were not examined. Furthermore, a weekly schedule of nab-PTX is more commonly used to treat patientswith breast cancer, and the significance of our findings forthe reduced dose of q3w nab-PTX may be limited. NabPTX at 100 mg/m2 can be administered weekly to reducethe incidence and degree of myalgia. Nonetheless, it was
not until recently that the weekly nab-PTX regimen was
adopted in Japan for treatment of patients with metastatic
breast cancer due to previous failures to demonstrate its

superiority to q3w docetaxel in terms of PFS [25]. There
should be room for less frequent regimens, especially inpatients with limited access to clinics or in those who
might benefit from minimizing the risk of coronavirus
infection during the COVID-19 pandemic.
In conclusion, the initial dose of nab-PTX affects subsequent taxane-related QoL, as well as cancer-related
fatigue. Low dose nab-paclitaxel at 180 mg/m2 q3w may
be an optimal dose in terms of PFS, taxane-related QoL
and cancer-related fatigue. Further evaluation is warranted
to confirm these findings in a larger trial.
Supplementary Information The online version contains supplementary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12282-0​ 21-0​ 1290-5.
Acknowledgements This work was supported by a Comprehensive
Support Project Award for Oncology Research in Breast Cancer(CSPOR-BC). The authors would like to thank all the patients who
participated in the ABROAD trial and their families. We also thank theinvestigators and research coordinators at the 41 participating institutions. We are also grateful to Ms. H. Shinano for the administrative
support required to carry out this research.
Author contributions Conceptualization: FH, HM and NT. Methodology: FH, KK, TS, NT, TT and JT. Software and formal analysis: KK.
Investigation: NT, JT, MK, MT, HK. YK, ES, YN, YH, TS, TI, TT, TA,
HM and FH. Data curation: TA. Writing of original draft: NT and KK.
Reviewing and editing: all authors. Visualization: YA, NT, KK and FH.
Supervision: HM. Data curation: FH and KK. Project administration:
FH. Funding acquisition: FH and HM.
Funding The ABROAD study was sponsored by the Comprehensive
Support Project for Oncology Research in Breast Cancer, with researchfunds provided by Taiho Pharmaceutical under the study contract.
Taiho Pharmaceutical took no part in this study other than providing
information relevant to proper use of the study drug.

Declarations
Conflict of interest Junji Tsurutani has received research funds from
Daiichi Sankyo; honoraria from Novartis, Taiho, Eisai, Chugai, andKyowa Kirin; personal fees for participating in advisory boards for Eisai and Asahi Kasei; and support for travel expenses from Daiichi Sankyo. Masato Takahashi has received an honorarium for a lecture from
Taiho. Yoichi Naito has received research funds from Roche Diagnostics; and honoraria for lectures from Roche Diagnostics, Novartis, Eisai, Chugai Pharmaceutical, Fuji Film Toyama Chemistry, and Taiho.
Hirofumi Mukai has received honoraria from Pfizer, Takeda, Daiichi
Sankyo and Taiho; and research grants from the Japanese government,
Daiichi Sankyo, and Pfizer. Hirofumi Mukai is a member of the Boardof Directors of the Japan Breast Cancer Society.
Ethics approval This study was reviewed and approved by independent
ethics committees and institutional review boards. Written informed
consent was obtained from all patients.
Data sharing Due to the nature of this research, participants in the
study did not agree for their data to be shared publicly, so supporting
data are not available.

13

Breast Cancer

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Breast Cancer

Authors and Affiliations
Naruto Taira1 · Kosuke Kashiwabara2 · Junji Tsurutani3 · Masahiro Kitada4 · Masato Takahashi5 · Hiroaki Kato6 ·Yuichiro Kikawa7 · Eiko Sakata8 · Yoichi Naito9 · Yoshie Hasegawa10 · Tsuyoshi Saito11 · Tsutomu Iwasa12 ·Tsutomu Takashima13 · Tomohiko Aihara14 · Hirofumi Mukai9 · Fumikata Hara15
1

Department of Breast and Endocrine Surgery, Okayama
University Hospital, 2‑5‑1 Shikata‑cho, Kita‑ku,
Okayama 700‑8558, Japan

9

Department of Medical Oncology, National Cancer Center
Hospital East, Chiba, Japan10

Department of Breast Surgery, Hirosaki Municipal Hospital,
Aomori, Japan

2

Clinical Research Promotion Center, University of Tokyo
Hospital, Tokyo, Japan

11

3

Advanced Cancer Translational Research Institute, Showa
University, Tokyo, Japan

Department of Breast Surgery, Japanese Red Cross Saitama
Hospital, Saitama, Japan

12

4

Breast Disease Center, Asahikawa Medical University
Hospital, Hokkaido, Japan

Department of Medical Oncology, Faculty of Medicine,
Kindai University, Osaka, Japan

13

5

Department of Breast Surgery, National Hospital
Organization Hokkaido Cancer Center, Hokkaido, Japan

Department of Breast and Endocrine Surgery, Osaka City
University Graduate School of Medicine, Osaka, Japan

14

Breast Center, Aihara Hospital, Osaka, Japan

15

Breast Oncology Center, Cancer Institute Hospitalof Japanese Foundation for Cancer Research, Tokyo, Japan

6

Department of Breast Surgery, Teine Keijinkai Hospital,
Hokkaido, Japan

7

Department of Breast Surgery, Kansai Medical University
Hospital, Osaka, Japan

8

Department of Breast Surgery, Niigata City General Hospital,
Niigata, Japan

13