JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Placebo-Controlled, Double-Blinded Phase III Study

Comparing Dexamethasone on Day 1 With Dexamethasone
on Days 1 to 3 With Combined Neurokinin-1 Receptor
Antagonist and Palonosetron in High-
Emetogenic Chemotherapy
Yuka Ito, Takashi Tsuda, Hiroko Minatogawa, Sayaka Kano, Kentaro Sakamaki, Masahiko Ando, Koichiro
Tsugawa, Yasuyuki Kojima, Naoki Furuya, Kunihiro Matsuzaki, Mamoru Fukuda, Sadatoshi Sugae, Ichiro Ohta,
Hitoshi Arioka, Yutaka Tokuda, Kazutaka Narui, Ayako Tsuboya, Takashi Suda, Satoshi Morita, Narikazu Boku,
Takeharu Yamanaka, and Takako Eguchi Nakajima

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article.
Published at jco.org on February 14, 2018.
The views expressed in this article belong
to the authors alone and do not
necessarily reflect the official positions of
the institutions to which the authors
belong or the funding source.
Clinical trial information:
UMIN000008867.
Corresponding author: Takako Eguchi
Nakajima, MD, PhD, Department of
Clinical Oncology, St Marianna University
School of Medicine, Sugao 2-16-1,
Miyamae-ku, Kawasaki, Kanagawa,
216-8511, Japan; e-mail: tnakajima@
marianna-u.ac.jp.
© 2018 by American Society of Clinical
Oncology
0732-183X/18/3699-1/$20.00
A B S T R A C T
Purpose
We evaluated the noninferiority of dexamethasone (DEX) on day 1, with sparing on days 2 and 3,
combined with neurokinin-1 receptor antagonist (NK1-RA) and palonosetron (Palo) compared with
the 3-day use of DEX in highly-emetogenic chemotherapy (HEC).
Patients and Methods
Patients who were scheduled to receive HEC (cisplatin $ 50 mg/m2 or anthracycline plus cyclo-
phosphamide) were randomly assigned to receive either DEX on days 1 to 3 (Arm D3) or DEX on day
1 and placebo on days 2 and 3 (Arm D1) combined with NK1-RA and Palo. The primary end point was
complete response (CR), defined as no emesis and no rescue medications during the overall (0 to
120 h) phase. The noninferiority margin was set at 215.0% (Arm D1 2 Arm D3).
Results
A total of 396 patients—196 and 200 patients in Arms D3 and D1, respectively—were evaluated. CR
rates during the overall period were 46.9% for Arm D3 and 44.0% for Arm D1 (95% CI, 212.6% to
6.8%; P = .007). CR rates during the acute (0 to 24 h) phase were 63.3% and 64.5% for Arms D3 and
D1, respectively (95% CI, 28.1% to 10.6%; P , .001), and they were 56.6% and 51.5%, re-
spectively, during the delayed (24 to 120 h) phase (95% CI, 214.8% to 4.6%; P = .023). Hot flushes
and tremors were observed more frequently as DEX-related adverse events on days 4 and 5 in Arm
D3, whereas anorexia, depression, and fatigue were observed more frequently on days 2 and 3 in
Arm D1. As an indication of quality of life, global health status was similar in both arms.
Conclusion
Antiemetic DEX administration on days 2 and 3 can be spared when combined with NK1-RA and Palo
in HEC.

J Clin Oncol 36. © 2018 by American Society of Clinical Oncology

(DEX) has long been used as an effective anti-

INTRODUCTION
Chemotherapy-induced nausea and vomiting
ASSOCIATED CONTENT (CINV) is one of the most common adverse
Appendix reactions associated with chemotherapy that can
DOI: https://doi.org/10.1200/JCO.
significantly diminish patient quality of life (QOL).
2017.74.4375
In recent years, new antiemetic drugs, such as
Data Supplement
DOI: https://doi.org/10.1200/JCO.
second-generation serotonin (5-HT3) receptor
2017.74.4375 antagonists,1-3 neurokinin-1 receptor antagonist
DOI: https://doi.org/10.1200/JCO.2017.
(NK1-RA),4-6 and netupitant/palonosetron,7-9
74.4375 have been developed, whereas dexamethasone
emetic treatment10; however, health care pro-
fessionals have raised concerns about adverse
reactions caused by the repeated administration
of DEX. Vardy et al11 investigated adverse re-
actions to DEX when used to prevent delayed
emesis in moderately emetogenic chemotherapy
(MEC), including anthracycline plus cyclophos-
phamide (AC), and reported such moderate-to-
severe adverse reactions to DEX as insomnia
(45%), indigestion and epigastric discomfort
(27%), and agitation (27%).

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 Ito et al
Antiemetic therapies that spare DEX on day 2 and thereafter
have been reported for MEC.12,13 Aapro et al12 reported a double-
blind, placebo-controlled randomized phase III study that compared
treatments with or without DEX on days 2 and 3 in combination
with DEX on day 1 and palonosetron (Palo) in patients with breast
cancer who received AC. The complete response (CR) rate in the day
1 arm was 53.6%, which was noted to be statistically noninferior to
the CR rate in the day 1 to 3 arm (53.7%). Moreover, the incidence of
insomnia as an adverse reaction to DEX was significantly lower in
the day 1 arm than in the day 1 to 3 arm. Second, Celio et al13 have
reported another randomized phase III study in which they eval-
uated the noninferiority of DEX sparing on days 2 and 3, combined
with Palo, in MEC, including AC. The study demonstrated the
noninferiority of DEX sparing for CR for overall, acute, and delayed
phases.
Some supportive care guidelines14-17 for the prevention of
CINV classify cisplatin (CDDP; $ 50 mg/m2)-based regimens and
AC as highly emetogenic chemotherapy (HEC) and recommend
the combined use of NK1-RA, a 5-HT3 receptor antagonist, and
DEX for HEC. At present, Multinational Association of Supportive
Care in Cancer/European Society for Medical Oncology and
National Comprehensive Cancer Network guidelines state that the
administration of DEX on days 2 and 3 can be spared for MEC and
AC.
In HEC, DEX sparing on days 2 and 3 has not yet been
evaluated. We conducted a phase III study to evaluate the non-
inferiority of DEX sparing on days 2 and 3 combined with NK1-RA
and Palo in HEC, including AC.
PATIENTS AND METHODS
Study Population
Patients who were eligible for inclusion in the study were adults older
than age 20 years with a histologically or cytologically confirmed malignant
tumor who were scheduled to receive primary chemotherapy that con-
tained CDDP $ 50 mg/m2 on day 1 or AC. Additional inclusion criteria
included the absence of nausea and vomiting in the 24 hours before
enrollment, an Eastern Cooperative Oncology Group performance status
of 0 or 1, adequate organ function as confirmed by laboratory data within
2 weeks before enrollment (AST , 100 IU/L, ALT , 100 IU/L, total
bilirubin , 2.0 mg/dL, serum creatinine , 1.5 mg/dL), a life expectancy
of $ 3 months, and written informed consent from the patient before
enrollment.
Main exclusion criteria included patients with hematopoietic ma-
lignancy, brain metastasis, contraindications for corticosteroid use, routine
use of corticosteroids, and use of any drug with antiemetic activity.
This study was conducted according to the Declaration of Helsinki
and was approved by the institutional review board at each site.
Study Design and Random Assignment
This was a multicenter, placebo-controlled, double-blinded, ran-
domized phase III study that aimed to clarify the noninferiority of DEX on
day 1 and DEX on days 1 to 3 when combined with NK1-RA and Palo in
HEC.
Eligible patients were randomly assigned to receive either DEX on
days 1 to 3 (Arm D3) or DEX on day 1 with placebo on days 2 and 3 (Arm
D1) as part of prophylactic antiemetic therapy. Random assignment was
centrally done by using the minimization method with balancing prog-
nostic factors for institution, age (, 60 years v $ 60 years), and regimen
(CDDP-containing regimen v AC).
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At each institution, one unblinded pharmacist was predesignated and
responsible for preparing the assigned study drug. Placebo was in-
distinguishable from DEX because the placebo for oral administration was
made by using a dose form that was similar to oral DEX, whereas saline
without DEX was used for intravenous administration.
Antiemetic Treatments
Patients in both arms received Palo and aprepitant (APR). Palo
0.75 mg was administered intravenously at 30 minutes before the start of
chemotherapy on day 1. Oral APR 125 mg or intravenous fosaprepitant
150 mg was administered 1 hour before the start of chemotherapy. Patients
who received oral APR on day 1 also received APR 80 mg on days 2 and 3.
The mode of DEX administration was as follows: patients in both
arms received DEX 12 mg intravenously on day 1; in Arm D3, patients
received intravenous or oral DEX 8 mg on days 2 and 3; and in Arm D1,
patients received an intravenous or oral placebo on days 2 and 3.
Patients were allowed to take rescue medication throughout the study
period for nausea or vomiting, if necessary. The choice of recommended
rescue medicine was made by each investigator from among pro-
chlorperazine, metoclopramide, domperidone, alprazolam, lorazepam,
and olanzapine.
End Points
Patients were asked to write in a diary each day throughout the overall
period (5 days). In this diary, the frequency of emetic events, use of rescue
medication, and the maximum nausea and DEX-related adverse events
(AEs) were measured by using a 4-point Likert scale (0, none; 1, mild; 2,
moderate; 3, severe). A blinded evaluator checked for missing values and, if
present, the patient was asked to provide the missing information. The
diary was collected at the end of the overall period.
Primary end point was CR—defined as no emetic episodes and no use
of rescue antiemetic medication—during the 120-hour period after the
start of chemotherapy (overall period).
Secondary end points were CR during the acute phase (0 to 24 h) and
the delayed phase (24 to 120 h); severity of nausea; DEX-related AEs, such
as hot flushes, tremor, anorexia, depression, fatigue, indigestion and/or
pyrosis, increased appetite, hiccups, nervousness, insomnia, and acne; AEs
evaluated by blinded investigators according to the Common Terminology
Criteria for Adverse Events version 4.018 during the overall period; and
QOL.
Exploratory end points were complete control (CC; no emetic epi-
sode, no use of rescue medication, and no more than mild nausea) and
total control (TC; no emetic episode, no use of rescue medication, and no
nausea) during the overall period and the acute and delayed phase.
QOL Analysis
QOL was assessed by using the European Organisation for Research
and Treatment of Cancer Quality of Life Questionnaire C3019 before the
start of chemotherapy and at the end of the overall period. Patients were
instructed to complete the survey forms and post them in the return
envelope addressed to the study coordinator. Global health status (GHS),
functional scales, and symptom scales were calculated according to the
European Organisation for Research and Treatment of Cancer Quality of
Life Questionnaire C30 Scoring Manual.20 A linear transformation was
used to standardize the raw score from 0 to 100—a higher score for GHS
and functional scales represented a better condition, whereas a higher score
for the symptom scales indicated a worse level of symptoms.
Statistical Analysis
The noninferiority of the primary end point was evaluated by using
the Farrington-Manning test.21 We set the noninferiority margin to 15.0%
of the difference between the two arms. The lower boundary of the 95% CI
should be compared with this margin. Nausea and adverse events were
compared by using Fisher’s exact test. P values for noninferiority tests were
JOURNAL OF CLINICAL ONCOLOGY
 Phase III Study to Spare Dexamethasone on Days 2 and 3 in HEC

reported as one sided, whereas other P values were two sided. In QOL
analyses, the mean and standard deviation were calculated. GHS was the Table 1. Patient Characteristics
main outcome for comparing treatment groups. QOL score was compared Characteristic Arm D1 (n = 200) Arm D3 (n = 196)
between treatment arms by using an analysis of covariance that included
Age, median (range) 54.1 (27-78) 55.0 (24-79)
the treatment arm and baseline QOL score as explanatory variables. We Sex
considered a one-sided P value of # .025 and a two-sided P value of # .05 Male 37 (18.5) 39 (19.9)
to be statistically significant. The full analysis set of this study was the Female 163 (81.5) 157 (80.1)
registered participant population who received at least part of the protocol Cancer type
treatment; however, participants who were revealed as ineligible for the Breast 155 (77.5) 150 (76.5)
study after registration and those who used prohibited concomitant Esophageal 18 (9) 21 (10.7)
medications or therapies were excluded from the analysis set. Gastric 16 (8) 13 (6.6)
Sample size calculation was based on an analysis of the primary end Lung 10 (5) 7 (3.6)
point. We assumed that CR rates during the overall period would be 50.0% Others 1 (0.5) 5 (2.6)
Chemotherapy
in both arms. One hundred seventy-five patients were required for each
AC 155 (77.5) 151 (77.0)
arm for at least 80% power to confirm noninferiority at a one-sided CDDP-containing regimens 45 (23.5) 45 (23.0)
significance level of 2.5%. After considering the possibility of dropouts, we NK1-RA
set our final target at 400 patients. Aprepitant 159 (79.5) 151 (77.0)
All statistical analyses were performed by using SAS (SAS/STAT User’s Fosaprepitant 41 (20.5) 45 (23.0)
Guide, Version 9.3; SAS Institute, Cary, NC).
NOTE. Data presented as No. (%) unless otherwise indicated.
Abbreviations: AC, anthracycline plus cyclophosphamide; Arm D1, dexa-
methasone day 1; Arm D3, dexamethasone day 1 to 3; CDDP, cisplatin; NK1-RA,
neurokinin-1 receptor antagonist.
RESULTS

Patient Characteristics
From October 2013 to October 2015, 401 patients were en- Efficacy and Safety
rolled and randomly assigned to either Arm D3 (n = 201) or Arm CR rates for the overall period—as the primary end
D1 (n = 200). Five patients did not receive the study treatment (Fig point—were 46.9% in Arm D3 and 44.0% in Arm D1, with
1)—three patients withdrew their consent before the start of the a difference of 22.9% (95% CI, 212.6% to 6.8%; P = .007), which
protocol treatment, and two patients had major protocol de- demonstrated that the primary end point was met (Table 2). CR
viations by using drugs with antiemetic activities at study baseline. rates in Arm D1 during the acute and delayed phases were also
Finally, 396 patients—196 and 200 patients in Arm D3 and Arm noninferior to those in Arm D3 in the respective phases (acute
D1, respectively—were included in the full analysis set. phase: 63.3% in Arm D3 and 64.5% Arm D1 [95% CI of
Patient characteristics were well balanced between the two difference, 28.1% to 10.6%; P , .001]; delayed phase: 56.6% in
arms (Table 1). Most patients (80%) were women—157 and 163 Arm D3 and 51.5% in Arm D1 [95% CI of difference, 214.8% to
patients in Arm D3 and Arm D1, respectively—and 77% of pa- 4.6%; P = .023]). Thus, the noninferiority of Arm D1 to Arm D3
tients had breast cancer—150 and 155 patients with Arm D3 and for CR was demonstrated in all the three end points.
Arm D1, respectively. CC rates during the overall period were 44.4% in Arm D3 and
40.0% in Arm D1, with a difference of 24.4% (95% CI, 214.0% to
5.2%; P = .015), thus demonstrating the noninferiority of Arm D1
to Arm D3 in CC; however, the noninferiority of DEX sparing for
Randomly assigned
(N = 401) CC during the delayed phase was not demonstrated (95%
CI, 25.0% to 4.1%; P = .029). TC rates during the overall period
were 29.6% in Arm D3 and 28.0% in Arm D1, with a difference
of 21.6% (95% CI, 210.5% to 7.3%; P = .002), thus also
Allocated to intervention Allocated to intervention demonstrating the noninferiority of Arm D1 to Arm D3 in TC
Arm D1 Arm D3 (Table 2 and Appendix Fig A1, online only).
(n = 200) (n = 201)
Severity of nausea, as evaluated with a Likert scale, was not
significantly different between the 2 arms on any day (Table 3).
Excluded During the acute phase, 80.5% of patients in Arm D1 and 78.0% in
Withdrew consent (n = 3) Arm D3 had a Likert scale reading of 0 or 1, which indicated no
Met study discontinuation
criteria (n = 2) more than mild nausea. During the delayed phase, the proportions
of patients with Likert scale readings of 0 or 1 were relatively high
(. 85%) in both arms. Although the proportions were slightly
Analyzed Analyzed lower in Arm D1 than in Arm D3 on days 2 and 3, these differences
(n = 200) (n = 196)
were not statistically significant.
The proportions of patients who used rescue medication
Fig 1. CONSORT diagram. Of the 401 randomly assigned patients, 201 and 200 during the overall period were 49.5% in Arm D3 and 50.0% in Arm
were confirmed to be eligible in the dexamethasone day 1 to 3 (Arm D3) and
D1, whereas 32.7% and 28.5% of patients and 38.8% and 43.0% of
dexamethasone day 1 (Arm D1) arms, respectively. Three patients withdrew
consent, and two patients met the study discontinuation criteria before the start of patients used rescue medication during the acute phase and
treatment in Arm D3 and were excluded from efficacy analyses. delayed phase in Arm D3 and Arm D1, respectively.

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 Ito et al

Table 2. CR Rate, CC Rate, and TC Rate

Outcome Arm D1 (n = 200) Arm D3 (n = 196) Risk Difference* (95% CI) P†
CR
Overall 88 (44.0) 92 (46.9) 22.9 (212.6 to 6.8) .007
Acute 129 (64.5) 124 (63.3) 1.2 (28.1 to 10.6) , .001
Delayed 103 51.5) 111 (56.6) 25.1 (214.8 to 4.6) .023
CC
Overall 80 (40.0) 87 (44.4) 24.4 (214.0 to 5.2) .015
Acute 123 (61.5) 120 (61.2) 0.3 (29.2 to 9.8) , .001
Delayed 99 (49.5) 108 (55.1) 25.6 (215.3 to 4.1) .029
TC
Overall 56 (28.0) 58 (29.6) 21.6 (210.5 to 7.3) .002
Acute 93 (46.5) 86 (43.9) 2.6 (27.1 to 12.3) , .001
Delayed 66 (33.0) 71 (36.2) 23.2 (212.5 to 6.1) .007

NOTE. Data presented as NO. (%) unless otherwise indicated.

Abbreviations: Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1 to 3; CC, complete control (no emetic episodes, no use of rescue medication, and no
more than mild nausea); CR, complete response (no emetic episodes and no use of rescue medication); TC, total control (no emetic episodes, no use of rescue
medication, and no nausea).
*Risk difference = 215% indicates noninferiority margin.
†One-sided P value # .025 was regarded as an indication of statistical significance.

With regard to AEs related to DEX that were prespecified in
the protocol, hot flushes on day 4 (Likert scale readings of 1 to 3:
36.4% in Arm D3 v 24.0% in Arm D1) and day 5 (31.3% in Arm
D3 v 19.6% in Arm D1) and tremors on day 5 (11.3% in Arm D3 v
5.5% in Arm D1) were observed more frequently in Arm D3 than
in Arm D1, whereas anorexia on day 2 (75.4% in Arm D1 v 71.3%
in Arm D3) and day 3 (86.7% in Arm D1 v 76.9% in Arm D3),
depression on day 2 (48.5% in Arm D1 v 36.9% in Arm D3), and
fatigue on day 2 (72.0% in Arm D1 v 64.6% in Arm D3) and day 3
(81.0% in Arm D1 v 70.3% in Arm D3) were more frequently
observed in Arm D1 than in Arm D3 (Table 4). No statistical
differences in the other items were observed between the two arms.
When the daily occurrences of DEX-related AEs were compared,
the differences between the two arms were relatively small, with the
exception of anorexia and fatigue, which demonstrated lower
proportions of Likert scale readings (0 or 1) on days 2 and 3 in Arm
D1 (anorexia: 72.8% v 59.3% on day 2, and 68.7% v 56.0% on day
3; fatigue: 81.0% v 63.5% on day 2, and 76.4% v 60.5% on day 3).
Incidences of other observed AEs of grade $ 3 evaluated by
each investigator during the overall period were similar in both
arms (Appendix Table A1, online only).
We performed subgroup analyses for patients who received
the AC regimen and for those who received a CDDP-containing
regimen (Table 5). CR, CC, and TC rates for patients who received
the AC regimen demonstrated a noninferiority difference between
Arm D3 and Arm D1 during the overall period. In contrast,
noninferiority was not demonstrated among the patients who
received a CDDP-containing regimen.
QOL Analysis
QOL questionnaires were collected from 99.3% of patients at
baseline and 98.5% at the end of the overall period. GHS scores
were 68.1 6 23.6 before the start of chemotherapy and 39.4 6 25.7
at the end of the overall period in Arm D3, and 68.1 6 22.9 and
38.1 6 24.8 in Arm D1, respectively (Table 6). The change in the
score was not statistically different between Arm D3 and Arm D1
(21.30 6 1.73; P = .454). Arm D3 demonstrated worse scores than
in Arm D1 for constipation and diarrhea, whereas Arm D3 dis-
played better scores for the physical category on the functional scale
and for appetite loss on the symptom scale. There were no significant
differences in the scores for other items between the two arms.
DISCUSSION
To our knowledge, this is the first study to demonstrate the
noninferiority of DEX sparing on days 2 and 3 compared with DEX
on days 1 to 3, when combined with NK1-RA and Palo in terms of
the overall CR in HEC. Although Celio et al12 demonstrated that

Table 3. Incidences of Patient-Reported Nausea From Day 1 to 5

Arm D1 (Likert scale) Arm D3 (Likert scale)
Nausea 0 1 2 3 0 1 2 3 P*
Day 1 101 (50.5) 60 (30.0) 28 (14.0) 11 (5.5) 92 (47.2) 60 (30.8) 29 (14.9) 17 (7.2) .869
Day 2 97 (48.5) 79 (39.5) 18 (9.0) 6 (3.0) 104 (53.3) 72 (36.9) 16 (8.2) 3 (1.5) .657
Day 3 87 (43.5) 85 (42.5) 22 (11.0) 6 (3.0) 99 (50.8) 83 (42.6) 11 (5.6) 2 (1.0) .093
Day 4 105 (52.5) 81 (40.5) 11 (5.5) 3 (1.5) 110 (56.4) 70 (35.9) 14 (7.2) 1 (0.5) .534
Day 5 120 (60.0) 68 (34.0) 10 (5.0) 2 (1.0) 116 (59.5) 69 (35.4) 7 (3.6) 3 (1.5) .865

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1 to 3.
*Two-sided P value # .05 was regarded as an indication of statistical significance.

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 Phase III Study to Spare Dexamethasone on Days 2 and 3 in HEC

Table 4. Patient-Reported Adverse Events Related to Dexamethasone

Arm D1 (Likert scale) Arm D3 (Likert scale)
Adverse Event 0 1 2 3 0 1 2 3 P*
Hot flushes
Day 1 128 (64.0) 48 (24.0) 18 (9.0) 6 (3.0) 145 (74.4) 34 (17.4) 12 (6.2) 4 (2.1) .1669
Day 2 120 (60.0) 62 (31.0) 12 (6.0) 6 (3.0) 125 (64.1) 56 (28.7) 9 (4.6) 5 (2.6) .8402
Day 3 125 (62.5) 64 (32.0) 10 (5.0) 1 (0.5) 121 (62.1) 56 (28.7) 12 (6.2) 6 (3.1) .2452
Day 4 152 (76.0) 41 (20.5) 5 (2.5) 2 (1.0) 124 (63.6) 52 (26.7) 16 (8.2) 3 (1.5) .0132
Day 5 160 (80.4) 33 (16.6) 5 (2.5) 1 (0.5) 134 (68.7) 48 (24.6) 11 (5.6) 2 (1.0) .0377
Tremor
Day 1 174 (87.0) 20 (10.0) 5 (2.5) 1 (0.5) 181 (92.8) 13 (6.7) 1 (0.5) 0 (0.0) .1177
Day 2 181 (90.5) 15 (7.5) 2 (1.0) 2 (1.0) 181 (92.8) 13 (6.7) 1 (0.5) 0 (0.0) .6704
Day 3 180 (90.0) 17 (8.5) 2 (1.0) 1 (0.5) 181 (92.8) 11 (5.6) 3 (1.5) 0 (0.0) .578
Day 4 184 (92.0) 12 (6.0) 4 (2.0) 0 (0.0) 177 (91.2) 14 (7.2) 2 (1.0) 1 (0.5) .6527
Day 5 189 (94.5) 8 (4.0) 2 (1.0) 1 (0.5) 173 (88.7) 20 (10.3) 2 (1.0) 0 (0.0) .0411
Anorexia
Day 1 80 (40.0) 63 (31.5) 27 (13.5) 30 (15.0) 80 (41.0) 59 (30.3) 35 (18.0) 21 (10.8) .4453
Day 2 49 (24.6) 69 (34.7) 47 (23.6) 34 (17.1) 56 (28.7) 86 (44.1) 33 (16.9) 20 (10.3) .0392
Day 3 27 (13.5) 85 (42.5) 53 (26.5) 35 (17.5) 45 (23.1) 89 (45.6) 45 (23.1) 16 (8.2) .0063
Day 4 49 (24.6) 85 (42.7) 40 (20.1) 25 (12.6) 53 (27.2) 82 (42.1) 46 (23.6) 14 (7.2) .3001
Day 5 69 (34.5) 82 (41.0) 33 (16.5) 16 (8.0) 63 (32.3) 90 (46.2) 27 (13.9) 15 (7.7) .7435
Depression
Day 1 111 (55.5) 62 (31.0) 19 (9.5) 8 (4.0) 125 (64.1) 54 (27.7) 13 (6.7) 3 (1.5) .2048
Day 2 103 (51.5) 71 (35.5) 17 (8.5) 9 (4.5) 123 (63.1) 60 (30.8) 9 (4.6) 3 (1.5) .0448
Day 3 90 (45.0) 85 (42.5) 16 (8.0) 9 (4.5) 111 (56.9) 63 (32.3) 16 (8.2) 5 (2.6) .0865
Day 4 90 (45.0) 89 (44.5) 14 (7.0) 7 (3.5) 105 (53.9) 65 (33.3) 17 (8.7) 8 (4.1) .156
Day 5 107 (53.5) 75 (37.5) 13 (6.5) 5 (2.5) 102 (52.3) 71 (36.4) 15 (7.7) 7 (3.6) .8928
Fatigue
Day 1 72 (36.0) 72 (36.0) 33 (16.5) 23 (11.5) 79 (40.5) 73 (37.4) 26 (13.3) 17 (8.7) .5832
Day 2 56 (28.0) 71 (35.5) 39 (19.5) 34 (17.0) 69 (35.4) 89 (45.6) 22 (11.3) 15 (7.7) .0014
Day 3 38 (19.0) 83 (41.5) 47 (23.5) 32 (16.0) 58 (29.7) 91 (46.7) 30 (15.4) 16 (8.2) .0035
Day 4 48 (24.0) 83 (41.5) 49 (24.5) 20 (10.0) 46 (23.6) 83 (42.6) 45 (23.1) 21 (10.8) .9841
Day 5 63 (31.5) 84 (42.0) 37 (18.5) 16 (8.0) 56 (28.7) 77 (39.5) 43 (22.1) 19 (9.7) .7166

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1 to 3.
*Two-sided P value # .05 was regarded as an indication of statistical significance.

the CR during the overall phase in an arm with DEX sparing on among patients who received AC. The difference between the results
days 2 and 3 was noninferior to an arm with DEX administered on of our study and those of the study by Celio et al may be a result of the
days 1 to 3 for MEC that contained AC, the noninferiority of the effect of NK1-RA during the delayed phase. Thus, DEX sparing in
DEX-sparing arm was not achieved during the delayed phase HEC should be combined not only with Palo, but also with NK1-RA.

Table 5. Subgroup Analyses for CR Rates of AC and CDDP-Containing Regimen

AC CDDP
Arm D1 Arm D3 Risk Difference Arm D3
Outcome (n = 155) (n = 151) (95% CI) P* Arm D1 (n = 45) (n = 45) Risk Difference (95% CI) P*
CR
Overall 62 (40.0) 62 (41.1) 21.1 (212.0 to 9.8) .006 26 (57.8) 30 (66.7) 28.9 (228.7 to 10.9) .272
Acute 86 (55.5) 81 (53.6) 1.8 (29.2 to 12.9) .001 43 (95.6) 43 (95.6) 0 (211.9 to 11.9) .007
Delayed 77 (49.7) 80 (53.0) 23.3 (214.4 to 7.8) .019 26 (57.8) 31 (68.9) 211.1 (230.8 to 8.6) .349
CC
Overall 54 (34.8) 59 (39.1) 24.2 (215.0 to 6.5) .025 26 (57.8) 28 (62.2) 24.4 (224.5 to 15.6) .151
Acute 81 (52.3) 79 (52.3) 20.1 (211.1 to 11.0) .004 42 (93.3) 41 (91.1) 2.2 (211.1 to 15.5) .006
Delayed 73 (47.1) 79 (52.3) 25.2 (216.3 to 5.9) .042 26 (57.8) 29 (64.4) 26.7 (226.6 to 13.3) .206
TC
Overall 38 (24.5) 35 (23.2) 1.3 (28.3 to 11.0) , .001 18 (40.0) 23 (51.1) 211.1 (231.5 to 9.2) .354
Acute 56 (36.1) 48 (31.8) 4.3 (26.2 to 14.9) , .001 37 (82.2) 38 (84.4) 22.2 (218.0 to 13.6) .057
Delayed 46 (29.7) 47 (31.1) 21.5 (211.7 to 8.8) .005 20 (44.4) 24 (53.3) 28.9 (229.3 to 11.5) .279

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: AC, anthracycline plus cyclophosphamide; Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1 to 3; CC, complete control (no emetic
episodes, no use of rescue medication, and no more than mild nausea); CDDP, cisplatin; CR, complete response (no emetic episodes and no use of rescue medication);
TC, total control (no emetic episodes, no use of rescue medication, and no nausea).
*One-sided P value # .025 was regarded as an indication of statistical significance.

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 Ito et al

Table 6. Quality-of-Life Analysis

Arm D1 Arm D3
Screening End of the Overall Screening End of the Overall Between-Group Difference 6SE of the Least Square
Variable Phase Period Phase Period Mean Scores at the End of the Overall Period P
Global health 68.1 6 22.9 38.1 6 24.8 68.1 6 23.6 39.4 6 25.7 21.30 6 1.73 .454
status*
Functional scales*
Physical 92.9 6 11.4 76.0 6 22.1 93.2 6 10.1 79.2 6 20.2 23.00 6 1.43 .037
Role 93.8 6 14.7 62.4 6 33.0 91.5 6 17.8 65.2 6 31.0 23.73 6 2.22 .094
Emotional 76.9 6 20.0 74.0 6 19.3 78.4 6 16.4 75.0 6 20.9 20.22 6 1.28 .862
Cognitive 86.6 6 17.0 76.6 6 21.1 87.2 6 16.3 77.9 6 23.3 20.93 6 1.49 .531
Social 83.7 6 21.1 66.2 6 29.7 83.4 6 21.9 67.5 6 30.1 21.31 6 1.98 .509
Symptom scales†
Fatigue 19.6 6 16.0 49.3 6 28.3 20.6 6 19.0 47.2 6 27.2 2.67 6 1.83 .145
Nausea and 2.1 6 8.0 22.8 6 23.6 1.5 6 7.2 21.1 6 23.4 1.65 6 1.67 .325
vomiting
Pain 13.3 6 17.7 18.9 6 25.4 14.0 6 18.2 17.3 6 24.7 1.97 6 1.68 .241
Dyspnea 9.8 6 18.2 22.3 6 27.0 7.7 6 15.3 20.9 6 24.8 0.49 6 1.76 .782
Sleep disturbance 13.2 6 21.1 26.8 6 29.1 12.5 6 19.3 26.3 6 31.1 0.15 6 2.00 .94
Appetite loss 10.5 6 19.1 52.0 6 33.9 11.4 6 20.5 45.8 6 32.4 6.56 6 2.31 .005
Constipation 14.4 6 23.6 39.5 6 32.4 10.3 6 20.5 44.8 6 31.9 27.11 6 2.18 .001
Diarrhea 8.0 6 17.1 9.7 6 19.4 8.2 6 15.1 13.9 6 24.1 24.23 6 1.53 .006
Financial impact 23.3 6 29.1 31.2 6 34.4 23.9 6 28.9 28.7 6 32.4 2.70 6 2.03 .183

Abbreviations: Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1 to 3.

*0 was the worst value and 100 was the best value for the global health status and functional scales.
†100 was the worst value and 0 was the best value for the symptom scales.

We hypothesized that DEX sparing could reduce the in-
cidences of DEX-related AEs and improve QOL; however, as shown
in Tables 4 and 6, not all scores for DEX-related AEs and QOL were
better in Arm D1 than in Arm D3. As expected, hot flushes and
tremors were more frequent on days 4 and 5 in Arm D3; however,
anorexia, depression, and fatigue were more frequent on days 2 and
3 in Arm D1. Furthermore, scores in the physical category of the
functional scale and for appetite loss were worse in Arm D1 than in
Arm D3 in the QOL analysis. In contrast, when we compared the
scores that were obtained during the screening phase with those
obtained at the end of the overall period, all QOL scores had
worsened. Among them, the GHS variables and the symptom
scales for appetite loss and constipation indicated dramatic dif-
ferences. We thought that these differences were likely caused by
the chemotherapy intervention. In particular, a large difference in
appetite loss was observed between Arm D1 and Arm D3. Ad-
ministration of DEX on days 2 and 3 in Arm D3 might have
suppressed the appetite loss.
Furthermore, the noninferiority of DEX sparing for CC
during the delayed phase was not demonstrated in this study. The
reason for this finding might be that the proportions of moderate
and severe nausea on days 2 and 3 were slightly higher in Arm D1
than in Arm D3. These findings suggest that DEX administration
on days 2 and 3 might reduce the incidences of nausea, anorexia,
depression, and fatigue during the delayed phase. Thus, sparing
DEX on days 2 and 3 should be carefully indicated by selecting
patients who have risk factors for CINV and who received a CDDP-
containing regimen on the basis of the results of subgroup analyses.
Conversely, possible long-term DEX-related AEs that were not
evaluated in this study, such as infectious complications,22 bone
metabolism,23 and diabetes,24 should be considered in clinical
practice. Consequently, we recommend that DEX sparing should
only be applied after careful patient selection, as described above.
This study has several limitations. First, the majority of the
patients were women with breast cancer. Second, the subgroup
analysis performed according to regimen lacked sufficient power,
and only a small proportion of patients received CDDP. Finally,
Palo was administered intravenously at a dose of 0.75 mg, which is
the approved dose in Japan; however, international antiemetic
guidelines recommend a Palo dose of 0.25 mg.
In conclusion, DEX sparing on days 2 and 3 can be an
option for antiemetic therapy in HEC when combined with
NK1-RA and Palo. An exploratory analysis suggested that DEX
sparing on days 2 and 3 might benefit patients who receive AC
chemotherapy more than those who receive a CDDP-containing
regimen.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Yuka Ito, Takashi Tsuda, Kentaro Sakamaki,
Satoshi Morita, Narikazu Boku, Takako Eguchi Nakajima
Financial support: Takako Eguchi Nakajima
Administrative support: Takako Eguchi Nakajima
Provision of study materials or patients: Yuka Ito, Takashi Tsuda, Hiroko
Minatogawa, Sayaka Kano, Koichiro Tsugawa, Yasuyuki Kojima, Naoki
Furuya, Kunihiro Matsuzaki, Mamoru Fukuda, Sadatoshi Sugae, Ichiro
Ohta, Hitoshi Arioka, Yutaka Tokuda, Kazutaka Narui, Ayako Tsuboya,
Takashi Suda, Narikazu Boku, Takako Eguchi Nakajima
Collection and assembly of data: Yuka Ito, Takashi Tsuda, Hiroko
Minatogawa, Sayaka Kano, Koichiro Tsugawa, Yasuyuki Kojima, Naoki

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 Phase III Study to Spare Dexamethasone on Days 2 and 3 in HEC

Furuya, Kunihiro Matsuzaki, Mamoru Fukuda, Sadatoshi Sugae, Ichiro Manuscript writing: All authors
Ohta, Hitoshi Arioka, Yutaka Tokuda, Kazutaka Narui, Ayako Tsuboya, Final approval of manuscript: All authors
Takashi Suda, Takako Eguchi Nakajima Accountable for all aspects of the work: All authors
Data analysis and interpretation: Kentaro Sakamaki, Masahiko Ando,
Satoshi Morita, Narikazu Boku, Takeharu Yamanaka, Takako Eguchi
Nakajima

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Affiliations
Yuka Ito, Hiroko Minatogawa, and Sayaka Kano, St Marianna University School of Medicine Hospital; Takashi Tsuda, Koichiro
Tsugawa, Yasuyuki Kojima, Naoki Furuya, Kunihiro Matsuzaki, Mamoru Fukuda, and Takako Eguchi Nakajima, St Marianna
University School of Medicine; Ayako Tsuboya, Kawasaki Municipal Tama Hospital, Kawasaki; Kentaro Sakamaki and Takeharu
Yamanaka, Yokohama City University School of Medicine; Sadatoshi Sugae and Ichiro Ohta, Yokohama City University Hospital;
Hitoshi Arioka, Yokohama Rosai Hospital; Kazutaka Narui, Yokohama City University Medical Center, Yokohama; Masahiko Ando,
Nagoya University Hospital, Nagoya; Yutaka Tokuda, Tokai University School of Medicine, Kanagawa; Takashi Suda, Takahata Public
Hospital, Takahata-Chou; Satoshi Morita, Graduate School of Medicine, Kyoto University, Kyoto; and Narikazu Boku, National Cancer
Center Hospital, Tokyo, Japan.
Prior Presentation
Presented at the 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016; the 2016 Annual
Meeting of the Japanese Society of Medical Oncology, Kobe, Japan, July 28-30, 2016; and the 2016 Japanese Society of Pharmaceutical
Health Care and Sciences Annual Meeting, Kyoto, Japan, September 17-19, 2016.

nnn

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 Ito et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Placebo-Controlled, Double-Blinded Phase III Study Comparing Dexamethasone on Day 1 With Dexamethasone on Days 1 to 3 With Combined
Neurokinin-1 Receptor Antagonist and Palonosetron in High-Emetogenic Chemotherapy
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Yuka Ito Hitoshi Arioka
Honoraria: Eizai, Otsuka Pharmaceutical Honoraria: Taiho Pharmaceutical, Chugai Pharma, Kyowa Hakko Kirin,
Ono Pharmaceutical
Takashi Tsuda Research Funding: Chugai Pharma, Taiho Pharmaceutical, Kyowa Hakko
No relationship to disclose Kirin
Hiroko Minatogawa Yutaka Tokuda
Honoraria: Chugai Pharma, Eizai, Pfizer, Taiho Pharmaceutical Honoraria: Kyowa Hakko Kirin
Sayaka Kano Research Funding: Chugai Pharma, Eizai, Taiho Pharmaceutical, Nippon
Honoraria: Celgene Kayaku, Kyowa Hakko Kirin, Novartis

Kentaro Sakamaki Kazutaka Narui

Honoraria: Chugai Pharma, Taiho Pharmaceutical, Novartis No relationship to disclose
Travel, Accommodations, Expenses: Genomic Health Ayako Tsuboya
Masahiko Ando Honoraria: Chugai Pharma, Bristol-Myers Squibb
Research Funding: Kyowa Hakko Kirin Takashi Suda
Koichiro Tsugawa No relationship to disclose
Honoraria: Chugai Pharma, Novartis, AstraZeneca, Allergan, Pfizer, Taiho Satoshi Morita
Pharmaceutical, Kyowa Hakko Kirin, Otsuka Pharmaceutical, Takeda Honoraria: Taiho Pharmaceutical
Consulting or Advisory Role: AstraZeneca, Pfizer, Novartis
Research Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Narikazu Boku
Kyowa Hakko Kirin (Inst), Eli Lilly (Inst), Shionogi Pharma (Inst), Eisai Honoraria: Taiho Pharmaceutical, Merck Serono, Ono Pharmaceutical,
(Inst) Shionogi Pharma, Chugai Pharma, Yakult Honsha, Eli Lilly
Research Funding: Taiho Pharmaceutical (Inst), Bristol-Myers Squibb
Yasuyuki Kojima (Inst), Ono Pharmaceutical (Inst)
Honoraria: Chugai Pharma, Eisai, Taiho Pharmaceutical, Allergan, Kyowa
Hakko Kirin, Pfizer, AstraZeneca Takeharu Yamanaka
Research Funding: Chugai Pharma (Inst) Honoraria: Chugai Pharma, Takeda, Taiho Pharmaceutical, Boehringer
Ingelheim
Naoki Furuya Research Funding: Takeda (Inst), Taiho Pharmaceutical (Inst)
No relationship to disclose
Takako Eguchi Nakajima
Kunihiro Matsuzaki Honoraria: Taiho Pharmaceutical, Eli Lilly, Chugai Pharma, Kyowa Hakko
No relationship to disclose Kirin, Hisamitsu Pharmaceutical, Sawai Pharmaceutical, Takeda, Bristol-Myers
Mamoru Fukuda Squibb, Ono Pharmaceutical, Bayer, Dainippon Sumitomo Pharma, Merck
No relationship to disclose Serono
Consulting or Advisory Role: Taiho Pharmaceutical
Sadatoshi Sugae Research Funding: Taiho Pharmaceutical, Ono Pharmaceutical,
No relationship to disclose AstraZeneca, Eli Lilly, Chugai Pharma, Kyowa Hakko Kirin, Hisamitsu
Ichiro Ohta Pharmaceutical, Amgen, Astellas Pharma, Merck Serono, Sawai
No relationship to disclose Pharmaceutical, Takeda, MSD, Dainippon Sumitomo Pharma, Eisai,
Yakult Honsha

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 Phase III Study to Spare Dexamethasone on Days 2 and 3 in HEC

Acknowledgment

The dexamethasone and placebo used in this study were produced by Nichi-Iko Pharmaceutical Co for a fee.

Appendix

CR (Overall)

CR (Acute)

CR (Delayed)

CC (Overall)

CC (Acute)

CC (Delayed)

TC (Overall)

TC (Acute)

TC (Delayed)

-15 -10 -5 0 5 10
Risk Difference (%)
Fig A1. Risk difference and noninferiority margin. A comparison of the risk
difference between the dexamethasone day 1 to 3 (Arm D3) and dexamethasone
day 1 (Arm D1) arms is shown. The solid line indicates a risk difference of 0. The
dashed line at a risk difference of 215% indicates the noninferiority margin. The
blue-tinted region to the right of the noninferiority margin corresponds to values at
which Arm D1 would be considered noninferior to Arm D3. CC, complete control;
CR, complete response; TC, total control.

Table A1. Observed Grade 3 # Adverse Events

Adverse Event Arm D1 Arm D3 P*
All, No. (%) 2 (1) 3 (1.53) .682
Hyponatremia 0 1
Thrombocytopenia 0 1
Syncope 0 1
Vomiting 1 0
Fatigue 1 0

Abbreviations: Arm D1, dexamethasone day 1; Arm D3, dexamethasone day 1

to 3.
*Two-sided P value # .05 was regarded as an indication of statistical
significance.

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