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

supsub2@kku.ac.th

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

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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

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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

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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

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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.

References

1. Herrstedt J. Antiemetics: an update and the MASCC guidelines

applied in clinical practice. Nat Clin Pract Oncol.

2008;5(1):32–43. doi:10.1038/ncponc1021.

2. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD,

Harker G, et al. Proposal for classifying the acute emetogenicity

of cancer chemotherapy. J Clin Oncol. 1997;15(1):103–9.

3. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC,

Somerfield MR, et al. Antiemetics: American society of clinical

oncology clinical practice guideline update. J Clin Oncol.

2011;29(31):4189–98. doi:10.1200/JCO.2010.34.4614.

4. de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J,

Elmer M, et al. The oral NK(1) antagonist, aprepitant, given with

standard antiemetics provides protection against nausea and

vomiting over multiple cycles of cisplatin-based chemotherapy: a

combined analysis of two randomised, placebo-controlled phase

III clinical trials. Eur J Cancer. 2004;40(3):403–10.

5. NLEM. Thai national list of essential medicines. 2013. http://

drug.fda.moph.go.th:81/nlem.in.th/sites/default/files/attachments/

essential_book_56.pdf. Accessed 11 May 2015.

6. Haniadka R, Rajeev AG, Palatty PL, Arora R, Baliga MS. Zin-

giber officinale (ginger) as an anti-emetic in cancer chemother-

apy: a review. J Altern Complement Med. 2012;18(5):440–4.

doi:10.1089/acm.2010.0737.

7. Walstab J, Kruger D, Stark T, Hofmann T, Demir IE, Ceyhan

GO, et al. Ginger and its pungent constituents non-competitively

inhibit activation of human recombinant and native 5-HT3

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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123

receptors of enteric neurons. Neurogastroenterol Motil.

2013;25(5):439. doi:10.1111/nmo.12107.

8. Abdel-Aziz H, Windeck T, Ploch M, Verspohl EJ. Mode of

action of gingerols and shogaols on 5-HT3 receptors: binding

studies, cation uptake by the receptor channel and contraction of

isolated guinea-pig ileum. Eur J Pharmacol.

2006;530(1–2):136–43. doi:10.1016/j.ejphar.2005.10.049.

9. Qian QH, Yue W, Chen WH, Yang ZH, Liu ZT, Wang YX.

Effect of gingerol on substance P and NK1 receptor expression in

a vomiting model of mink. Chin Med J. 2010;123(4):478–84.

10. Ryan JL, Heckler CE, Roscoe JA, Dakhil SR, Kirshner J, Flynn

PJ, et al. Ginger (Zingiber officinale) reduces acute chemother-

apy-induced nausea: a URCC CCOP study of 576 patients.

Support Care Cancer. 2012;20(7):1479–89. doi:10.1007/s00520-

011-1236-3.

11. Marx WM, Teleni L, McCarthy AL, Vitetta L, McKavanagh D,

Thomson D, et al. Ginger (Zingiber officinale) and chemother-

apy-induced nausea and vomiting: a systematic literature review.

Nutr Rev. 2013;71(4):245–54. doi:10.1111/nure.12016.

12. Chrubasik S, Pittler MH, Roufogalis BD. Zingiberis rhizoma: a

comprehensive review on the ginger effect and efficacy profiles.

Phytomedicine. 2005;12(9):684–701. doi:10.1016/j.phymed.

2004.07.009.

13. American Society of Clinical O, Kris MG, Hesketh PJ, Somer-

field MR, Feyer P, Clark-Snow R, et al. American Society of

Clinical Oncology guideline for antiemetics in oncology: update

2006. J Clin Oncol. 2006;24(18):2932–47. doi:10.1200/JCO.

2006.06.9591.

14. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The

Edmonton Symptom Assessment System (ESAS): a simple

method for the assessment of palliative care patients. J Palliat

Care. 1991;7(2):6–9.

15. Common Terminology Criteria for Adverse Events (CTCAE)

v4.03. 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_

2010-06-14_QuickReference_5x7.pdf.

16. Gralla RJ, de Wit R, Herrstedt J, Carides AD, Ianus J, Guoguang-

Ma J, et al. Antiemetic efficacy of the neurokinin-1 antagonist,

aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients

receiving anthracyclines or cyclophosphamide in addition to

high-dose cisplatin: analysis of combined data from two Phase III

randomized clinical trials. Cancer. 2005;104(4):864–8. doi:10.

1002/cncr.21222.

17. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G,

Eldridge K, Hipple A, et al. Addition of the neurokinin 1 receptor

antagonist aprepitant to standard antiemetic therapy improves

control of chemotherapy-induced nausea and vomiting. Results

from a randomized, double-blind, placebo-controlled trial in

Latin America. Cancer. 2003;97(12):3090–8. doi:10.1002/cncr.

11433.

18. Hesketh PJ, Grunberg SM, Herrstedt J, de Wit R, Gralla RJ,

Carides AD, et al. Combined data from two phase III trials of the

NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corti-

costeroid for prevention of chemotherapy-induced nausea and

vomiting: effect of gender on treatment response. Support Care

Cancer. 2006;14(4):354–60. doi:10.1007/s00520-005-0914-4.

19. Danwilai K, Konmun J, Sripanidkulchai B-O, Subongkot S.

Antioxidant activity of ginger extract as a daily supplement in

cancer patients receiving adjuvant chemotherapy: a pilot study.

Cancer Manag Res. 2017;9:11.

20. Zick SM, Ruffin MT, Lee J, Normolle DP, Siden R, Alrawi S,

et al. Phase II trial of encapsulated ginger as a treatment for

chemotherapy-induced nausea and vomiting. Support Care Can-

cer. 2009;17(5):563–72. doi:10.1007/s00520-008-0528-8.

21. Manusirivithaya S, Sripramote M, Tangjitgamol S, Sheanakul C,

Leelahakorn S, Thavaramara T, et al. Antiemetic effect of ginger

in gynecologic oncology patients receiving cisplatin. Int J

Gynecol Cancer. 2004;14(6):1063–9. doi:10.1111/j.1048-891X.

2004.14603.x.

22. Panahi Y, Saadat A, Sahebkar A, Hashemian F, Taghikhani M,

Abolhasani E. Effect of ginger on acute and delayed

chemotherapy-induced nausea and vomiting: a pilot, randomized,

open-label clinical trial. Integr Cancer Ther. 2012;11(3):204–11.

doi:10.1177/1534735411433201.

23. Gilliam LA, St Clair DK. Chemotherapy-induced weakness and

fatigue in skeletal muscle: the role of oxidative stress. Antioxid

Redox Signal. 2011;15(9):2543–63. doi:10.1089/ars.2011.3965.

24. Jordan K, Jahn F, Aapro M. Recent developments in the pre-

vention of chemotherapy-induced nausea and vomiting (CINV): a

comprehensive review. Ann Oncol. 2015. doi:10.1093/annonc/

mdv138.

69 Page 10 of 10 Med Oncol (2017) 34:69

123