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Integrative Cancer Therapies

Effect of Ginger on Acute and Delayed 11(3) 204­–211

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DOI: 10.1177/1534735411433201

Vomiting:  A Pilot, Randomized, Open-Label

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Clinical Trial

Yunes Panahi, PhD1, Alireza Saadat, MD2, Amirhossein Sahebkar, PharmD3,

Farshad Hashemian, PhD4, Mojgan Taghikhani, PharmD4, and Ehsan Abolhasani, MD5

Abstract

Background. Nausea and vomiting are among the most prevalent and disturbing side effects of chemotherapy. Therefore,
there is a need for additional antiemetic agents that could effectively reduce chemotherapy-induced nausea and vomiting
(CINV), whether alone or in combination with current standard therapies. Since clinical data on the effectiveness of ginger
in patients with advanced breast cancer is lacking, the present study aimed to evaluate the effects of ginger against both
acute and delayed forms of CINV in a population with advanced breast cancer as the main malignancy. Methods. In this
pilot, randomized, open-label clinical trial, 100 women (mean age = 51.83 ± 9.18 years) with advanced breast cancer who
were initially assigned to standard chemotherapy protocol with docetaxel, epirubicin, and cyclophosphamide (the TEC
regimen) were randomized to receive ginger (1.5 g/d in 3 divided doses every 8 hours) plus standard antiemetic regimen
(granisetron plus dexamethasone; the ginger group) or standard antiemetic regimen alone (control group). The duration
of treatment with ginger was specified to 4 days from the initiation of chemotherapy. Prevalence, score, and severity of
nausea, vomiting, and retching were assessed using a simplified form of Rhodes index in the first 6 hours, between 6 to 24
hours, and days 2, 3, and 4 postchemotherapy. Results. A significantly lower prevalence of nausea was observed in the ginger
group during 6 to 24 hours postchemotherapy. Despite this effect, no other significant additional benefit from ginger (1.5
g/d) was observed against prevalence or severity of nausea, vomiting, and retching in any of the assessed periods. Conclusion.
Addition of ginger (1.5 g/d) to standard antiemetic therapy (granisetron plus dexamethasone) in patients with advanced
breast cancer effectively reduces the prevalence of nausea 6 to 24 hours postchemotherapy. However, there is no other
additional advantage for ginger in reducing prevalence or severity of acute or delayed CINV.

Keywords
ginger, chemotherapy-induced nausea and vomiting (CINV), Rhodes index, breast cancer, docetaxel, epirubicin, cyclophos-
phamide

Introduction experienced by up to 80% and anticipatory CINV by

approximately 14% to 63% of patients.4 5-HT3 receptor
Nausea and vomiting are among the most prevalent and
disturbing side effects of chemotherapy.1,2 These side 1
Research Center of Chemical Injuries, Baqiyatallah University of Medical
effects may lead to several adverse impacts in patients Sciences, Tehran, Iran
receiving chemotherapeutic agents, such as decreased qual- 2
Department of internal Medicine, Baqiyatallah University of Medical
ity of life, anxiety, depression, and lack of compliance to Sciences, Tehran, Iran
3
the medication.2,3 Chemotherapy-induced nausea and vom- Biotechnology Research Center and School of Pharmacy, Mashhad
University of Medical Sciences (MUMS), Mashhad, Iran
iting (CINV) is classified into 3 types: acute CINV, which 4
Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
occurs during the first 24 hours postchemotherapy; delayed 5
Medicine Faculty, Shaheed Beheshti University of Medical Sciences,
CINV, which begins after24 hours postchemotherapy and Tehran, Iran
may last for up to 6 or 7 days; and finally anticipatory
Corresponding Author:
CINV, which affects people who have experienced severe
Yunes Panahi, Research Center of Chemical Injuries, Baqiyatallah
nausea and vomiting in their previous administrations University of Medical Sciences, PO Box 19945-581, Molla-Sadra Street,
of chemotherapeutic agents. The prevalence of untreated Tehran, Iran
CINV is about 70% to 80%, with delayed CINV being Email: yunespanahi@yahoo.com
Panahi et al. 205
antagonists represent a widely used class of antiemetic
agents that are among the first choices for the treatment and
prevention of CINV. However, in spite of their effectiveness,
still a considerable fraction of patients experience CINV.5-11
For instance, 10% to 30% of patients treated with 5-HT3
receptor antagonists have been reported to experience acute
cisplatin-induced emesis,9-11 and even a higher rate of
patients experience delayed cisplatin-induced emesis.12,13
There are also other reports indicating a prevalence of 48%
to 67% for CINV after receiving conventional antiemetic
therapy.2,5,6,8 Besides, unlike acute CINV, delayed and
anticipatory types of CINV appear to be resistant to pharma-
cological treatments, thereby remaining poorly controlled by
currently available medications.2,7,12-17 With respect to the
above-mentioned problems, there is a great demand for the
introduction of new and safe agents that could effectively
reduce CINV rate. One of the potential sources for such
agents is medicinal plants, and among them, ginger (Zingiber
officinale, family Zingiberaceae) is a promising candidate.
Ginger has a widespread use as a spice and flavoring
agent and has a long reputation in both Asian (including
Indian [Ayuverdic], Chinese, and middle eastern) and
Western traditional medicines.18,19 The powdered rhizome
of Z officinale has long been used as a herbal remedy for
gastrointestinal disorders such as nausea, vomiting, dyspep-
sia, constipation, flatulence, and colic.18,19 Modern scien-
tific research has also confirmed that ginger might be
effective against nausea and vomiting induced by motion
sickness, sea sickness, surgery, and pregnancy.20-25 With
respect to CINV, there is evidence on the efficacy of ginger
in animals.18,26 Ginger possesses several interesting phar-
macological activities that may be effective against CINV.
These mechanisms include reversing cisplatin-induced
inhibition of gastric emptying in rats,27 5-HT3 receptor
antagonistic activity,28 and scavenging free radicals that
may cause emesis.29 The antiemetic activities of ginger
could be mainly attributed to its pungent constituents gin-
gerols and shogaols, both of which are phenolic com-
pounds.30 However, clinical trials on the efficacy of ginger
against CINV have been relatively few and with inconsis-
tent results,31-36 with almost no previous reports in a homog-
enous patient population and with advanced breast cancer
as their main malignancy. Therefore, the present random-
ized trial was designed to evaluate the antiemetic activity of
ginger against both acute and delayed types of CINV in
patients with advanced breast cancer who were undergoing
their first experience of chemotherapy.
Methods
Subjects and Design
This was a randomized, open-label, clinical trial that was
performed between July 2008 and November 2009 in the
Oncology Unit of the Baqiyatallah Hospital. The participants
included were women who had cancer (mainly new cases
of advanced breast cancer diagnosed by the oncologist and
thus undergoing their first experience of chemotherapy).
Most of these patients were initially assigned to the compo-
nents of TEC regimen, including docetaxel, epirubicin, and
cyclophosphamide. Docetaxel is associated with intermedi-
ate emetic risk, whereas epirubicin and cyclophosphamide
are highly emetogenic.37 Therefore, the patients who were
under single or combinational therapy with components of
the TEC regimen may be considered to experience chemo-
therapy with moderate to high emetogenic risk. None of the
women were pregnant, lactating, or undergoing concurrent
radiotherapy. Exclusion criteria were participation in
another study with different drugs; history of bone marrow
or stem cell transplantation; presence of respiratory, cardio-
vascular, liver, renal, metabolic, or gastrointestinal dis-
eases; and history of motion sickness. From the 110
initially evaluated women, 100 were qualified to enter the
trial. All these 100 women were randomly assigned to gin-
ger (1.5 g/d in 3 divided doses every 8 hours) plus standard
antiemetic regimen (granisetron plus dexamethasone; gin-
ger group; n = 50) or standard antiemetic regimen alone
(control group; n = 50). The first dose of ginger was con-
sumed about 30 minutes after the completion of chemo-
therapy. The participants of this open-label trial were
individually and alternatively allocated to ginger or control
group with the first allocation being chosen randomly. At
the beginning of study and before patient recruitment,
blank questionnaires were numbered and alternatively
coded as ginger or control. The first code was chosen ran-
domly (by lottery). Then recruited patients were catego-
rized into ginger or control group from questionnaire 1,
based on the predefined allocation. Powdered and dried
ginger root was prepared and validated by the Iran Herb
Medical Society and administered as 500 mg capsules pre-
pared by the Razak Laboratories Corporation (Tehran,
Iran). The duration of treatment with ginger was specified
as 4 days from the initiation of chemotherapy, to allow the
evaluation of ginger’s effects on both acute and delayed
CINV. The day of chemotherapy was considered as day 1.
Apart from medical interventions, patients were advised to
eat easily digestible foods and avoid emetogenic ones.
The study was approved by the institutional ethics com-
mittee and conducted according to the principles of the
Declaration of Helsinki. Written informed consent was
obtained from all participants.
Assessment of the Prevalence and Severity of CINV
Participants were asked to record their symptoms in each
day of trial using a simplified form of the Rhodes Index of
Nausea, Vomiting, and Retching (RINVR).38,39 The RINVR
is a self-reporting 8-item, 5-point Likert-type tool that
206 Integrative Cancer Therapies 11(3)
Assessed for eligibility
(n = 110)
Randomized (n = 100)
Allocaon
Allocated to ginger
(n = 50)
Drop-outs (n = 13)
Reason:
Lost to follow-up or lack
of compliance(n= 9)
Completed and returned
Analyzed
the questionnaire
(n = 37)
Figure 1. Flowchart of the trial
measures the frequency and duration as well as the distress
caused by the symptoms of nausea, vomiting, and retching.
The modified form of RINVR, which was used in the pres-
ent study, contained 8 questions asking about the preva-
lence and duration of nausea, vomiting, and retching;
volume of vomit; and the distress caused by these symp-
toms. For each of the 8 questions, lack of symptoms was
given 0 points, whereas the most severe or prevalent symp-
toms were given 3 points. Thus, the total score for each
subject ranged from 0 to 24, with higher scores indicating
more symptoms. A total score of 0 was considered as lack
of nausea and vomiting, whereas scores 1 to 8, 9 to 16, and
17 to 24 were considered as mild, moderate, and severe
forms of CINV, respectively. Prevalence (number of epi-
sodes) score and severity of nausea, vomiting, and retching
were assessed in the first 6 hours postchemotherapy,
between 6 and 24 hours postchemotherapy, and days 2, 3,
and 4 of the trial. Postchemotherapy nausea and vomiting
data were collected by a self-report diary approach using
the aforementioned questionnaire. The participants were
asked to fill the questionnaire in each of the days of the trial
at home. Assessment of adverse effects was based on self-
reports. Patients were asked to report the adverse effects in
their questionnaire. They were also asked for adverse
effects while returning questionnaires.
Not meeting the inclusion
criteria
(n = 10)
Allocated to placebo
(n = 50)
- Drop-outs (n = 9)
Reason:
Lost to follow-up or lack
of compliance(n = 9)
Completed and returned
the questionnaire
(n = 41)
Statistical Analysis
Statistical analyses were performed using SPSS software
for Windows (version 13.0; SPSS Inc, Chicago, IL). Values
were presented as number (%) or mean ± standard devia-
tion. Between-group (ginger vs control) comparisons were
performed using independent-samples t test (for quantita-
tive variables) or χ2 and Fisher’s exact test (for categorical
variables). Power calculations were performed using the PS
software (version 3.0), with α = .05. Per protocol (com-
pleter) approach was used for data analysis. The reason for
not performing intent-to-treat analysis was lack of access to
the posttrial data of subjects who dropped from the study as
they did not fill or return their questionnaires.
Results
From the 110 initially screened women with advanced
breast cancer, 100 met the eligibility criteria and entered the
trial (age range = 35-74 years, mean age = 51.83 ± 9.18
years). Of these 100 women, 78 completed the trial (37 in
the ginger group and 41 in the control group) with filled
questionnaires and were included in the final analysis
(Figure 1). The reasons for dropping out were mainly being
lost to follow-up and lack of compliance (based on self-report).
Panahi et al. 207

Table 1. Prevalence of Nausea,Vomiting, and Retching in Ginger and Control Groups

Period Ginger Group Control Group P χ2a Power

Nausea First 6 hours 9 (24.3%)b 17 (41.5%) .11 2.57 0.35

  6-24 hours 13 (35.1%) 24 (58.5%) .04 4.27 0.56
  2nd day 17 (45.9%) 22 (55.0%) .43 0.63 0.12
  3rd day 20 (54.0%) 22 (55.0%) .93 0.01 0.05
  4th day 21 (56.8%) 19 (47.5%) .42 0.66 0.14
Vomiting and retching First 6 hours 9 (24.3%) 11 (26.8%) .80 0.06 0.06
  6-24 hours 7 (18.9%) 12 (29.8%) .26 1.27 0.17
  2nd day 13 (35.1%) 11 (27.5%) .47 0.52 0.12
  3rd day 13 (35.1%) 12 (30.0%) .63 0.23 0.07
  4th day 16 (43.2%) 14 (35.0%) .46 0.55 0.11
a
Pearson χ2 values with 1 degree of freedom.
b
Values are presented as number (%). Comparisons were performed using χ2 or Fisher’s exact tests with 1 degree of freedom. Power calculations were
performed using the PS software (version 3.0), with α = .05.

Table 2. Rhodes Index Scores of Nausea,Vomiting, and Retching in Ginger and Control Groups

Period Ginger Group Control Group P t Value Power

Minimum Maximum Mean ± SD Minimum Maximum Mean ± SD

First 6 hours 0 15 3.22 ± 4.45a 0 13 2.98 ± 3.95 .80 0.25 0.06

6-24 hours 0 16 3.11 ± 4.04 0 17 4.10 ± 4.42 .31 1.03 0.17

2nd day 0 19 4.35 ± 4.84 0 14 4.32 ± 4.36 .98 0.02 0.05

3rd day 0 16 4.78 ± 4.82 0 20 4.22 ± 5.06 .62 0.49 0.08

4th day 0 23 5.70 ± 5.60 0 2 4.47 ± 5.45 .33 0.97 0.10

a
Values are presented as mean ± standard deviation. Comparisons were made using independent-samples t test. Power calculations were performed
using the PS software (version 3.0), with α = .05.

The difference in dropout rate between the 2 groups was
not found to be significant (P = .33, χ2 = .93). Hence, it does
not appear that dropouts were because of the reaction to the
side effects of ginger. The groups were comparable in their
baseline demographic characteristics. Side effects reported
for ginger were heartburn, headache, and vertigo.
Effect of Ginger on the Prevalence of
Nausea,Vomiting, and Retching
Addition of ginger to the standard antiemetic therapy was
found to be associated with a significant reduction in the
prevalence of nausea, but not vomiting and retching, at 6 to
24 hours postchemotherapy in the ginger group compared
with the control group (P = .04; Table 1). However, there was
no significant difference in the prevalence of nausea, vomit-
ing, and retching between the ginger and control groups at all
other assessed intervals—the first 6 hours, second, third, and
fourth days postchemotherapy (P > .05; Table 1).
Effect of Ginger on the Rhodes Index Scores
of Nausea,Vomiting, and Retching
Overall, the mean scores for nausea, vomiting, and retching
were not significantly different between ginger and control
groups and this was true for all assessed intervals—the first
6 hours, 6 to 24 hours, and second, third, and fourth days
postchemotherapy (P > .05; Table 2).
208 Integrative Cancer Therapies 11(3)

Table 3. Severity of Nausea,Vomiting, and Retching in Ginger and Control Groupsa

Severity of
Period Symptoms Ginger Group Control Group P χ2b Power
First 6 hours No symptom 18 (48.6 %)c 22 (53.7%) .66 0.19 0.07

  Mild 12 (32.4%) 13 (31.7%) .94 0.005 0.05

  Moderate 7 (18.9%) 6 (14.6%) 0.61 0.26 0.08
  Severe 0 (0%) 0 (0%) 1.00 — —
6-24 hours No symptom 17 (45.9%) 14 (34.1%) .29 0.04 0.19

  Mild 15 (40.5%) 19 (46.13%) .61 0.27 0.08

  Moderate 5 (13.5%) 7 (17.1%) .66 0.19 0.06
  Severe 0 (0%) 0 (0%) 1.00 — —
2nd day No symptom 15 (40.5%) 14 (35.0%) .62 0.25 0.08

  Mild 13 (35.1%) 18 (45.0%) .38 0.78 0.14

  Moderate 8 (21.6%) 8 (20.0%) .86 0.03 0.06
  Severe 1 (2.7%) 0 (0%) .48 — 0.20
3rd day No symptom 14 (37.8%) 14 (35.0%) .80 0.07 0.06

  Mild 14 (37.8%) 17 (42.5%) .68 0.17 0.06

  Moderate 8 (21.6%) 8 (20.0%) .86 0.03 0.06
  Severe 1 (2.7%) 1 (2.5%) 1.000 — 0.05
4th day No symptom 12 (32.4%) 18 (45.0%) .26 1.28 0.21

  Mild 12 (32.4%) 11 (27.5%) .64 0.22 0.08

  Moderate 12 (32.4%) 10 (25.0%) .47 0.52 0.10
  Severe 7 (2.7%) 1 (2.5%) 1.00 — 0.05
a
Severity of symptoms were assessed based on the Rhodes index.
b
Pearson χ2 values with 1 degree of freedom.
c
Values are presented as number (%). Comparisons were performed using χ2 or Fisher’s exact tests with 1 degree of freedom. Power calculations were
performed using the PS software (version 3.0), with α = .05.

Effect of Ginger on the Severity of Nausea,
Vomiting, and Retching
There was no significant difference between the ginger and
control groups in the number of individuals in each of the 4
assessed subclasses based on the severity of symptoms
(lack of symptoms, mild, moderate, and severe symptoms).
The lack of significant difference was observed at all
assessed intervals—the first 6 hours, 6 to 24 hours, and
second, third, and fourth days postchemotherapy (P > .05;
Table 3). The power of each statistical test was calculated.
The powers were low (Table 3) may imply that by larger
populations, significant results may be anticipated.
Discussion
The results of the present study indicated a significantly
lower prevalence of nausea in the ginger group during 6 to
24 hours postchemotherapy. Despite this effect, no other
significant additional benefit from ginger (1.5 g/d) was
observed against prevalence or severity of acute or delayed
chemotherapy-induced nausea, vomiting, and retching in
patients with advanced breast cancer. Noteworthy, there
were ˜17% and 10% reduction in the prevalence of nausea
during the first 6 hours and second day of chemotherapy,
respectively. Although these reductions were not found to
be significant from the statistical point of view (probably
because of insufficient power), they might be of clinical
relevance and thus deserve to be verified by larger trials.
Unlike nausea/vomiting related with other situations
such as pregnancy, motion sickness, and surgery, the effi-
cacy of ginger to reduce the CINV remains relatively
unknown with only few studies in this regard. Therefore,
further investigations in this regard appear necessary and
might be useful to become available to the scientific com-
munity. To our knowledge, there have been 6 previous
reports on the efficacy of ginger against CINV,31-36 of which
3 are available only in the abstract form.31,32,36 The study by
Panahi et al. 209
Table 4. Comparison of Clinical Trials on the Efficacy of Ginger Against CINV
Dose of Ginger Source of Ginger
33
Sontakke et al 2 g/d Powdered dried root Acute CINV
Manusirivithaya et al34 1 g/d Powdered root
Zick et al35 1.0 and 2.0 g/d Dried root extract Acute and delayed CINV No additional benefit against acute
Ryan et al36 0.5, 1.0, and 1.5 g/d Not defined
Current study 1.5 g/d Powdered dried root Acute and delayed CINV Effective against acute nausea but
Abbreviation: CINV, chemotherapy-induced nausea and vomiting.
Pace31 investigated the effectiveness of ginger compared
with placebo in a group of 41 leukemic patients who were
under chemotherapy plus antiemetic agent prochlorpera-
zine. The results indicated a significant decrease in the
acute nausea symptom score in the ginger versus placebo
group.31 However, in the mentioned study (published in the
abstract form), the effect of ginger on delayed CINV was
not assessed. In the second study, by Pecoraro et al,32 a
greater complete treatment response of acute CINV was
reported in subjects receiving ginger compared with pla-
cebo. This was again a small study (12 participants) with
limitation regarding examination of ginger effect on delayed
CINV.
The third study, by Sontakke et al,33 which had a ran-
domized, prospective, crossover, and double-blind design,
evaluated the effects of ginger in comparison with metoclo-
pramide and ondansetron among 60 patients receiving low-
dose cyclophosphamide in combination with other
chemotherapeutic agents causing mild emesis. The results
implied the effectiveness of ginger in controlling nausea
and vomiting, with its antiemetic efficacy being equal to
that of metoclopramide but lower than that of ondansetron.
The study of Sontakke et al33 is not directly comparable to
the present work, as they administered ginger instead of the
standard antiemetic therapy such as a 5-HT3 antagonist,
whereas in the current work ginger was coadministered
with the standard regimen (granisetron plus dexametha-
sone). In addition, the latter study did not investigate the
effect of ginger on the prevalence or severity of delayed
CINV.
The fourth investigation was a randomized, double-
blind, crossover study that evaluated the efficacy of ginger
(1 g/d) against both acute and delayed types of cisplatin-
induced emesis in 48 patients with gynecologic (ovary or
cervix) cancer. Based on the results, addition of ginger to
the standard antiemetic regimen of patients under cisplatin
Type of CINV Assessed Findings
Effective against acute CINV
Acute and delayed CINV No additional benefit against
acute CINV; control of delayed
CINV with equal efficacy to
metoclopramide
or delayed CINV
Acute and delayed CINV Effective against acute nausea but
not vomiting
not vomiting; no additional benefit
against delayed CINV
therapy had no significant benefit against acute CINV.
However, in the delayed phase of chemotherapy (days 2-5),
the efficacy of ginger in controlling nausea and vomiting
was not found to be significantly different from that of
metoclopramide (40 mg/d).34 These results are almost in
line with the findings of the fifth study by Zick et al,35 who
conducted a large randomized and double-blind trial among
162 patients. The patients were randomized to receive 1 g/d
ginger, 2 g/d ginger or placebo for 3 days, and all were
receiving a 5-HT3 receptor antagonist and/or aprepitant as
standard antiemetic therapy. The results implied that ginger,
at either dose, had no significant additional benefit in
decreasing the prevalence or severity of acute or delayed
CINV. In the same study, high-dose ginger (2 g/d) was asso-
ciated with more severe episodes of delayed nausea com-
pared with low-dose ginger (1 g/d) or placebo. In addition,
subjects under both ginger (at either dose) and aprepitant
were found to have more severe delayed nausea compared
with those who took only aprepitant.
Finally, the most recent report on this topic pertains to a
presentation by Ryan et al36 at the 2009 ASCO Annual
Meeting. This was a well-designed multi-site, phase II/III
randomized, placebo-controlled, double-blind clinical trial
which aimed at the evaluation of ginger effectiveness (0.5,
1.0 or 1.5 g daily) against acute CINV in 644 patients, as
well as determination of its most effective dose. The results
indicated that all doses of ginger significantly reduced nau-
sea with doses of 0.5 g and 1 g being the most effective.
However, the effect of ginger on vomiting was not found to
be significant.
With respect to acute CINV, the results of the current
study is consistent with those of Ryan et al,36 indicating that
addition of ginger to standard antiemetic therapy causes
additional reduction in chemotherapy-induced nausea but
not vomiting during the first day of chemotherapy. With
respect to delayed CINV, the findings of this work and that
210 Integrative Cancer Therapies 11(3)
of Zick et al35 implied that addition of ginger does not
reduce the prevalence or severity of delayed CINV beyond
what is achieved by standard therapy with granisetron plus
dexamethasone. However, it must be noted that the findings
of the current study may not be directly comparable to some
of the previous reports because of differences in the source
and dose of ginger, supplementation design, and chemo-
therapeutic regimen (Table 4). Among the 5 studies with
adequately published information in this field (taking into
account the present trial), 3 started ginger before the initia-
tion of chemotherapy33,34,36 and 2 (including this study and
that of Zick et al35) started ginger after the initiation of chemo-
therapy. In either type of trials, there have been both positive
and negative findings. Nevertheless, it appears that initiation
of ginger supplementation before or after chemotherapy is an
influential factor on ginger’s efficacy against CINV.
Regarding the type of cancer and administered chemo-
therapy regimen, it is worth noting that the participants of
this study probably constituted a more homogenous group
compared with previous studies.33,35,36 Nevertheless, the
present study had limitations that should be taken into con-
sideration. The main issue is lack of blindness. This lack of
blindness was because of the pilot nature of the study and
difficulties in placebo preparation and successful blinding
as ginger possesses unique and familiar aroma.40 However,
this lack of blindness and patients’ awareness of the treat-
ment might have caused a so-called reverse placebo effect,41
thereby leading to a more severe evaluation of CINV symp-
toms and consequent underestimation of ginger efficacy.
Besides, it must be noted that the relatively fewer number of
participants and thereby insufficient power could be a rea-
son for the negative findings in the present study. An exam-
ple of this latter issue is the prevalence of nausea in the first
6 hours postchemotherapy, which is about 17% lower in the
ginger group, but not statistically different from that in the
control group. As another limitation, the effect of ginger on
the rate of chemotherapy-associated adverse events as well
as efficacy of chemotherapy were not evaluated. In addi-
tion, although ginger is generally safe, accurate assessment
of its potential adverse events and interactions in patients
undergoing chemotherapy is needed. Finally, the relatively
low prevalence and severity of CINV in both ginger and
control groups raise the possibility of a “floor effect” that
might be responsible for the lack of significant differences
between the groups. Therefore, caution must be applied in
considering the implications of the current results.
In summary, the data from the current study indicated that
addition of ginger (1.5 g/d) to standard antiemetic therapy
(granisetron plus dexamethasone) in patients with advanced
breast cancer who were under chemotherapy was associated
with decreased prevalence of nausea during 6 to 24 hours
postchemotherapy. Nevertheless, no other significant effect
was observed against prevalence of nausea in the first 6 hours
postchemotherapy, severity of acute CINV, and prevalence or
severity of delayed CINV. Future larger scale double-blind
trials are recommended to verify the results of the current
pilot trial. Prospective studies and longer periods of follow-
up are also helpful to assess the efficacy of ginger supple-
mentation on the prevalence of CINV symptoms in patients
receiving multiple cycles of chemotherapy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was financially supported by the Baqiyatallah
University of Medical Sciences.
References
 1. Hickok JT, Roscoe JA, Morrow GR, King DK, Atkins JN,
Fitch TR. Nausea and emesis remain significant problems
of chemotherapy despite prophylaxis with 5-hydroxytryp-
tamine-3 antiemetics: a University of Rochester James P.
Wilmot Cancer Center Community Clinical Oncology Pro-
gram Study of 360 cancer patients treated in the community.
Cancer. 2003;97:2880-2886.
  2. Cohen L, de Moor CA, Eisenberg P, Ming EE, Hu H. Chemo-
therapy-induced nausea and vomiting: incidence and impact
on patient quality of life at community oncology settings. Sup-
port Care Cancer. 2007;15:497-503.
  3. Ballatori E, Roila F, Ruggeri B, et al. The impact of chemo-
therapy-induced nausea and vomiting on health-related quality
of life. Support Care Cancer. 2007;15:179-185.
 4. Berger AM, Clark-Snow RA. Nausea and vomiting. In: De
Vita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles
and Practice in Oncology. 6th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2001:2869-2880.
  5. Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt
J. Delayed nausea and vomiting continue to reduce patients’
quality of life after highly and moderately emetogenic che-
motherapy despite antiemetic treatment. J Clin Oncol.
2006;24:4472-4478.
  6. Feyer P, Kleeberg UR, Steingraber M, Gunther W, Behrens
M. Frequency of side effects in outpatient cancer care and
their influence on patient satisfaction: a prospective survey
using the PASQOC(R) questionnaire. Support Care Cancer.
2008;16:567-575.
  7. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of che-
motherapy-induced nausea and emesis after modern antiemet-
ics. Cancer. 2004;100:2261-2268.
 8. Henry DH, Viswanathan HN, Elkin EP, Traina S, Wade S,
Cella D. Symptoms and treatment burden associated with can-
cer treatment: results from a cross-sectional national survey in
the U.S. Support Care Cancer. 2008;16:791-801.
Panahi et al. 211
  9. Manusirivithaya S, Chareoniam V, Isariyodom P, Sungsalo D.
Comparison of ondansetron-dexamethasone-lorazepam versus
metoclopramide-dexamethasone-lorazepam in the control of
cisplatin induced emesis. J Med Assoc Thai. 2001;847:966-972.
10. Marty M, Pouillart P, Scholl S, et al. Comparison of the
5-hydroxytryptamine-serotonin antagonist, ondansetron with
high-dose metoclopramide in the control of cisplatin-induced
emesis. N Engl J Med. 1990;322:816-821.
11. Roila F, Tonato M, Cognetti F, et al. Prevention of cispla-
tin-induced emesis: a double-blind multicenter randomized
crossover study comparing ondansetron and ondansetron plus
dexamethasone. J Clin Oncol. 1991;9:675-678.
12. Rossel R, Moreno I, Abed A. Delayed emesis after cisplatin
treatment: incidence, source and management. In: Diaz Rubio
E, Martin M, eds. Antiemetic Therapy: Current Status and
Future Prospects. Madrid, Spain: Creaciones Elba; 1992:202.
13. Kris MG, Tyson LB, Clark RA, Grall RJ. Oral ondansetron for
the control of delayed emesis after cisplatin: report of phase
II study and a review of completed trials to manage delayed
emesis. Cancer. 1992;70:1012-1016.
14. Morrow GR, Roscoe JA, Hickok JT. Time of first occurrence,
severity, and persistence of nausea following initial chemo-
therapy in 322 patients: a URCC CCOP study. Support Care
Cancer. 2001;9:290.
15. Jacobsen PB, Bovbjerg DH, Redd WH. Anticipatory anxiety
in women receiving chemotherapy for breast cancer. Health
Psychol. 1993;12:469-475.
16. Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nau-
sea and emesis: comparisons of ondansetron (zofran), granisetron
(kytril), and tropisetron (navoban). Cancer. 1995;76:343-357.
17. Morrow GR, Roscoe JA. Anticipatory nausea and vomiting:
models, mechanisms and managemenr. In: Dicato MA, ed.
Medical Management of Cancer Treatment Induced Emesis.
London, England: Martin Dunitz; 1998:149-166.
18. Sharma SS, Kochupillai V, Gupta SK, Seth SD, Gupta YK. Anti-
emetic efficacy of ginger (Zingiber officinale) against cisplatin-
induced emesis in dogs. J Ethnopharmacol. 1997;57:93-96.
19. Visalyaputra S, Petchpaisit N, Somcharoen K, Choavaratana
R. The efficacy of ginger root in the prevention of postopera-
tive nausea and vomiting after outpatient gynaecological lapa-
roscopy. Anaesthesia. 1998;53:506-510.
20. Grontved A, Brask T, Kambskard J, Hentzer E. Ginger root
against seasickness. Acta Oto-Laryngol. 1988;105:45-49.
21. Mowrey DB, Clayson DE. Motion sickness, ginger, and psy-
chophysics. Lancet. 1982;1:655-657.
22. Bone ME, Wilkinson DJ, Young JR, McNeil J, Carlton S.
Ginger root: a new antiemetic—the effect of ginger root on
postoperative nausea and vomiting after major gynaecological
surgery. Anaesthesia. 1990;45:669-671.
23. Phillips S, Ruggier R, Hutchinson SE. Forum. Zingiber offici-
nale (ginger): an antiemetic for day case surgery. Anaesthesia.
1993;48:715-717.
24. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger
treatment of hyperemesis gravidarum. Eur J Obstet Gynecol
Reprod Biol. 1990;38:19-24.
25. Vutyavanich T, Kraisarin T, Ruangsri RA. Ginger for nausea
and vomiting in pregnancy: randomized, double-masked, pla-
cebo-controlled trial. Obstet Gynecol. 2001;97:577-582.
26. Yamahara J, Rong HQ, Naitoh Y, Kitani T, Fujimura H. Inhibi-
tion of cytotoxic drug-induced vomiting in suncus by a ginger
constituent. J Ethnopharmacol. 1989;27:353-355.
27. Sharma SS, Gupta YK. Reversal of cisplatin-induced delay in
gastric emptying in rats by ginger (Zingiber officinale). J Eth-
nopharmacol. 1998;62:49-55.
28. Huang QR, Iwamoto M, Aoki S, et al. Anti-5-hydroxytrypta-
mine3 effect of galanolactone, diterpenoid isolated from gin-
ger. Chem Pharm Bull (Tokyo). 1991;39:397-399.
29. Aeschbach R, Loliger J, Scott BC, et al. Antioxidant actions of
thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol.
Food Chem Toxicol. 1994;32:31-36.
30. Wilkinson JM. Ginger: a review of its medicinal uses. Biomed
Res. 1999;1:23-32.
31. Pace J. Oral ingestion of encapsulated ginger and reported
self-care action for the relief of chemotherapy-associated
N&E. Dissertations Abstracts International. 1987;47:3297-B.
32. Pecoraro A, Patel J, Guthrie T, Ndubisi B. Efficacy of ginger
as an adjunctive anti-emetic in acute chemotherapy-induced
nausea and vomiting. Paper presented at: ASHP Mid-Year
Clinical Meeting; December 6-10, 1998; Las Vegas, NV.
33. Sontakke S, Thawani V, Naik MS. Ginger as an antiemetic in
nausea and vomiting induced by chemotherapy: a random-
ized, cross-over, double blind study. Indian J Pharmacol.
2003;35:32-36.
34. Manusirivithaya S, Sripramote M, Tangjitgamol T, et
al. Antiemetic effect of ginger in gynecologic oncology
patients receiving cisplatin. Int J Gynecol Cancer. 2004;14:
1063-1069.
35. Zick SM, Ruffin MT, Lee J, et al. Phase II trial of encapsulated
ginger as a treatment for chemotherapy-induced nausea and
vomiting. Support Care Cancer. 2009;17:563-572.
36. Ryan JL, Heckler C, Dakhil SR, et al. Ginger for chemother-
apy-related nausea in cancer patients: a URCC CCOP ran-
domized, double-blind, placebo-controlled clinical trial of 644
cancer patients. J Clin Oncol. 2009;27(15, suppl pt 1):9511.
37. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for
the use of antiemetics: evidence-based, clinical practice guide-
lines. J Clin Oncol. 1999;17:2971-2994.
38. Rhodes VA, McDaniel RW. The index of nausea, vomiting,
and retching: a new format of the index of nausea and vomit-
ing. Oncol Nurs Forum. 1999;26:889-894.
39. Kim TH, Choi BM, Chin JH, Lee MS, Kim DH, Noh GJ. The
reliability and validity of the rhodes index of nausea, vomiting
and retching in postoperative nausea and vomiting. Korean J
Anesthesiol. 2007;52:S59-S65.
40. Zick SM, Blume A, Normolle D, Ruffin M. Challenges in
herbal research: a randomized clinical trial to assess blinding
with ginger. Complement Ther Med. 2005;13:101-106.
41. de Craen AJ, Kaptchuk TJ, Tijssen JG, Kleijnen J. Placebos
and placebo effects in medicine: historical overview. J R Soc
Med. 1999;92:511-515.