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ORIGINAL PAPER
A phase II randomized double-blind placebo-controlled studyof 6-gingerol as an anti-emetic in solid tumor patients receivingmoderately to highly emetogenic chemotherapy
J. Konmun1,5,7 • K. Danwilai2,7 • N. Ngamphaiboon3 • B. Sripanidkulchai5 •
A. Sookprasert4 • S. Subongkot5,6,7
Received: 7 March 2017 / Accepted: 22 March 2017
� Springer Science+Business Media New York 2017
Abstract 6-Gingerol is a natural compound extracted from
ginger. Preclinical studies demonstrated that 6-gingerol has
an anti-emetic activity by inhibiting neurokinin-1, sero-
tonin, and dopamine receptors. Several clinical trials
examined crude ginger powder for preventing chemother-
apy-induced nausea and vomiting (CINV), but none of
them was conducted with a standardized bioactive com-
pound. Patients who received moderately to highly eme-
togenic adjuvant chemotherapy were randomized to
receive 6-gingerol 10 mg or placebo orally twice daily for
12 weeks. Ondansetron, metoclopramide, and dexametha-
sone were given to all patients. The primary endpoint was
complete response (CR) rate defined as no emesis or rescue
treatment at any time. Eighty-eight patients were random-
ized to receive 6-gingerol (N = 42) or placebo (N = 46).
Most patients received highly emetogenic chemotherapy
(93%). Overall CR rate was significantly higher in 6-gin-
gerol group as compared with that of the placebo (77 vs.
32%; P\ 0.001). The difference in means of appetite
score was significant (P = 0.001) and more noticeable
over time. Mean FACT-G score indicating quality of life
was significantly higher (86.21) in 6-gingerol group at
64 days as compared with that of placebo group (72.36)
(P\ 0.001). No toxicity related to 6-gingerol was
observed. Patients treated with 6-gingerol reported signif-
icantly less grade 3 fatigue (2 vs. 20%; P = 0.020).
6-Gingerol significantly improved overall CR rate in
CINV, appetite and quality of life in cancer patients
receiving adjuvant chemotherapy. A phase III randomized
study of 6-gingerol is warranted to confirm these results.
Keywords 6-Gingerol � CINV � Ginger � Chemotherapy �Nausea
Introduction
Chemotherapy-induced nausea and vomiting (CINV) is one
of the most common side effects reported in patients
receiving systemic chemotherapy. Despite standard anti-
emetic medications, approximately 10–30% of patients
experience CINV, which result in increasing acute com-
plications, reducing efficacy of chemotherapy, and poten-
tially decreasing survivals [1, 2].
The abstract was presented at the 2014 ASCO Annual Meeting, June
1st, 2014, Chicago, IL. USA (Abstract Number: 9647).
Electronic supplementary material The online version of thisarticle (doi:10.1007/s12032-017-0931-4) contains supplementarymaterial, which is available to authorized users.
& S. Subongkot
1 Department of Pharmacy, Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand
2 Department of Pharmacy Practice, Faculty of Pharmaceutical
Sciences, Naresuan University, Phitsanuloke, Thailand
3 Medical Oncology Unit, Department of Medicine, Faculty of
Medicine, Ramathibodi Hospital, Mahidol University,
Bangkok, Thailand
4 Medical Oncology Unit, Department of Medicine, Khon
Kaen University, Khon Kaen, Thailand
5 Center for Research and Development of Herbal Health
Products, Faculty of Pharmaceutical Sciences, Khon Kaen
University, Khon Kaen, Thailand
6 Clinical Pharmacy Division, Faculty of Pharmaceutical
Sciences, Khon Kaen University, 123 Mittraphap road,
Khon Kaen 40002, Thailand
7 The College of Pharmacotherapy of Thailand, Nonthaburi,
Thailand
123
Med Oncol (2017) 34:69
DOI 10.1007/s12032-017-0931-4
The American Society of Clinical Oncology (ASCO)
clinical practice guideline suggested the use of the three-drug
combination of a 5-hydroxytryptamine-3 (5-HT3) receptor
antagonist, dexamethasone, and neurokinin-1 (NK-1)
receptor antagonist for preventing CINV in patients receiv-
ing highly emetogenic chemotherapy (HEC) [3]. The two-
drug combination of a 5-HT serotonin receptor antagonist
and dexamethasone is recommended for patients who
receivemoderately emetogenic chemotherapy (MEC) [3]. In
combined data from 2 phase III randomized studies of
aprepitant, a 5-HT3 receptor antagonist, in combination with
ondansetron and dexamethasone in patients who received
HEC, aprepitant increased complete response rate from 46 to
61% in the 1st cycle of chemotherapy when compared with
placebo. The benefit continued throughout all cycles of
chemotherapy (P B 0.006) [4]. Even though the three-drug
combination demonstrated high potency in preventingCINV
in patients who receiveHEC, a standard of care inmany low-
to middle-income countries remains problematic due to
limited access ofNK-1 receptor antagonist such as aprepitant
and fosaprepitant. In Thailand, NK-1 receptor antagonist is
not currently reimbursable by the government-funded health
care program which supports majority of patients in the
country [5]. The two-drug combination with addition of
other pharmacological classes of anti-emetic drugs such
metoclopramide, lorazepam, and domperidone, remains a
treatment of choice for patientswho receiveHEC. Therefore,
an affordable with highly efficacious anti-emetic regimen is
an unmet need.
Ginger (Zingiber officinale Roscoe) is a medicinal plant
with many claimed therapeutic usages such as antiflatu-
lence, anti-emetic, reliving gingivitis, expectorant, and
appetite stimulant. The ginger phytochemicals consist of
6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol.
Nonetheless, 6-gingerol is the most active compound [6].
Preclinical study demonstrated that 6-gingerol non-com-
petitively inhibited activation of human recombinant and
native 5-HT3 receptors of enteric neurons [7]. In addition,
gingerol, especially 6-gingerol, and 6-shogaol markedly
suppressed central and peripheral dopamine, substance P,
and NK-1 receptors [6, 8, 9]. A number of clinical studies
examined anti-emetic activity of ginger in preventing
CINV. A large phase III study of ginger randomized 576
cancer patients to receive placebo or multiple doses of
ginger administered twice daily for 6 days, starting 3 days
before the first day of chemotherapy [10]. The primary
endpoint of this study was severity of chemotherapy-in-
duced nausea on day 1 of chemotherapy. Ginger supple-
mentation in patients receiving standard 5-HT3 receptor
antagonist and dexamethasone significantly reduced
severity of acute chemotherapy-induced nausea when
compared with the placebo. However, a benefit of ginger in
delayed emesis was not observed. Though several clinical
data support the use of ginger supplementation in pre-
venting CINV, a systemic review of 7 clinical studies was
unable to demonstrate a clear benefit of ginger supple-
mentation in CINV [11]. To our knowledge, most of
clinical studies used various doses of crude ginger sup-
plementation. None of these studies was conducted by
using a standardized bioactive compound. 6-Gingerol is a
potential active compound from ginger rhizomes, con-
taining anti-emetic, antioxidant and anti-inflammatory
properties [12]. Thus, we conducted a randomized, double-
blind, placebo-controlled phase II study of 6-gingerol in
preventing CINV in solid tumor patients who received
moderately to highly emetogenic adjuvant chemotherapy.
Methods
Study design
This study was a multicenter randomized, double-blind,
placebo-controlled phase II study, fully funded by the
National Research University and Thailand Research Fund.
Solid tumor patients who received moderately to highly
emetogenic adjuvant chemotherapy were randomly
assigned (1:1) to receive 6-gingerol or placebo. The pri-
mary endpoint of the study was an overall complete
response (CR) rate, defined as no emetic events or rescue
treatment during both acute and delayed phases for all
cycles of chemotherapy. The secondary endpoints were the
overall CR rate of acute and delayed phases, the CR rates
in the 1st cycle of chemotherapy, severity of nausea and
vomiting, tolerability, appetite score and patient-reported
outcomes on health-related quality of life (HRQoL). The
study was conducted at two cancer institutions in Thailand
(Ramathibodi and Srinagarind hospital) in accordance with
the Declaration of Helsinki and Good Clinical Practice
guidelines. The protocol was approved by the Ethic
Committee of both participating sites. All patients provided
an informed consent and agreed to participate in the study.
Patients
Patients eligible criteria were C18 year-old and newly
diagnosis with histology of solid tumors with Eastern
Cooperative Oncology Group (ECOG) performance status
B2. All patients must complete surgical resection of pri-
mary tumor and planned for at least 3 consecutive cycles of
moderately to highly emetogenic adjuvant chemotherapy
for curative intent. Emetogenic potential of chemotherapy
regimens was defined by standard guidelines and recom-
mendations [3]. Food containing ginger was not allowed
within 2 weeks of the beginning of treatment and during
the study treatment. Patients who had access to standard
69 Page 2 of 10 Med Oncol (2017) 34:69
123
neurokinin-1 (NK1) antagonists such as aprepitant or fos-
aprepitant were not eligible. Absolute neutrophil count
C1500 cells/mL, Hb C10 g/dL, platelet count
C100,000 cells/mL, AST and ALT B2.5 upper limit of
normal (ULN), bilirubin B1.5 ULN, and creatinine B 1.5
ULN were required. Patients with history of ginger
hypersensitivity, pregnancy or breast-feeding, and previous
chemotherapy were excluded. Warfarin, olanzapine, and all
appetite stimulants were not permitted during the study.
Treatments
The ginger and placebo capsules were manufactured by the
Center for Research and Development of Herbal Health
Products, faculty of pharmaceutical science, Khon Kaen
university, Thailand (License Number 10560). The 6-gin-
gerol capsules contained a ginger extract, referenced as
6-gingerol 5 mg (1.4% w/w of ginger extract). The placebo
capsules consisted of diluents/binder (microcrystalline
cellulose PH 102; Avicel PH 102) and Thixotropic thick-
ening (colloidal silicon dioxide) in order to match the
weight of the 6-gingerol capsules. Eligible patients were
randomly assigned to receive 6-gingerol 10 mg or placebo
orally twice daily continuously utilizing a block of four
method for randomization. The treatment was started three
days prior (Day-3) to the first day of chemotherapy
administration (Day 1) and continued to 12 weeks of
treatment or completion of planned chemotherapy. The
concept of giving three doses before starting chemotherapy
followed a previous phase 3 URCC CCOP ginger study
[10]. Since 6-gingerol was expected to be well-tolerated
and less toxic, the continuous dosing with 6-gingerol was
planned in this study. All patients received standard nausea
and vomiting-preventing medications, including dexam-
ethasone and ondansetron 30 min prior to administration of
chemotherapy [13]. For highly emetogenic chemotherapy
(HEC) regimen, patients must receive ondansetron 8 mg
IV on day1 and dexamethasone 12 mg IV on day 1 and oral
daily on day 2–4. For moderately emetogenic chemother-
apy (MEC) regimen, patients must receive ondansetron
8 mg IV on day 1 and dexamethasone 8 mg IV on day 1
and oral daily on day 2–4. All patients received metoclo-
pramide 10 mg orally three times daily on day 2–4. Rescue
anti-emetics were allowed at any time during the study for
nausea and/or vomiting at the request of patients or treating
physicians’ discretion.
Endpoints and assessments
Clinical assessments
Complete response (CR) was defined as no emetic events
or rescue treatment required during both acute and delayed
phases. Acute phase vomiting was defined as any emetic
events occurred within 24 h after administration of
chemotherapy, while delayed phase vomiting was defined
as any emetic events occurred during 24–120 h after
chemotherapy administration.
Intensity of nausea and appetite was measured daily by
the Numerical Rating Scale (NRS) using Edmonton’s
Symptom Assessment Scale (ESAS) ranging from 0 to 10
[14]. For nausea, patients who reported a score of zero on
the NRS were considered as no nausea. Mild, moderate,
and severe nausea were defined as score of 1–3, 4–6, and
C7, respectively. Nausea and vomiting events were self-
recorded daily from day 0 to 120 h after each cycle of
chemotherapy and continued throughout the study. Chan-
ges in the NRS appetite score at 4 time points including day
1, 22, 43, and 64 prior to chemotherapy administration on
Day 1 of each cycle were collected to evaluate dynamic
change of appetite over time during the study.
The quality of life will be measured by using version 4
of the Functional Assessment of Cancer Therapy-General
(FACT-G) instrument at day 1, 22, 43, and 64 of treatment.
FACT-G Thai version has been translated with the standard
procedure. Each question consisted of Likert scale with
scores from 0 to 4. The scores were subsequently calcu-
lated for each quality of life domains.
All adverse events were defined by the Common Ter-
minology Criteria for Adverse Events (CTCAE) version
4.03 [15]. All patients treated with 6-gingerol or placebo
were continuously monitored adverse events throughout
the study until 30 days after of the last treatment of
6-gingerol or placebo. All patients were required to com-
plete a daily diary for 5 days starting on day 1 of
chemotherapy of each cycle. The diary included number of
vomiting episodes, nausea score, appetite score, quality of
life, use of rescue anti-emetic, and hospitalization. Com-
pliance and adverse events were evaluated by weekly
phone call by the investigators throughout the study
(Supplement 1).
Statistical analysis
Previous phase III studies demonstrated overall CR rate of
patients who received ondansetron and dexamethasone
ranging between 26 and 48% [16–18]. Since 6-gingerol
was tested as a potential active compound, a robust anti-
emetic activity was expected to explore whether 6-gingerol
should be further investigated in a larger phase III study.
Therefore, we estimated an increase in the overall CR rate
(defined as both acute and delayed phases during all cycles
of chemotherapy) in the 6-gingerol group from 40 to 65%
when compared with the placebo group. Assuming that the
number of CR rate was binomially distributed, the fol-
lowing design had a two-sided alpha level of 0.05 with
Med Oncol (2017) 34:69 Page 3 of 10 69
123
90% power to detect an improvement of CR rate from 40 to
65%. A total of 40 evaluable patients on each group were
required to test the null hypothesis. We anticipated accru-
ing an additional 12 patients (15%) accounting for ineli-
gibilities, poor compliance, cancellations, major violations,
and/or other reasons. Thus, a total of 92 evaluable patients
were required to conduct the study.
Demographic data, patient characteristics, treatment
outcomes and side effects were reported by using
descriptive statistics. All continuous variable data were
tested for normal distribution and reported as the
mean ± standard deviation (SD) for normally distributed
data and the median for nonparametric data. Mean changes
of appetite and quality of life scores from baseline to day
22, 43 and 64 within treatment groups were analyzed by
repeated measures ANOVA. On day 64 post-treatment,
quality of life scores were compared to those of the base-
line using paired t test if the data are normal distributed;
otherwise, Wilcoxon signed ranks test will be applied. The
mean of independent variables in the treatment groups and
control group were compared using unpaired t test or
nonparametric Mann–Whitney U test. The significance of
any difference in proportions was tested with the Pearson’s
Chi-square or Fisher’s exact tests for nonparametric data.
All statistical analyses were two-sided and P\ 0.05 con-
sidered significant. All analyses were performed using the
STATA/SE software version 11.0 (STATA, College Sta-
tion, TX).
Results
Patient characteristics
Between January 2012 and July 2013, 96 patients were
screened for eligibility. Forty-eight patients were randomly
assigned to receive placebo, whereas 46 patients were
randomized to 6-gingerol (Fig. 1). Six randomized patients
were subsequently excluded from the study before initia-
tion of treatment due to withdraw consent (N = 3), referred
for treatment at another hospital (N = 2), and unable to
swallow a capsule (N = 1). Thus, 42 and 46 eligible
patients were treated with 6-gingerol and placebo, respec-
tively. Seven participants were excluded from the efficacy
analysis due to reporting olanzapine use for an underlying
psychological condition (N = 1) and withdrawal of con-
sent within the first week of treatment (5 allocated placebo,
and 1 allocated 6-gingerol). Therefore, 81 patients were
eligible for primary analysis.
Participants’ baseline characteristics are summarized in
Table 1. Most patients were female (93%), with median
age of 53 year-old (range 19–81). Majority of patients in
the study received HEC regimen (93%), which the most
common regimens were anthracycline-based (68%) and
platinum-based chemotherapy (21%) (Supplement 2).
Seventy-two percent of patients in this study had diagnosis
of breast cancer. All patient characteristics were well bal-
anced between both groups, except for patients who were
treated with 6-gingerol presented with earlier stage at
diagnosis of cancer when compared with the placebo
group.
Clinical efficacy
The overall CR rate was significantly higher in patients
treated with 6-gingerol compared with placebo (77 vs.
32%; P\ 0.001) (Fig. 2). The CR rates remained signifi-
cantly higher in both acute (88 vs. 58%; P = 0.003) and
delayed (77 vs. 32%; P\ 0.001) phases. In the 1st cycle of
chemotherapy, the CR rate of all (85 vs. 49%; P = 0.001)
and delayed (85 vs. 54%; P = 0.004) phases were signif-
icant higher in the 6-gingerol group. However, there was
no statistically difference between both groups in acute
phase CINV (97 vs. 83%; P = 0.057).
The mean change of appetite score of patients receiving
placebo progressively decreased over time compared to
patients treated with 6-gingerol (Fig. 3). The result
demonstrated statistically difference between 6-gingerol
and placebo by a generalized estimating equation method
comparing the scores in the 2 groups at days 22, 43, and 64,
and adjusted for the baseline score at Day 1 (r -1.65, 95%
CI -2.64 to -0.67; P = 0.001).
Throughout the study, the incidence of all grade vom-
iting by the CTCAE was significantly lower in patients
treated with 6-gingerol (22 vs. 68%; P\ 0.001), similar to
grade 3 vomiting (0 vs. 19%; P\ 0.001) (Supplement 3).
No grade 4 vomiting was observed in this study. Patients
treated with 6-gingerol reported significantly less severity
of overall nausea when compared with placebo (mild 55 vs.
17%; moderate 15 vs. 39%; and severe 5 vs. 34%;
P\ 0.001).
Quality of life
Comparison of the FACT-G score between two groups at
multiple time points is demonstrated in the Supplement 4.
At the end of study (Day 64), the FACT-G total score
showed both clinically different and statistical significantly
higher in 6-gingerol group (86.21 ± 13.6 vs. 72.36 ± 18.9,
P\ 0.001). However, the physical (23.89 ± 4.24 vs.
18.1 ± 6.14, P\ 0.001), emotional (20.92 ± 3.07 vs.
17.56 ± 5.23, P\ 0.001) and functional wellbeing
domains (19.97 ± 5.08 vs. 17.08 ± 5.86, P = 0.023) were
statistically significant improved, but not clinically differ-
ent. When compared the FACT-G score within the group
(Supplement 5), the FACT-G total score, physical and
69 Page 4 of 10 Med Oncol (2017) 34:69
123
social/family wellbeing domains were maintained in the
patients treated with 6-gingerol, while significantly
declined in the placebo group. Moreover, 6-gingerol
improved emotional and functional wellbeing overtime.
6-Gingerol significantly improved mean change of the
FACT-G total score (P = 0.005), physical (P\ 0.001) and
emotional (P = 0.006) wellbeing when compared with
placebo (Fig. 4).
Safety and tolerability
Eighty-eight patients who ever received 6-gingerol
(N = 42) and placebo (N = 46) were evaluated for safety
and tolerability. None of the patients was discontinued
from the study due to toxicity. Three patients were dis-
continued from the study before completion of 12 weeks
assessment period. One patient who received 6-gingerol
was discontinued due to grade 3 vomiting requiring hos-
pitalization on cycle 1 day 3 of chemotherapy. Two
patients on placebo group were discontinued due to ter-
mination of chemotherapy after cycle 2 and grade 2 dys-
pepsia, respectively. No dose reduction was required in
both groups. Overall compliance of the study was 98.4%,
which 6-gingerol and placebo groups were 99.1 and 97.7%,
respectively (Supplement 1). The most common adverse
events for all grades were anemia, fatigue, myalgia, and
rising creatinine, which were similar in both groups
(Table 2). These adverse events were likely related to
chemotherapy. No significant adverse event related to
6-gingerol was observed. Interestingly, patients who were
treated with 6-gingerol reported significant lower grade 3
fatigue when compared with placebo (2 vs. 20%;
P = 0.020).
Discussion
To our knowledge, this is the first randomized study using
an active compound, 6-gingerol, extracted from Zingiber
officinale for preventing CINV. In this phase II study, we
demonstrated anti-emetic activity of 6-gingerol in addition
to ondansetron, metoclopramide, and dexamethasone in
solid tumor patients who received moderately to highly
emetogenic chemotherapy. The acute phase CR during the
first cycle of chemotherapy was not statistically significant
between both groups; however, the benefit of 6-gingerol
appeared to be more noticeable in the delayed phase and
the following cycle of chemotherapy. The difference in
Fig. 1 Consort diagram
Med Oncol (2017) 34:69 Page 5 of 10 69
123
overall CR rate was more pronounced when compared with
the CR rate in the first cycle. The mean change of appetite
score of patients who received placebo progressively
decreased over time, while patients treated with 6-gingerol
did not. Furthermore, patients receiving 6-gingerol
appeared to maintain quality of life score comparing with
placebo and demonstrated significantly different after the
third treatment cycle. These results suggested that the
effect of 6-gingerol appeared to be more efficacious for
chronic use. Continuous daily dosing might be an impor-
tant strategy to improve efficacy of 6-gingerol. According
to recent study, the result showed the reduction in oxidative
stress and increase antioxidant activity when patient taking
continuously [19]. In contrast to other randomized phase II
and III studies of crude ginger supplementation in pre-
venting CINV, none of these studies used the continuous
dosing regimen of ginger [10]. A large phase III URCC
CCOP study reported a benefit of ginger in reducing acute
chemotherapy-induced nausea, but failed to demonstrate
the effect on the delayed phase and vomiting [10]. Another
three randomized phase II studies of ginger did not show
any benefits in both acute and delayed phases [20–22].
Thus, the benefit of crude ginger powder in preventing
CINV remains unclear. Several explanations such as vari-
ous doses of ginger powder, different sources and seasons
of ginger harvested, and extraction techniques among these
studies may result in diverse amounts of active compounds
used in the clinical trials.
Continuous dosing of 6-gingerol was safe and well-tol-
erated. No toxicity related to 6-gingerol was observed in
this study. The phase III URCC CCOP study of ginger
supplementation reported a small number of patients
experienced gastrointestinal symptoms such as grade 2
heartburn, bruising/flushing, and rash related to ginger, and
resulted in consent withdrawal [10]. None of which was
observed in this study. Most of adverse events were likely
related to chemotherapy and well balanced between both
groups, except for fatigue. Interestingly, patients who were
treated with 6-gingerol reported significantly less grade 3
fatigue comparing to patients treated with placebo. A
previous study showed that chemotherapy, especially
anthracycline-based regimen, disrupted striated muscle
function through oxidative stress, leading to fatigue and
weakness in skeletal muscle [23]. 6-Gingerol had anti-
Table 1 Baseline patient characteristics
Characteristics All N = 81 (%) 6-Gingerol N = 40 (%) Placebo N = 41 (%) P value
Median age 53 52 55 0.405
Range 19–81 19–81 37–79
Age B 50 30 (37) 17 (43) 13 (32) 0.315
Female sex 75 (93) 36 (90) 39 (95) 0.432
Mean body weight (kg) ± SD 61.0 ± 12.6 61.0 ± 10.6 61.0 ± 14.5 0.982
Weight loss C 10% from baseline at diagnosis 5 (6) 3 (8) 2 (5) 0.675
Chemotherapy regimen
Anthracycline-based 55 (68) 26 (65) 29 (71) 0.673
Platinum-based 17 (12) 10 (25) 7 (17)
Other 9 (11) 4 (10) 5 (12)
Emetogenic potential
Highly emetogenic chemotherapy 75 (93) 37 (93) 38 (93) 1.000
Moderately emetogenic chemotherapy 6 (7) 3 (7) 3 (7)
Cancer type
Breast cancer 58 (72) 27 (68) 31 (76) 0.709
Ovarian cancer 11 (13) 6 (15) 5 (12)
Other 12 (15) 7 (17) 5 (12)
Stage
I 11 (13) 9 (22) 2 (5) 0.031
II 33 (41) 12 (30) 21 (51)
III 37 (46) 19 (48) 18 (44)
ECOG performance status
0–1 79 (98) 40 (100) 39 (95) 0.494
2 2 (2) 0 2 (5)
ECOG eastern cooperative oncology group
69 Page 6 of 10 Med Oncol (2017) 34:69
123
oxidative and anti-inflammatory properties, which was
confirmed by the PD assessment in this study. Therefore,
we speculated that the decrease in grade 3–4 chemother-
apy-induced fatigue might be related to the anti-oxidative
effects of 6-gingerol, in part. In addition, improvement in
CINV may correlate with patient’s wellbeing during
chemotherapy and lead to the lower incidence of grade 3
fatigue in the 6-gingerol group. Since the toxicity of
6-gingerol was not observed in this study, a phase I dose-
escalation study is warranted to identify the most effective
dose and schedule of 6-gingerol for preventing CINV.
Due to the lack of pharmacokinetic studies of 6-gin-
gerol, drug interaction should be explored in the future
study. Adding 6-gingerol to NK1 receptor antagonist
should be evaluated with caution. In a randomized phase II
study of encapsulated ginger in 162 cancer patients,
approximately 30% of patients received aprepitant. No
benefit of ginger in both acute and delayed CINV was
demonstrated. Interestingly, the subgroup of patients who
had ginger in combination with aprepitant developed more
severe acute nausea than patients who received placebo
[20].
To date the NK1 receptor antagonists in addition to
5HT3 antagonist and dexamethasone remain the standard
of care for preventing CIVN in patients who receive highly
emetogenic chemotherapy [3, 13]. The development of
NK1 receptor antagonist such as aprepitant and fos-
aprepitant represents the most significant advance in anti-
emetic for CINV. New highly selective NK1 receptor
antagonists such as netupitant/palonosetron (NEPA) and
rolapitant are moving toward clinical practice [24]. How-
ever, access to these NK1 receptor antagonists in the real
Fig. 2 Percentages of patients
with complete response (CR),
defined as no emesis and no
rescue therapy in overall
treatment (a), and cycle 1 (b)
Med Oncol (2017) 34:69 Page 7 of 10 69
123
Fig. 3 Mean appetite score of
patients treated with 6-gingerol
and placebo. P value
demonstrates statistically
difference between 6-gingerol
and placebo by a generalized
estimating equation method
comparing the scores in the 2
groups at days 22, 43, and 64,
and adjusted for the baseline
score at day 1
Fig. 4 Mean change in FACT-G total (a), physical wellbeing subscale (b), social or family wellbeing (c), emotional wellbeing (d), functionalwellbeing subscale (e)
69 Page 8 of 10 Med Oncol (2017) 34:69
123
world remains challenging, especially in the developing
countries due to economical status and reimbursement
policies. Development of 6-gingerol, an active compound
extracted from ginger may be a future alterative affordable
option for CINV prevention.
Conclusion
6-Gingerol in addition to ondansetron, metoclopramide,
and dexamethasone significantly reduced CR rate in both
acute and delayed phases CINV. A phase III randomized
study of 6-gingerol is warranted to confirm these results.
Pharmacokinetics and benefits of 6-gingerol in improve-
ment of chemotherapy inducing fatigue and wellbeing
should be explored in the future study.
Acknowledgments The authors would like to acknowledge Assist.
Pro. Youwanush Kongdan, Assist. Pro. Ronnarat Suvikapakornkul,
and Ass. Pro. Bandit chunworathayi for patient accrual at Ramathi-
bodi Hospital, Bangkok and Srinagarind Hospital, Khon Kaen,
respectively, and Center for Research and Development of Herbal
Health Products, Khon Kaen University, for product development.
Funding This study was funded by National Research University and
Thailand research fund. (Grant number: FC 3.1.14 PhD).
Compliance with ethical standards
Conflict of interest The authors have declared no conflicts of
interest.
Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki Declaration and its later amendments or comparable ethical
standards.
Informed consent Informed consent was obtained from all individ-
ual participants included in the study.
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Table 2 All grades adverse
events by the CTCAE v 4.0Adverse events 6-Gingerol (N = 42) Placebo (N = 46) P value
Grade 1–2 (%) Grade 3–4 (%) Grade 1–2 (%) Grade 3–4 (%)
Hematologic
Anemia 22 (53) 0 23 (50) 0 0.733
Neutropenia 3 (7) 5 (12) 1 (2) 3 (7) 0.317
Thrombocytopenia 1 (2) 0 1 (2) 0 1.000
Febrile neutropenia 0 1 (2) 0 1 (2) 1.000
Non-hematologic
Fatigue 30 (71) 1 (2)a 32 (70) 9 (20)a 0.020
Myalgia 28 (67) 3 (7)a 35 (76) 5 (11)a 0.368
Creatinine increased 11 (26) 1 (2) 8 (17) 0 0.318
ALT increased 4 (10) 0 5 (11) 1 (2) 0.624
ALP increased 2 (5) 0 4 (9) 0 0.680
AST increased 0 0 3 (7) 0 0.244
Dyspepsia 0 0 3 (7) 0 0.244
Headache 1 (2) 0 0 (0) 0 0.471
CTCAE common terminology criteria for adverse events, ALT alanine aminotransferase, AST aspartate
aminotransferase, ALP alkaline phosphatasea These adverse events were reported only in grade 3
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