Supportive Care in Cancer

https://doi.org/10.1007/s00520-018-4344-5

REVIEW ARTICLE

Meta-analysis of randomized controlled trials of the efficacy of propolis

mouthwash in cancer therapy-induced oral mucositis
Chen-Chen Kuo 1,2 & Ruey-Hsia Wang, PhD 2 & Hsiu-Hung Wang, PhD 2 & Chun-Hua Li 2,3

Received: 8 January 2018 / Accepted: 6 July 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose This meta-analysis aimed to evaluate the efficacy and safety of propolis mouthwash in cancer patients with therapy-
induced oral mucositis.
Methods This was a systematic review of randomized control trails (RCTs). We searched ten electronic databases for studies
published prior to April 06, 2017. The included RCTs were published in English and Chinese. The Jadad score was used to
evaluate the quality of the articles identified. Two reviewers independently evaluated each of the studies. The data were entered
into Review Manager (RevMan) 5.3 software and checked for accuracy. Outcome incidence analysis was performed using odds
ratios (ORs).
Results Of the 352 articles identified, five potentially relevant articles met our inclusion criteria. These 5 RCTs included a total of
209 participants. The Jadad score for methodological quality was 3.60 ± 0.55. No obvious publication bias was noted. The
incidence of severe oral mucositis was significantly lower in the propolis group than in the control group (OR = 0.35, p = 0.
003). The corresponding 95% confidence interval (CI) was 0.18 to 0.70. Between-study heterogeneity was low (I2 = 0.000, p =
0.45). No side effects were reported.
Conclusions Propolis mouthwash is effective and safe in the treatment of severe oral mucositis. To maintain propolis safety,
propolis usage should occur under the supervision of medical staff and health professionals. Future multi-center studies and a
clinical protocol are needed to confirm the current findings regarding the efficacy and safety of propolis mouthwash.

Keywords Propolis mouthwash . Oral mucositis . Chemotherapy or radiotherapy . Meta-analysis

Introduction acute complications of chemotherapy or RT. Oral mucositis

Chemotherapy and radiotherapy (RT) are the most commonly
used types of cancer treatment, and oral mucositis is one of the
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00520-018-4344-5) contains supplementary
material, which is available to authorized users.
* Hsiu-Hung Wang, PhD
hhwang@kmu.edu.tw
1
The Cancer Prevention and Treatment Center, St. Martin De Porres
Hospital, Chiayi, Taiwan
2
College of Nursing, Kaohsiung Medical University,
Kaohsiung, Taiwan
3
Department of Nursing, Yuhing Junior College of Health Care and
Management, Kaohsiung, Taiwan
caused by chemotherapy occurs within 3–5 days and peaks at
7 to 14 days after chemotherapy initiation [1]. Radiation-
induced oral mucositis affecting patients with head and neck
cancer occurs within 2 weeks and peaks from 2 to 6 weeks
after treatment initiation [2, 3]. Oral mucositis presents as an
epithelial and subepithelial injury during chemotherapy or RT
and progresses through the following five stages: (1) the ini-
tiation stage, (2) the message generation stage, (3) the signal-
ing and amplification stage, (4) the ulceration stage, and (5)
the healing stage [2, 3]. Mucositis presents as mild redness
(erythema), edema, sensitivity, pain, ulceration, discomfort,
and hemorrhage.
Oral mucositis is defined by a variety of scoring systems
[4]. These scales generally utilize the 5-grade classification
system to grade oral mucositis severity. The clinical severity
of the mucosal injury varies from mild (grade = 1) to moderate
(grade = 2) to severe (grade = 3 or 4) [3]. The incidence of oral
mucositis in patients receiving high-dose RT/chemotherapy is

40–76% [1]. Fifty-six percent of patients receiving chemo-
therapy experience moderate-to-severe oral mucositis (grades
3–4), while approximately 34% of patients receiving conven-
tional RT experience moderate-to-severe oral mucositis [2, 4,
5]. Severe oral mucositis may lead to localized or systemic
infections, difficulty in eating and swallowing, weight loss or
malnutrition, treatment interruption or even death [6, 7]. We
found that the average hospitalization cost for patients with
oral mucositis was $6277 per chemotherapy cycle, while the
average cost for patients without oral mucositis was $3893 per
chemotherapy cycle [8]. Thus, preventing chemotherapy or
RT-induced mucositis may help decrease health care costs.
The strategies for preventing oral mucositis induced by
RT or chemotherapy involve pharmaceutical and non-
pharmaceutical interventions [6]. Among the pharmaceu-
tical interventions, keratinocyte growth factor (palifermin)
was shown to have beneficial effects with respect to the
prevention of mucositis. Other pharmaceuticals, including
amifostine, intravenous glutamine, granulocyte-colony
stimulating factor (G-CSF), sucralfate, and antibiotic loz-
enges containing polymyxin/tobramycin/amphotericin
(PTA), were shown to have less beneficial effects with
respect to the prevention of mucositis [9]. Among the
non-pharmaceuticals, cryotherapy (ice chips) was shown
to have strong beneficial effects, while lasers, aloe vera,
and honey were shown to have weaker beneficial effects
[9]. Routine care with oral mouthwashes is also recom-
mended for the treatment of oral mucositis [10].
In many parts of the world, people used propolis as early as
300 BC. Propolis has been used as a medicine both internally
and externally, e.g., as a mouthwash [11]. Propolis may exert
its effects via the following mechanisms: First, propolis is a
natural resinous substance that acts as a glue in the building,
repair, and protection of hives [12]. In clinical practice, prop-
olis has anti-inflammatory, anti-ulcer, antibacterial, antifungal,
antiviral, antioxidant, radiation protective, anticancer, and an-
titumor effects [13–15]. Second, the components of propolis
include phenol acids, flavonoids, caffeic acid (CA), CA
phenethyl ester (CAPE), terpenes, aromatic aldehydes, fatty
acids, stilbenes,β-steroids, and various other substances [11,
13]. Propolis contains a rich flavonoid that may exert anti-
inflammatory effects by inhibiting reactive oxygen or nitrogen
compounds [16]. Flavonoids are economical treatment agents
for patients with RT-induced oral mucositis [14]. Yildiz et al.
[17] reported that CAPE induced pulmonary injury in vivo,
namely in rats receiving RT, through its antioxidant effects.
Third, propolis has been reported to have clinically relevant
antiseptic effects and to promote wound healing [18, 19]. The
positive effects of propolis on oral mucositis have been attrib-
uted to its anti-inflammatory, antimicrobial, and antioxidant
effects. Over the last decade, increasing numbers of studies
have focused on propolis as a treatment for oral mucositis in
patients with cancer.
Support Care Cancer
Currently, a propolis-related product is classified by the
United States Food & Drug Administration (FDA) as a dietary
supplement product [20, 21]. Thus, there have been concerns
expressed in recent years by the FDA relative to warning
letters for propolis-related products. The most common prob-
lems include the following: (1) may not meet Current Good
Manufacturing Practice (cGMP) regulations [20–22], (2) un-
approved new drugs or misbranded drugs, as the FDA ap-
proves a new drug on the basis of the best scientific data sent
by a drug sponsor to show the drug is safe and effective [22],
(3) commercial advertisement for uses violates 201(p) of the
Federal Food, Drug, and Cosmetic Act, such as a product
claims to mitigate, treat, cure, or prevent of one or more dis-
eases [20, 22], (4) Badequate directions for use^ means the
directions by which a layman can use a drug safely for its
intended purposes, whereby prescription drugs can only be
used safely at the direction, and under the supervision, of a
licensed practitioner [20], (5) propolis-related products must
contain 20% or more the recommended daily intake (RDI) or
daily reference value (DRV) of nutrients [22], and (6) the
suggested use states that the consumer take 2–5 drops once
[21]. In addition, we refer to the Management of Product
License Applications for Natural Health Products guidance
document for Health Canada regarding propolis-oral. The
dosage for relief of mouth/throat infections in adults is 0.2–
0.6 g per day. If the duration of usage has been exceeded by
1 month, a health practitioner should be consulted [23].
Incidentally, New Zealand (Bee Product Warning Statement-
Dietary Supplement) Food Standards 2002 showed that prop-
olis may cause severe allergic reactions [24].
Most of these warnings and points mentioned above will
not impact future research and clinical use because propolis is
considered by the U.S. FDA to be safe and effective. With
regard to propolis allergy, this should be exclusion criteria in
selecting research subjects in future research. With regard to
the recommended dose of propolis, we must comply with the
U.S. FDA’s labeling regulation under 21 Code of Federal
Regulations (CRF) Part 101.9 (b) and 101.12 (b). The only
suggested dose is not to exceed 5 drops once, according to the
FDA [21]. However, the FDA has not clearly ruled out use by
all populations. The product monographs from Health Canada
only provide the daily adult dose for propolis-oral [23], and it
does not mention a child’s dose in product monographs.
In 2014, the Mucositis Study Group of the Multinational
Association of Supportive Care in Cancer and International
Society of Oral Oncology (MASCC/ISOO) published clinical
practice guidelines for mucositis in cancer therapy. However,
due to inadequate or conflicting evidence for natural and mis-
cellaneous agents, no guideline for honey (propolis) has been
proposed [25]. As a consequence, the results of studies on
propolis as a treatment for oral mucositis that have been con-
ducted over the past 5 years have lacked consistency. Two
articles, one systematic review, and one RCT about propolis
Support Care Cancer
mouthwash have been published. However, these studies did
not use specific inclusion criteria or failed to obtain significant
results [8–10, 26, 27]. In 2015, Bolouri et al. [14] reported that
propolis efficiently prevents and heals RT-induced oral muco-
sitis. However, we have not found any newer evidence regard-
ing the efficacy of propolis as a treatment for oral mucositis
[7]. Most of the previous studies regarding propolis had small
samples. Thus, it is necessary to summarize the existing clin-
ical trial evidence and to perform a comprehensive meta-
analysis to obtain an accurate estimation of the effects of
propolis on oral mucositis. The aim of this systemic review
was to explore the evidence on the efficacy and safety of
propolis mouthwash as a treatment for therapy-induced oral
mucositis in patients with cancer.
Methods
This study was performed in accordance with the Preferred
Reporting Items for Systematic Review and Meta-analysis
(PRISMA) statement [28].
Search strategies
This systematic review and meta-analysis evaluated the effi-
cacy of propolis mouthwash as a treatment for oral mucositis
in patients receiving RT or chemotherapy. PubMed, CINAHL
Plus with Full Text (including MEDLINE Complete, EBSCO,
and Dentistry & Oral Science Source), ProQuest, the
Cochrane Central Register of Controlled Trails, Google
Scholar, EBMASE, Ovid, Web of Science, and Science
Direct were searched for relevant RCTs published prior to
April 06, 2017. No language restrictions were imposed.
Furthermore, we conducted additional searches of other
sources, such as Chinese Electronic Periodical Services
(CEPS) and clinical trial registries. The following keywords
were used in the searches: Bcancer,^ and Bradiotherapy^ or
Bchemotherapy^ or Bchemoradiotherapy,^ and Bpropolis^ or
Bbee glue,^ and Boral mucositis^ or Bmucositis^ or
Bstomatitis.^ The results were saved to an Endnote X7 citation
manager. The full electronic search strategies used in this
study are listed in Appendix 1, and the flow diagram for the
systematic review is shown in Fig. 1.
Inclusion criteria
The following RCTs were included in the review: (1) studies
with an experimental design, (2) studies including patients
with cancer who were receiving chemotherapy or RT, (3)
studies with no age limits, (4) original studies published in
English or Chinese, (5) studies in which propolis was used
as an intervention, (6) studies in which severe oral mucositis
(grades 3–4) was used as an outcome measurement, and (7)
studies with a Jadad score of 3 or more.
Exclusion criteria
The following studies or data were excluded from the review:
(1) animal or laboratory studies, (2) multiple reports based on
the same study data, (3) unpublished papers or data, and (4)
studies in which the outcome of interest could not be analyzed
or from which the proper data could not be extracted.
Type of intervention
The intervention was propolis mouthwash, which was used as
a treatment for severe oral mucositis.
Quality appraisal
The quality of the included studies was assessed by the Jadad
score. Previous studies have reported that the Jadad score has
high internal consistency and external validity [10, 29]. The
score reflects item allocation concealment and whether the
analysis involved a randomized group [10, 29]. The score is
a 3-item instrument and ranges from 0 to 5 [30]. The score is
determined based on the method used for randomization, the
method used for blinding, the withdrawal, and dropout rates
[10, 29]. The Jadad score also includes two extra items, name-
ly allocation concealment and intent-to-treat (ITT) analysis.
Moreover, the Jadad score reflects the risks of various forms
of bias, including selection bias, performance bias, detection
bias, and attrition bias [29]. A Jadad score of 3 indicates that
an RCT is of high quality [31]. Publication bias is a wide
problem that may seriously constrain attempts to estimate an
effect. Publication bias has been associated with funnel plot
asymmetry. Generally, funnel plots are considered to be unre-
liable for the examination of publication bias, especially if the
number of studies is small or less than 10 in meta-analysis [32,
33]. Publication bias was evaluated using Begg’s funnel plot
(large studies) and Egger’s test (small or less than 10 studies),
which may be used to accurately test for funnel plot asymme-
try [32–34].
Data extraction
Two reviewers (one clinical expert and one nurse educator)
independently evaluated the eligible studies. The review arti-
cles were selected in three phases. In phase I, the reviewers
scanned the titles and abstracts of the identified studies inde-
pendently and excluded the abstracts of animal or in vitro
studies. In phase II, screening was conducted based on the
PICO criteria, and the full texts of the eligible articles were
reviewed. In phase III, the full texts of the articles were
reviewed to determine the validity of the screening
 Support Care Cancer

Fig. 1 PRISMA (Preferred

Records idenfied through Addional records idenfied
Reporting Items for Systematic
database searching through other sources:

Identification
reviews and Meta-Analyses) flow (n =346) CEPS(4),clinical trail registries(2)
diagram [28] (n = 6)

Records aer duplicates

removed

Screening
Records screened
(n =136)
Arcies excluded because they did
not meet the eligibility criteria
(n =99)

Full-text arcles assessed

for eligibility
Eligibility

(n =37) Full-text arcles excluded,

with reasons (n =31)
Reference list of studies
*The parcipants were not
(n = 2)
chemotherapy or radiotherapy
Studies included in paents (n=3)
qualitave synthesis *Clinical examinaon protocol (n=1)
(n =8) *Abstract only, no data (n=1)
*No severe mucosis grading (n=6)
Records aer Jadad score *The same research group (n=5)
<3 removed (n = 3) *The study is not a pure Propolis
Included

Studies included in product (n=4)

quantave synthesis * The study is not an RCT (n=2)
(meta-analysis) *Case report (n=3)
(n = 5) *The study is an animal study (n=6)

instruments, according to their sensitivity, specificity, and
workload [35]. Studies selected by both reviewers (CCK and
CHL) were included in the review. Uncertainty or disagree-
ment between the two review authors was resolved by the
achievement of consensus or through discussions with a third
reviewer (one nursing expert). The Jadad score must have
been higher than 3 [35]. The reviewers’ judgments were
assessed by the kappa statistic. Strength of agreement was
defined as poor (0. 00 to 0.20), fair (0. 21 to 0.40), moderate
(0. 41 to 0.60), material (0. 61 to 0.80), or almost perfect (0. 81
to 1.00) [36]. When we identified studies containing insuffi-
cient information, we contacted the corresponding authors to
request additional data.
Outcome measures
The primary outcome was the overall incidence of severe oral
mucositis in the study period. Severe oral mucositis is defined
as grade 3 or 4 oral mucositis. Four instruments, namely the
National Cancer Institute Common Terminology Criteria
(NCI-CTC, version 4), the Radiation Therapy Oncology
Group (RTOG) scale, the World Health Organization
(WHO) scale, and NCI CTCAE (versions 3 and 4), were ap-
plied for grading in the study. The grading scale ranged from 1
to 5. According to the Oral Mucositis Assessment Symptom
(OMAS) scale, oral mucositis scores ≥ 3 are indicative of the
presence of clinically symptomatic mucositis. The secondary
outcome was the total incidence of propolis mouthwash-
related adverse events (AEs) in patients with cancer.
Data synthesis
The data were entered into Review Manager (RevMan) 5.3
software and checked for accuracy [37]. Outcome incidence
analysis was performed using odds ratios (ORs) with 95%
confidence intervals (CIs). The review estimated heterogene-
ity across the studies (Fig. 2). The Q test and I2 were used to
show whether significant heterogeneity was present. I2 values
of ≤ 25, 50, and ≥ 75% represented low, moderate, and high
heterogeneity, respectively. If p > 0.1, and I2 < 50%, a fixed-
Support Care Cancer
Fig. 2 Forest plot of the overall incidence of severe (grade 3 or 4) oral mucositis
effects model was applied for the analysis; however, if p ≤ 0.1,
and I2 ≥ 50%, a random-effects model was applied [36].
Results
Literature search
A total of 352 potentially relevant studies were identified via
searches of the ten databases mentioned above, and an addi-
tional six studies were identified through other sources iden-
tified through the literature searches. Using the professional
document management software EndNote, X7, we were able
to eliminate 136 duplicate studies. We excluded 99 studies
after reviewing their titles and abstracts, as we determined that
they clearly did not conform to the inclusion criteria. Thirty-
one studies were excluded after reviews of their full texts and
critical appraisals. Two additional articles were retrieved via
manual searches of article reference lists. Three studies whose
Jadad scores were less than 3 were removed. Thus, five stud-
ies were ultimately included in the present systematic review
(Fig. 1).
Characteristics of the included studies
Participant characteristics
The five RCTs were published from 2013 to 2016. The earliest
RCT was published in 2013 (20%), and the other studies were
published in 2015 and 2016. Four of the studies were pub-
lished in English, and one of the studies was published in
Chinese. The studies included a total of 209 participants. A
total of 103 participants used propolis in the intervention
group, and 106 participants used propolis in the control group.
Sixteen (15.5%) participants in the propolis group and 36
(34.0%) participants in the control group suffered from severe
oral mucositis. The participants ranged from 1 to 87 years.
The studies were performed in the following geographic re-
gions: the Middle East (Iran, n = 3), Europe (Slovenia, n = 1),
and Asia (Taiwan, n = 1). Four of the five studies involved
patients treated with chemotherapy, and the remaining study
involved patients treated with RT. Two studies involved
patients with head and neck cancer, two studies involved pa-
tients with leukemia (one included patients with lymphoma,
soft tissue tumors, and brain tumors), and one study involved
patients with lung cancer. The other potential confounding
factors were considered consistent across the studies.
Detailed information pertaining to the study designs, popula-
tions, interventions, outcome assessments, results, and quality
scores is shown in Table 1.
Intervention characteristics
Propolis mouthwash was administered to hospitalized patients
at 5–15 ml/dose two or three times daily for 7–180 days.
Quality assessment
All of the included studies were included in the Jadad scale
assessment. Methodological quality was high, as the mean
score was 3.60 (SD ± 0.55). Among the five studies, three
had a score of 4, and two had a score of 3. The results are
summarized in Table 1. Kappa (inter-rater agreement) was
used to evaluate the agreement between raters or judges. The
overall kappa was 0.61, which was in the Bmaterial^ agree-
ment range. Heterogeneity disappeared in the meta-analysis of
five studies (I2 = 0%, p = 0.45), and the results are summarized
in Fig. 1; the results of Egger’s test were not statistically sig-
nificant (p = 0.289). No obvious publication bias was noted in
this meta-analysis [32].
Analysis of overall effects
Primary outcome
Five studies including 209 participants provided data on the
overall incidence of severe oral mucositis. The OAG, NCI-
CTC, and WHO scales were used in two studies, and the
OMAS scale was used in one study. A fixed-effects model
was used to determine the incidence of mucositis. Propolis
mouthwash decreased the risk of severe oral mucositis com-
pared with the control treatment (OR = 0.35, p = 0. 003, 95%
CI 0.18 to 0.70) (Fig. 1). The overall dropout rate ranged from
Table 1 Basic characteristics of the study included

Original study; Design; levels of Participants (no. randomized Age; population; Intervention, frequency, duration, Result Quality
country evidencea and controlled), setting gender and OM assessment scale score

Tomazevic T and Jazbec Double blind RCT; E = 19, C = 21; chemotherapy 1–19 years; children; 1. 15 ml propolis and placebo1. Dropout rate 20% 4
J (2013); Slovenia [7] Level 1b male = 20, female = 20 2. Two times daily 2. There was no significant difference
3. For 180 days between the study groups (p = 0.59)
4. OAG 3. No reports of side effects were noted.
Bolouri AJ, et al. (2015); Triple blind RCT; E = 10, C = 10; radiotherapy 15–87 years; children 1. Dropout rate 0%
1. 15 ml 3% propolis and placebo 4
Iran [14] Level 1b + adults; male = 14, 2. Three times daily 2. The case group had a significantly
female = 6 3. For 35 days (p < 0.05) lower grade of oral mucositis
4. NCI-CTC in all of the follow-ups
3. Propolis water-based mouthwash is
safe and effective in OM
Eslami H, et al. (2016); Double blind RCT; E = 24, C = 24; chemotherapy 1–81 years; children 1. E = 10 ml CHX + fluconazole 1. Dropout rate 0% 3
Iran [6] Level 1b + adults; male = 24, + propolis mouthwash, C = 10 ml 2. The difference was significant
female = 24 CHX + fluconazole mouthwash (p = 0.0007)
2. Three times daily 3. No side effects were reported
3. For 14 days
4. NCI-CTC
Akhavan-Karbassi MH, Double blind RCT; E = 20, C = 20; chemotherapy > 18 years; adults; male =?, 1. 5 ml propolis and placebo 1. Dropout rate 0% 4
et al. (2016); Iran [38] Level 1b female =? (diluted water) 2. There was a significant difference
2. Three times daily in OM (p = 0.0008)
3. For 7 days 3. No significant adverse events were
4. WHO and OMAS scale reported.
Tang KL & Lin CC A single blind RCT; E = 30, C = 31; chemotherapy 41–80 years; adults; 1. 0.8% propolis and placebo 1. Dropout rate 13% 3
(2016); Taiwan [39] Level 1b male = 40, female = 21 (Diswater) 2. The OAG score was significantly lower
2. Two times daily in the propolis group (p < 0.001)
3. For 14 days 3. Adverse events?
4. WHO and OAG

a
Oxford Centre for Evidence-based Medicine—Levels of Evidence (March 2009)
Support Care Cancer
Support Care Cancer
0 to 20%. The dropout rate was 0% in three studies, 13% in
one study, and 20% in another study, as shown in Table 1.
Secondary outcomes
Five studies investigated the incidence of AEs during the
study; however, no serious side effects were directly associat-
ed with the treatment of cancer therapy-induced oral mucosi-
tis. One study showed that propolis mouthwash was safe and
effective, and another study showed that propolis was well
tolerated among patients (Table 1).
Discussion
This review investigated studies exploring whether propolis
reduces the incidence of severe oral mucositis in patients with
cancer. The five studies included in the review were RCTs. No
meta-analyses were included. The five RCTs were pooled
using meta-analysis. The systematic review showed that the
incidence of the severe oral mucositis in the control group was
34%, a result consistent with those of Trotti et al. [4]. The
incidence of severe oral mucositis in the control group was
twice as high as that in the propolis group. In addition, prop-
olis mouthwash attenuated oral mucositis. The OR was 0.35,
and the RR was 0.47. These results were also consistent with
those of Stokman et al. [3], who reported that the OR for the
effects of amifostine was 0.37, and Trotti et al. [4], who re-
ported that the RR for low-level laser therapy (LLL therapy),
was 0.46. Thus, propolis mouthwash, amifostine, and LLL
therapy displayed similar efficacies with respect to attenuating
severe oral mucositis in patients with cancer who were receiv-
ing chemotherapy or RT. Therefore, propolis mouthwash is an
effective, acceptable, and available self-administered treat-
ment for oral mucositis.
The results showed that adults and children experienced
superior reductions in severe oral mucositis compared with
other groups of individuals. The five studies were published
from 2013 to 2016. This review found that research studies
performed before 2015 noted that propolis mouthwash had no
significant effect on oral mucositis. The result was consistent
with MASCC/ISOO, which showed inadequate or conflicting
evidence for natural and miscellaneous agents (propolis) [25].
In contrast, more recent studies noted that propolis mouth-
wash had a significant effect on severe oral mucositis. We
found that the design of the early RCTs may not be sufficient
for demonstrating the effects of propolis on oral mucositis. We
compared the efficacy of treatment for more than 14 days with
that of treatment for less than 14 days. The results showed that
there was no significant difference in treatment efficacy be-
tween the two groups. That is, the short-term effects of prop-
olis are not better than its long-term effects. Therefore, we
recommend that future studies include adults and administer
propolis at 10–15 ml/dose three times daily for at least 14 days.
The results serve as strong evidence indicating that propolis
mouthwash is beneficial for patients with cancer with oral
mucositis. Currently, there is no formulation of the U.S FDA
and Health Canada for a recommended dose for children
[20–23]. However, it is also not yet clear whether propolis
use truly benefits children. Thus, we strongly suggest that
future research should exclude children.
Sinha et al. [31] reported that a Jadad score of 3 or greater
was indicative of a high-quality RCT [35]. As the Jadad score
for this study was 3.60, this was a high-quality meta-analysis.
Recently published studies did not report on the side effects of
propolis in patients with cancer. Eslami et al. reported that
most patients (91.6%) were interested in continuing to use
propolis mouthwash [6]. Additionally, Eslami et al. showed
that propolis attenuated severe oral mucositis to a greater ex-
tent than hypozalix and the control treatment within 5 days
after treatment initiation [6]. An Iranian study showed that
propolis has an acceptable odor, is non-invasive and easy to
use, has a lower price, and is considered a natural agent with
no side effects. Propolis appears to be well tolerated and ap-
propriate for participants in most studies. Although the five
RCTs did not report any side effects, Miguel and Antunes
[40]showed that the chemical components of propolis, which
vary by country, may lead to AEs. Thus, studies regarding the
efficacy and safety of propolis should account for geographi-
cal location.
Based on the above results, we can conclude that the meta-
analysis had four limitations. First, the results were based on
data for a small sample (5 RCTs including 209 participants).
This fact weakens the evidence showing that propolis can be
used as a mouthwash in patients receiving chemotherapy or
RT. Second, only studies published in English or Chinese
were included in this systematic review and meta-analysis.
Studies on propolis that were published in other languages
were not considered. Korea has published numerous RCTs
of propolis in Complementary and Alternative Medicine
[11]. Thus, the exclusion of studies published in languages
other than Chinese or English may have been a limitation of
the study. Third, we did not assess patients with mild oral
mucositis (grade 1 or 2). The assessment scales used in each
study lacked consistency. Fourth, because the study included
only five RCTs, we could not perform subgroup analysis to
obtain more information.
In conclusion, propolis mouthwash is effective and safe in
the treatment of oral mucositis in patients with cancer who are
receiving chemotherapy or RT. Propolis as a dietary supple-
ment is regulated by the FDA and Health Canada as a food
and not as a drug [20–23]. Therefore, a propolis-related prod-
uct is not generally recognized as being safe and effective. To
maintain propolis safety, propolis usage should occur under
the supervision of medical staff and health professionals. The
meta-analysis results are favorable and indicate that propolis

can be used in clinical practice. Well-designed studies regard-
ing other interventions are needed to improve the amount and
quality of evidence guiding future clinical care. Future studies
involving multiple centers and clinical protocols are neces-
sary, as are studies in which propolis is administered to only
adults for at least 14 days to strengthen the current evidence
and to confirm the efficacy of propolis mouthwash.
Acknowledgments We would like to thank Professor Huey-Shys Chen
for providing guidance with the meta-analysis conducted in this study. We
are also grateful to Assistant Professor Pei-Chao Lin for providing assis-
tance with the meta-analysis software and instructions. Additionally, we
thank Ya-Ping Gung, who assisted with article searches in library
databases.
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