Supportive Care in Cancer (2022) 30:8689–8703

https://doi.org/10.1007/s00520-022-07190-4

REVIEW ARTICLE

Efficacy of oral and topical antioxidants in the prevention

and management of oral mucositis in head and neck cancer patients:
a systematic review and meta‑analyses
Afsheen Raza1 · Nelli Karimyan1 · Amber Watters2 · Chitra P. Emperumal1 · Kamal Al‑Eryani3 ·
Reyes Enciso4

Received: 29 December 2021 / Accepted: 30 May 2022 / Published online: 10 June 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022

Abstract
Purpose To evaluate the effectiveness of antioxidants in the prevention and management of oral mucositis in adults under-
going radiotherapy and/or chemotherapy with diagnosed head and neck cancer (HNC) compared to placebo intervention.
Methods Cochrane, EMBASE, PubMed, and Web of Science databases were used to search for randomized controlled
trials (RCTs) comparing oral or topical antioxidants with placebo in clinically diagnosed HNC adult patients receiving
radiotherapy with/without chemotherapy. The primary outcome was to assess the efficacy of the antioxidant to prevent and
decrease the incidence/prevalence and severity of oral/oropharyngeal mucositis. The risk of bias was assessed following
Cochrane’s guidelines.
Results The database search resulted in 203 records up to February 19, 2021. Thirteen RCTs were included with 650
HNC-diagnosed patients. Included studies showed a statistically significant improvement in mucositis severity score for all
antioxidants except melatonin. However, further studies are needed as only one study reported outcomes for zinc, propolis,
curcumin, and silymarin. Patients receiving vitamin E were 60% less likely to develop severe mucositis grade 2 or higher than
those receiving placebo in one study (P = 0.040). Patients receiving zinc were 95% less likely to develop severe mucositis
(grades 3–4) in one study compared to placebo (P = 0.031). One meta-analysis showed no statistical difference in the risk
of having severe mucositis (grades 3–4) with 199 patients compared to placebo for honey (n = 2 studies, P = 0.403). Meta-
analyses could not be conducted for zinc, propolis, curcumin, melatonin, silymarin, and selenium due to the lack of studies
reporting similar outcomes for the same intervention.
Conclusion Though oral and topical antioxidants significantly improved mucositis severity scores in HNC patients receiving
radiotherapy with/without chemotherapy in individual studies, the quality of the evidence was low due to the small number
of studies and unclear/high-risk bias. Additionally, large RCTs are needed to confirm these results.

Keywords Antioxidants · Head and neck cancer · Oral mucositis · Meta-analyses · Systematic review

1
* Reyes Enciso Orofacial Pain and Oral Medicine, Herman Ostrow School
renciso@usc.edu of Dentistry of USC, Los Angeles, CA, USA
2
Afsheen Raza Providence Cancer Institute, Portland, ORE, USA
afsheenraza114@gmail.com 3
Department of Diagnostic Sciences, Herman Ostrow School
Nelli Karimyan of Dentistry of USC, CA, Los Angeles, USA
nekosh@gmail.com 4
Department of Geriatrics, Special Patients and Behavioral
Amber Watters Science, Herman Ostrow School of Dentistry of University
awattersdds@gmail.com of Southern California, 925 West 34th Street, room #4268,
Los Angeles, CA, USA
Chitra P. Emperumal
cpemperumal@gmail.com
Kamal Al‑Eryani
aleryani@usc.edu

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8690
Introduction
Oral mucositis (OM) is defined as inflammation of the
oral mucosa, which can range from erythema to ulcera-
tion [1]. Head and neck cancer (HNC) patients undergo-
ing radiotherapy (RT) or chemoradiotherapy (CRT) can
experience symptoms of OM [2]. For patients receiving
a high dose of RT or CRT for HNC, OM can be a dose-
limiting complication, resulting in severe pain, difficulty
in eating, poor quality of life, and weight loss. Bactere-
mia and sepsis in immunocompromised states may result
in longer hospital admissions, increased number of inpa-
tient visits, and greater economic burden for patients and
health systems [3]. Underreporting of oral sequelae and
the use of multiple grading systems make the prevalence
of OM during HNC treatment difficult to generalize [4].
The severity and incidence of OM are dependent on the
type, dose, and duration of therapy, as well as complex
biological and genetic level factors. Higher incidence is
reported in patients receiving RT and CRT versus chemo-
therapy (CT) alone [5].
The development of OM in patients undergoing RT
starts at the epithelial surface due to the generation of
reactive oxygen species (ROS) which results in DNA dam-
age [6]. OM resulting from CT begins in the basal layer
of the epithelium, when the anti-cancer agent penetrates
from submucosal vasculature. Chemotherapy-induced OM
can be aggravated due to immunosuppression [6]. Many
theories include microbial flora in the etiology and propa-
gation of OM; however, conclusive evidence is lacking [7].
The World Health Organization (WHO), the Radiation
Therapy Oncology Group (RTOG), the National Cancer
Institute (NCI), and the Mucositis Study Group (1999) [8]
have developed OM grading scales that are widely utilized
in clinical and research settings.
Antioxidants are substances that may prevent oxidative
damage to cells and act as a scavenging system against
free radicals [9]. Free radicals (or ROS) may be generated
through exposure to environmental factors such as foods,
chemicals, industrial byproducts, and trauma and may play
an important part in the pathogenesis of cancer [1, 10].
ROS are mediators of cell death, yet most cancer therapies
depend on ROS production for efficient tumor eradication
[11]. Antioxidants could be endogenous or exogenous,
enzymatic or non-enzymatic, and belong to various cat-
egories (Online Resource Table 1). Antioxidants can act on
cell membranes, mitochondria, and cytosol to exert anti-
inflammatory and anti-apoptotic effects. Examples of anti-
oxidants include vitamins, flavonoids, and minerals [12].
Systematic reviews focusing on randomized controlled
trials (RCTs) have reported the efficacy of antioxidants on
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Supportive Care in Cancer (2022) 30:8689–8703
the management of OM [13, 14]. In the 2020 edition of
MASCC/ISOO Clinical Practice Recommendations [15],
previous recommendations supporting zinc as a preven-
tive measure in the 2014 edition [3] were reversed to no
guidelines possible due to lack of level I and II evidence.
Glutamine oral tablets in 30–60-mg doses were added as
a suggestion but are not recommended in par-enteral form
due to severe adverse effects. Honey was added as a sug-
gestion in 2020, in both topical and oral forms, for the
prevention of OM. Additionally, concentrated calcium
phosphate mouthwash was added, but no guidelines could
be recommended due to conflicting results among popula-
tions [15].
Objectives
The goal of this systematic review with meta-analyses was
to assess the effects of oral and topical antioxidants in the
prevention and/or management of oral and oropharyngeal
mucositis in HNC-diagnosed patients treated with RT or
CRT.
Methods
Research question
RCTs included studies investigating the efficacy of oral and
topical antioxidants for the management or prevention of
oral and oropharyngeal mucositis in HNC patients undergo-
ing RT or CRT. This systematic review with meta-analyses
used PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) statement as a guideline and
was registered with PROSPERO #CRD42021231153. The
PICOS question under study was:
• Population: HNC patients undergoing radiotherapy with
or without chemotherapy.
• Intervention: Oral or topical antioxidants.
• Comparison: Placebo (color and taste matched tablets).
• Outcomes: The primary outcomes were the incidence/
prevalence of oral/oropharyngeal mucositis and the
severity of mucositis. The secondary outcomes included
prevalence and severity of xerostomia and erythema;
wound formation; normalcy of eating and drinking; qual-
ity of life; pain intensity; the need for other medication;
duration of mucositis (time); adverse events.
• Settings: oncology departments of universities and hos-
pitals.
Supportive Care in Cancer (2022) 30:8689–8703
Inclusion/exclusion criteria
Studies included were English language publications of
RCTs on the efficacy of antioxidants to treat and prevent OM
in HNC patients receiving RT with/without CT. Reviews,
systematic reviews, animal studies, pilot studies, editori-
als, abstracts, meta-analyses, and clinical guidelines were
excluded, as well as studies comparing to interventions dif-
ferent than a placebo.
Database search, collection, extraction,
and management
Four databases were searched (EMBASE, Cochrane,
Medline, and Web of Science), and the search strategy is
described in Online Resource Table 2.
Two authors (N.K. and A.R.) assessed half of the refer-
ences each after the removal of duplicates, and their inclu-
sion/exclusion results were reviewed by a third author (C.E.).
If a disagreement among the reviewers existed, a fourth
author (R.E.) helped make the final decision. The reference
sections of all included studies, systematic reviews, and clini-
cal guidelines were reviewed by three authors (N.K., A.R.,
and C.E.). New studies were submitted to inclusion/exclusion
criteria again by the same three authors (N.K., A.R., and
C.E.). The full article was reviewed, with a fourth author
(R.E.) making the final inclusion/exclusion decision in agree-
ment with the three authors. Three reviewers obtained data
regarding the studies independently (AR, NK, CE), including
study design, funding, number of centers, recruitment period,
inclusions/exclusions criteria, and control and intervention
groups' demographics, along with intervention methods and
sample size and the outcomes of the results. After discussion,
the authors agreed on the final tables.
Risk of bias assessment
The risk of bias was evaluated by three reviewers separately
(A.R., N.K., C.E.) and the corresponding author (R.E), fol-
lowing the protocol in the Cochrane handbook [16].
Statistical analysis and evidence quality
Trials reporting OM in patients with HNC undergoing RT,
with/without CT, receiving oral or topical antioxidants com-
pared to placebo were included in the meta-analyses. Review
authors calculated weighted means and standard deviations
based on tabular frequency data reported in two studies [17,
18] using standard formulas. When original studies reported
means and 95% confidence intervals (CIs), we calculated the
standard error of the mean (SEM) as (95%_UPPER – 95%_
LOWER)/3.92 based on Cochrane’s manual. When authors
8691
reported interquartile range (IQR) = (Q25, Q75) and medians
(m), we calculated mean = (Q25 + m + Q75)/3 and the standard
deviation (SD) as (Q75 – Q25)/1.35. When SEM was reported,
we calculated SD as SEM × sqrt(N), with N = sample size.
For mucositis scores (0–4 WHO OMAS or 0–4 NCI-CTC
v2 or 0–4 RTOG OM), treatment effects were analyzed as
the difference in means (DM) of post-treatment mucositis
scores with 95% CI. For the incidence of severe mucositis
(subjects with severe mucositis grades 2–3 in OMAS scale
or mucositis grade 2 or higher in RTOG scale) and the num-
ber of people requiring analgesics, treatment effects were
analyzed as risk ratios (RRs) with 95% CI.
We calculated Cochran’s Q test [19] and I2 statistic [20]
to assess heterogeneity and used random-effects model if
Q-test P < 0.10 and fixed-effect model if P ≥ 0.10. Compre-
hensive Meta-Analysis software (version 3) was used (Bio-
stat, Englewood, NJ, USA).
Subgroup analyses were conducted for each oral/topical
antioxidant. Unfortunately, sensitivity analyses for low ver-
sus unclear/high risk though planned could not be conducted
due to the small number of studies per intervention.
The quality of evidence was reviewed, and the results
were summarized with the help of GRADE profiler (GRA-
DEpro) software [21].
Results
Summary of search results
The primary database searching provided 353 references
plus 18 additional records from other sources. The duplicates
were removed; after that, 202 references were scanned by
three review authors (N.K., A.R., C.E.), which were reduced
to 39 records based on the titles and abstracts. The 39 manu-
scripts were fully analyzed for inclusion based on the full
text. Thirteen manuscripts were included. The reasons for
exclusion were no HNC patients (n = 2), no placebo group
(n = 6), proceedings abstract (n = 3), no antioxidant (n = 9),
more than one antioxidant (n = 1), not an RCT (n = 1), pro-
tocol (n = 1), different outcomes (n = 1), and different con-
dition (n = 3). The same search (Online Resource Table 2)
was conducted again on February 12, 2021, to include any
new records, and one relevant study was found [22]. The
PRISMA diagram in Fig. 1 presents the search results.
Included studies
A total of thirteen double-blinded RCTs were included in the
qualitative analysis [17, 18, 22–32] with details presented
in Tables 1 and 2.
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8692 Supportive Care in Cancer (2022) 30:8689–8703

Fig. 1  PRISMA flow diagram

Records idenfied through Addional records idenfied

Identification
database searching through other sources
(n = 353) (n = 19)

Records aer duplicates removed

(n = 203)

Screening Records screened Records excluded

(n = 203) (n =211)

Full-text arcles excluded,

Full-text arcles assessed
with reasons
for eligibility
(n =27)
(n = 40)
Eligibility

n = 6 no placebo

n = 3 poster/abstract
Studies included in n = 9 no anoxidant
qualitave synthesis
(n = 13) n=1 mix of anoxidants

n = 1 Not an RCT

n= 1 protocol

Studies included in n =1 different outcome

quantave synthesis
Included

n=3 different condion

(meta-analysis)
n = 3 not HNC
(n = 2)

Population Interventions

The age of the research subjects included in the systematic
review ranged from 15 to 87 years old [22, 32] (Table 1).
The RCTs were conducted in Iran [17, 22, 23, 26, 29, 30,
32], the USA [25], England [27], Cyprus [28], Turkey [18],
Brazil [31], and Thailand [24] (Table 1). Centers providing
the intervention varied from radiotherapy/oncology
departments [18, 25, 28–30], RT centers [23, 26], and
oncology centers [22, 24, 31]. Additionally, not all patients
received the same treatment: some patients received only
RT [26, 28, 31, 32], some received CRT [17, 18, 22–25,
27, 29, 30]. Patients had a diagnosis of squamous cell
carcinoma (SCC) of the head and neck [23, 26, 28], oral
cancer [18, 22, 24, 29, 30], or pharyngeal cancer [25, 27,
31] (Table 2).
Interventions included oral/topical antioxidants (Table 1),
such as:
TOPICAL AND SYSTEMIC
• Manuka honey: Patients were advised to rinse with
manuka honey (20 mL), and to swallow it slowly, 4 times
per day for 4 weeks during RT, and for 2 weeks after
treatment [27].
• Melatonin: In one study [24], both topical 10-mL mela-
tonin oral gargle (local) 15 min before CT and 20 mg oral
melatonin capsules once daily for 7 weeks (systemic).
• One 400 mg vitamin E oil capsule was dissolved in the
saliva, then patient will rinse the oral cavity for 5 min and
swallow it 5 min before RT and after 8–12 h at home [31].

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Supportive Care in Cancer (2022) 30:8689–8703 8693

Table 1  Summary of included studies

Reference Design, N Tx group N Placebo group N Gender (M/F) Tx group AGE Placebo AGE
year, Tx (P) P (range in y, (range in y,
country average ± SD) average ± SD)

Akhavan-Kar- DBRCT​ 40 3% propolis 20 Placebo 20 Not stated > 18 y > 18 y

bassi et al. [17] 2016 mouthwash 3 mouthrinse
Iran times per day
Babaee et al. [26] DBRCT​ 40 2% calendula 20 Placebo mouth- 20 20 M/20F 46–72 y 46–72 y
2013 mouthwash 2 wash 52.2 mean 52.8 mean
Iran times per day
Bardy et al. [27] DBRCT​ 127 20 mL manuka 64 Golden syrup 63 99 M/28F 39–85 y 38–83 y
2017 honey rinse 4 group 59.0 mean 58 mean
England times per day
Charalambous DBRCT​ 72 Thyme honey 36 Saline rinses 36 52 M/20F > 18 y > 18 y
et al. [28] 2018 rinses 20 mL in 61.5 mean 61.53 mean
Cyprus 100 mL water 3
times per day
Delavarian et al. DBRCT​ 32 80 mg curcumin 16 Placebo tablet 16 19 M/13F ≥ 18 y ≥ 18y
[29] 2019 nanomicelle with lactose 62.18 ± 15.07 55.87 ± 15.33
Iran oral capsules mean mean
once a day
Elyasi et al. [30] DBRCT​ 27 140 mg oral sily- 13 Placebo tablets 14 13 M/14F 18–65 y 18–65 y
2016 marin tablets 3 60.31 mean 57.85 mean
Iran times per day
Ertekin et al. [18] DBRCT​ 30 50 mg oral zinc 15 Placebo capsules 15 21 M/6F 36–69 y 18–71 y
2004 sulfate 3 times (3 were excluded) 53.0 mean 59 mean
Turkey per day
Ferreira et al. [31] DBRCT​ 54 400 mg of vita- 28 Placebo capsules 26 48 M/6F ≥ 21 y ≥ 21 y
2004 min E capsule 2 53.5 mean 57.3 mean
Brazil times per day
Javadzadeh Bol- DBRCT​ 20 Propolis mouth- 10 Placebo capsules 10 14 M/6F 15–87 y 15–87 y
ouri et al. [32] 2015 wash 15 mL 3 53.2 mean 53.2 mean
Iran times per day
Laali et al. [22] DBRCT​ 71 Selenium tablets 37 Placebo 34 50 M/21F 22–81 y 18–81 y
2020 200mcg 2 times capsules 52.1 mean 54.7 mean
Iran per day
Moslemi et al. DBRCT​ 40 30 mg oral zinc 20 Placebo capsules 20 21 M/16F 18–78 y 29–78 y
[23] 2014 sulfate capsule with starch (3 dropped out) 49 mean 52 mean
Iran 3 times per day
Onseng et al. [24] DBRCT​ 39 0.2% melatonin 19 Placebo mouth- 20 26 M/13F 18–60 y 18–60 y
2017 oral gargle & wash and 47.3 mean 49.6 mean
Thailand 20 mg capsules capsules
once a day
Su et al. [25] DBRCT​ 58 Aloe vera mouth- 28 Placebo mouth- 30 46 M/12F 57.0 mean 55.0 mean
2004 wash 20 mL 4 wash
USA times per day 20 mL

DBRCT​, double-blinded randomized clinical trial; F, female; M, male; N, sample size; P, placebo; Tx, treatment; y, years

• Aloe vera: 20 mL swish and swallow 4 times per day, TOPICAL

beginning on the first day of RT until the completion of
the RT course [25].
• Propolis 3% 15 mL solution, instructed to rinse and
swallow, 3 times per day for 5 weeks [32].
• Thyme honey mouthrinse: Subjects were instructed to
dilute 20 mL of thyme honey in purified water and gargle
3 times per day for 7 weeks [28].
• Calendula: Patients undergoing RT or CRT were advised
to use oral mouthwash calendula 5 mL 2 times a day [26].

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 Table 2  Summary of inclusion criteria, diagnosis, RT dosage, and other criteria
Reference
13
Akhavan-Karbassi et al. [17]
Babaee et al. [26]
Bardy et al. [27]
Charalambous et al. [28]
Delavarian et al. [29]
Elyasi et al. [30]
Ertekin et al. [18]
Ferreira et al. [31]
Javadzadeh Bolouri et al. [32] • HNC
Laali et al. [22]
8694
Inclusion criteria Dx of HNC Inclusion criteria— RT and/or chemo- RT dosage Other criteria
therapy
• Histopathologically confirmed cases • HNC undergoing CT of different N/A • Patients 18 years or older
of HNC cytotoxic agents including metho-
trexate, selected for RT
• Patients with proven squamous cell • Patients receiving curative RT or 6000- 7000 cGy • Minimum age of 18 years
cancers of head and neck chemoradiotherapy • Mean age 52 years
• Radiotherapy was implemented
during 30 to 35 sessions in 7 weeks
period
• Patients with squamous cell car- • Patients who have been listed to 50-55GY • 18 years and older
cinoma of the oropharynx or oral have 4 weeks of acceleration RT
cavity • Stage of the tumor (new primary
• Presence of HNC intact or post-operative)
• Dose of radiation (50–52.5 Gy
alone, 50–52.5 Gy plus synchronous
CT, 55 Gy alone, or 55 Gy plus
synchronous chemotherapy)
• Patients with HNC diagnosis (squa- • Patients referred for Intensity Modu- 50 and 60 Gy in the oral cavity • Patients with OM degree 1 or above
mous cell carcinoma) with primary lated Radiation Therapy (IMRT) based on the RTOG criteria;
and non-metastatic cancer • Three weeks preceded RT • Age > 18 years old
• Presence of HNC • At least 50% of patient’s oral cavity 50 Gy or greater • Minimum age of 18 years
was included in the field of radiation
• Dx of HNC • Patients who intended to be treated 60 Gy/6 weeks to at least 50% oral • Age 18–65 years
with RT for the first time cavity
• Exposure of at least half of oral cav-
ity to radiation
• Histologically proven HNC • Patients who received curative RT 4000–7000 cGy • More than 18 years of age
or CRT​ • Karnofsky’s
performance status < 70 [52]
• Patients with a confirmed histologic • A minimal irradiated buccal 50–60 Gy in 5–6 weeks • Age at least 21 years
diagnosis of cancer of the oral cavity mucosal area 12.2 ­cm2 or greater; 70 Gy/7 weeks • ECOG Score grade 2 or lower [52]
and oropharynx the limits of this area, measured on • Tolerance of solid food at study entry
verification films, were the hard pal-
ate (superior), the floor of the mouth
(inferior), the anterior border of
the vertical portion of the mandible
(posterior), and the distal border of
the irradiation field (anterior)
• Undergoing RT 50–70 Gy • Age over 15 years old
• At least half of the mouth to be
under radiation
• HNC • Undergoing RT in at least 2/3 of oral 60–70 Gy • Age 18–81 years
cavity with or without CT • Karnofsky performance scale < 70%
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 Supportive Care in Cancer (2022) 30:8689–8703 8695

• Propolis 3% mouthrinse (30% extract), 5 mL of solution

• Karnofsky performance status greater

• Karnofsky performance status greater

• Could eat and swallow and agreed to

swish and rinse, 3 times per day for 7 days [17].

• Karnofsky performance status > 60

SYSTEMIC

• Patients aged 18–60 years

• Patient aged 18–78 years

• Silymarin: Treatment group received 140 mg silymarin

tablets 3 times per day for 6 weeks [30].
• Curcumin: 80 mg (1 capsule) once daily throughout the
than 70 [52]

than 70 [52]
Other criteria

not smoke
RT period [29].
• Zinc sulfate capsules: 50 mg thrice daily, starting day 1

[52]
of RT until 6 weeks after treatment [18] or 30 mg capsule
3 times per day, starting 10 days before RT until 8 weeks
after end of RT [23].
• Selenium 200 mcg 2 times a day throughout the RT
period [22].

Co‑interventions
4000–7000 cGy

Seven studies had co-interventions, such as local anesthetic

Inclusion criteria— RT and/or chemo- RT dosage

• Histologically confirmed stage II–IV • Scheduled to receive radiation doses 50–70 Gy

solutions and analgesic agents [18]; mouthrinses in any com-

50 Gy

bination of baking soda, Benadryl, nystatin, viscous lidocaine,

and antibiotics as well as systemic antifungal agents for active
• Patients who were to start treatment
• Patients with proven squamous HNC • Patients received curative RT or CT

infection and dietary supplements as needed [25], topical nio-

operative RT patients were eligible
diation therapy and had never been

• Both primary radical RT and post-

anatomic site of the pharyngeal or
with concurrent RT and chemora-
6000 cGy total radiation dose of
external beam RT to at least one

some suspension [24], saline rinses [22, 27, 32], paracetamol/

of at least 50 Gy to at least one
• Planned treatment was at least

codeine, or dipyrone analgesics as needed were used [31].

treated with CT before
third of the oral cavity

Outcomes
for enrollment

Primary outcomes included OM severity and incidence

oral mucosa

reported using WHO mucositis score (0–4 scale) [33]; the

National Cancer Institute Common Terminology Criteria
therapy

(NCI-CTC v2 and v3) grading system (0–4 scale); Radia-

tion Therapy Oncology Group grading system (RTOG) on
a 0–4 scale [34, 35]; and Oral Mucositis Assessment Score
M0 carcinoma of the head and neck
• Patients were eligible for the study
if they were newly diagnosed with

(OMAS) on a 0–3 scale [36].

HNC head and neck cancer, RT radiotherapy, CT chemotherapy
Inclusion criteria Dx of HNC

Risk of bias

RCTs were assessed for risk of bias (Online Resource

Tables 3 and 4; Fig. 2). In summary, nine studies were
unclear [17, 22–24, 27, 29–32], and four were at high risk
of bias [18, 25, 26, 28].
HNC

Adverse events

Online Resource Table 5 presents the adverse events. Eight

of the studies did not report any side effects/adverse events
Table 2  (continued)

Moslemi et al. [23]

in the intervention group as well as in the placebo group [17,

Onseng et al. [24]

23, 24, 26, 28–30, 32]. Two studies [27, 31] presented mild
Su et al. [25]

adverse events, such as taste and consistency intolerability

Reference

of placebo gel, mild nausea, vomiting, and fever. One study

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8696 Supportive Care in Cancer (2022) 30:8689–8703

Fig. 2  Summary of risk of bias

of eligible RCTs

[18] presented moderate grade 3 vomiting in the intervention
group, and another trial presented patients with renal failure
[22].
Results of meta‑analysis
Incidence of severe mucositis
One meta-analysis showed no statistical difference in the risk
of having severe mucositis (grades 3–4) with 199 patients
compared to placebo for honey (n = 2 studies, P = 0.403),
Fig. 3.
Results of included studies
Meta-analyses could not be conducted for most of the out-
comes as only one study was found for some of the interven-
tions; however, we present in this review the Forest plots for
visualization purposes (Fig. 4).
Post‑treatment severity of oral mucositis
Forest plots for curcumin, honey, melatonin, propolis, sily-
marin, and zinc compared to placebo are shown in Fig. 4a for
the differences in average post-treatment mucositis severity

Fig. 3  Results of meta-analysis comparing antioxidants to placebo intervention for H&N cancer. Incidence of severe mucositis (grade 3 or 4)

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Supportive Care in Cancer (2022) 30:8689–8703
Fig. 4  Results of Forest plots comparing antioxidants to placebo
intervention for H&N cancer patients in original studies: a difference
in post-treatment mucositis severity (scale 0–4); b incidence of severe
(0–4 scale). Studies reported OM severity using the WHO
mucositis score [33], RTOG grading system [34, 35], and
NCI-CTC v2-v3 criteria. All antioxidants except melatonin
showed a statistically significantly lower post-treatment
mucositis score than placebo interventions (P ≤ 0.001); how-
ever, more studies are needed as only one study reported
8697
mucositis (grade 3 or 4); c incidence of severe mucositis (RTOG
score 2 or higher); d patients who required analgesics
outcomes for zinc, curcumin, honey, melatonin, propolis,
and silymarin (Fig. 4a).
Incidence of severe mucositis
Forest plots for incidence of severe mucositis (grades 3 or
4 with WHO OM score or RTOG) for melatonin, propolis,
13
8698
Fig. 4  (continued)
selenium, vitamin E, and zinc compared to placebo are
shown in Fig. 4b. Patients receiving zinc were 95.2%
less likely to develop severe mucositis (RR = 0.048; 95%
CI = 0.003 to 0.753; P = 0.031; Fig. 4b) in one study [18].
Forest plots showed no statistical difference in the risk of
having severe mucositis (grades 3–4) compared to placebo
for selenium (n = 1 study, P = 0.449), melatonin (n = 1 study,
P = 0.427), and propolis (n = 1 study, P = 0.237), Fig. 4b.
Patients receiving vitamin E were 60% less likely to develop
severe mucositis RTOG grade 2 or higher in one study [25] than
those receiving placebo (RR = 0.400; 95% CI = 0.167 to 0.958;
P = 0.040; Fig. 4c). Forest plots showed no statistical difference in
the risk of having severe mucositis (RTOG grade 2 or higher) for
aloe vera compared to placebo (n = 1 study, P = 0.205; Fig. 4c).
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Supportive Care in Cancer (2022) 30:8689–8703
Number of patients requiring analgesics
Forest plots showed no statistically significant difference in
the risk of requiring analgesics for aloe vera (n = 1 study,
P = 0.573), honey (n = 1 study, P = 0.850), or melatonin
(n = 1, P = 0.276) compared to the placebo group, Fig. 4d.
Summary of evidence quality
The quality of the evidence was low for incidence of severe
mucositis with honey (Table 3) due to the small sample size, the
small number of studies, and the unclear/high risk of bias. The
quality of the evidence was very low for all other outcomes and
interventions as only one study was available for each intervention.
Supportive Care in Cancer (2022) 30:8689–8703
Table 3  GRADE assessment of quality of the evidence for honey compared to placebo
Honey compared to placebo for HNC patients to prevent or treat oral mucositis
Incidence of severe 199 ⊕  ⊕  ⊝  ⊝
mucositis (2 studies) LOW1,2
Grade 3 or 4 1–7 weeks due to risk of bias, impre-
cision
CI confidence interval, RR risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the
estimate
Very low quality: We are very uncertain about the estimate
1
All studies at unclear or high risk of bias
2
Small sample size (less than 400 total number of patients) and small number of studies
Discussion
Main findings
Patients with HNC are managed with one or more treatment
modalities, including surgical resection, radiotherapy, and
systemic therapy. The goal of therapy may be curative or
palliative, with the efficacy of the cancer outcome balanced
against morbidity and quality of life impacts of the disease
and its treatment. In severe cases, OM may lead to difficulty
eating, dysphagia, severe pain, and dryness of mouth, result-
ing in increased hospital visits, cessation of treatment, and
further worsening of quality of life [37]. In our systematic
review, we only included RCTs comparing oral/topical anti-
oxidants with placebo. The risk of bias for all studies was
unclear/high (Fig. 2).
All antioxidants except melatonin and selenium showed
statistically significantly lower mucositis severity scores than
placebo interventions in the original studies. Meta-analyses
could not be conducted for most of the outcomes as only
one study was found for zinc, curcumin, propolis, silymarin,
selenium, and vitamin E. However, we are showing the Forest
plots for visualization purposes. In summary, the quality of
the evidence was low for incidence of severe mucositis with
honey (Table 3) and very low for all other outcomes.
Agreements/disagreements with other studies
and reviews
Honey
Khanal et al. [38] compared topical honey with lidocaine in
patients undergoing RT and showed that honey could limit
8699
RR 0.308 636 per 1000 treated with 440 fewer patients
(0.019 to 4.868) placebo would have per 1000 treated
severe mucositis with honey will have
severe mucositis
(from 624 fewer to 1000
more)
the severity of mucositis. In another study, manuka honey
did not improve OM, but both manuka honey and syrup
were associated with a decrease in bacterial infection [27].
Pure natural honey (prophylactic) was effective in reducing
OM resulting from RT with/without CT in one study [39].
Despite its limitations, one study [28] showed thyme honey’s
favorable effects on the management of RT-induced OM. It
also showed that honey was effective in improving swallow-
ing, dysphagia, and oral and throat pain, and decreased HNC
patients’ weight loss[28]. Manuka and kanuka essential oils
(mouthwash) showed a delayed onset of RT-induced mucosi-
tis and reduced pain and oral symptoms [40]. Due to the
small sample size, additional investigations are warranted
[39]. In one trial [41], patients in Malaysia with HNC, who
were undergoing RT, swished and swallowed honey, both
prior to and after RT. Honey was effective in improving and
preventing OM compared to no intervention. According to
one review [42], manuka honey did not show positive results.
Propolis
One pilot study showed extract of propolis prevented and
healed RT-induced mucositis [32], while an additional
double-blinded RCT [17] concluded propolis mouthwash
used during CT decreased the severity of OM, wound and
erythema scores compared to placebo mouthrinse [17, 32].
Vitamin E
Ferreira et al. [31] concluded HNC patients undergoing RT
experienced reduced symptoms and incidence of OM while
undergoing RT, when receiving a vitamin E–containing
13
8700
mouthrinse. One trial [43] reported a favorable effect of
vitamin E in CT-induced mucositis, while another investi-
gation [44] concluded that vitamin E did not improve OM.
Confirmatory studies with a larger number of patients need
to be undertaken to verify these results [45].
Calendula
Two studies included in our systematic review showed that
calendula officinal is an effective treatment for decreasing
OM severity in patients treated with CT [26] and RT [23].
Aloe vera
Severe mucositis incidence was significantly lower in the
aloe vera group versus placebo in patients treated with RT
[46]. However, our subgroup analysis showed no difference
in the incidence of severe mucositis (RTOG 2 or higher) nor
a decreased need for analgesics [25].
Zinc
Forest plots showed that zinc significantly improved the severity
of OM and agree with the conclusions by De Freitas Cuba et al.
[47], that oral zinc can be considered beneficial in preventing
OM during RT ± CT. Two studies [18, 48] found no differences
between zinc supplementation versus placebo for the prevention
of any severity of mucositis in patients with HNC receiving RT.
Silymarin
According to one trial [30], oral formulation of 420 mg sily-
marin administered in 3 doses may reduce the severity and
delay the onset of RT-induced OM.
Curcumin
One RCT [29] demonstrated a favorable effect of nanomi-
celle curcumin in the prevention and reduction of the sever-
ity of RT-induced OM.
Selenium
One trial [49] failed to demonstrate selenium supplements
reduced side effects of CT and RT, or the effects of surgery.
Further investigation agreed that selenium supplementation dur-
ing radiation had no effect on the severity/incidence of OM [22].
Melatonin
According to one study [24], adjuvant melatonin delayed the
onset of OM and reduced the need for opioid pain manage-
ment in patients receiving CRT. However, melatonin did not
13
Supportive Care in Cancer (2022) 30:8689–8703
significantly improve post-treatment mucositis severity (0–4
grade; Fig. 4a), nor the incidence of severe mucositis (grade
3–4; Fig. 4b), nor the need for analgesics (Fig. 4c) in this
study [24] according to the included studies.
Applicability of evidence
Our search was conducted in four databases up to 02/19/2021
and limited to English published articles. The results of this
systematic review are applicable to 15–87-year-old patients
and a treatment duration of 1 to 8 weeks (short term). These
results are applicable to males and females and apply to
patients mostly from Iran, though there were also patients
included from USA, Europe, England, Brazil, and Thailand.
Heterogeneity of the review
Heterogeneity found in this systematic review was due to
the diversity of oral/topical interventions used with vary-
ing routes of administration (oral tablets, mouthrinses) as
described in Table 1. Duration of the intervention/control
measures in the included RCTs ranged widely from 1 to
8 weeks. Seven studies had differing co-interventions includ-
ing local anesthetic solutions and analgesic agents [18],
mouthrinses [25], topical niosome suspension [24], saline
rinses [22, 27, 32], and paracetamol/codeine [31].
Another factor that induced heterogeneity was the different
grading criteria used to assess OM. Due to the heterogeneity
in the outcome measures described above and the different
interventions, these resulted in a small number of studies
pooled for each subgroup analysis with a final small sample
size resulting in low quality of the evidence. Additionally, not
all patients had the same type of cancer or received the same
treatment, some patients received only RT [26, 28, 31, 32],
some received CRT [17, 18, 22–25, 27, 29, 30].
Implications for research
Our findings coincide with previous research results that
oral and topical antioxidants can have a beneficial effect on
reducing the severity of OM, but high-quality randomized
placebo-controlled trials are needed to make recommenda-
tions or guidelines for using natural products. Future RCTs
should minimize biases, have no co-interventions, be dou-
ble-blinded, not be funded by the manufacturer of the prod-
ucts under study, have long-term follow-up, and study dif-
ferent dosages and large sample size. This systematic review
can be used as a guideline for further studies. In particular,
larger high-quality studies are needed for zinc, propolis sily-
marin, and vitamin E topical oil as they show promising
results in reducing the severity of OM.
There is controversy about antioxidants interfering with
radiotherapy in cancer patients among oncologists. However,
Supportive Care in Cancer (2022) 30:8689–8703
Moss (2007) [50] concluded that “dietary antioxidants do
not conflict with the use of radiotherapy in the treatment of
a wide variety of cancers and may significantly mitigate the
adverse effects of that treatment.“ In a recent review, Salehi
et al. [51] concluded that antioxidants available as supple-
ments have “at best little value in preventing chronic disease
course,” or could even be harmful in cancer patients. An
understanding of “smart antioxidants” is needed that could
cause a redox imbalance in tumor cells but not in normal
tissues [51].
Implications for clinical practice
HNC patients are treated with a variety of regimens that may
include surgery, radiotherapy, and chemotherapy. OM can
cause severe pain with difficulties in chewing, speech, and
mastication. Pharmacological treatments such as anesthetic
gels or rinses have been used for mucositis, but they may
come with side effects and merely palliate discomfort. Oral
or topical antioxidants may act as supplements to combat
mucositis. Due to a small number of studies and sample size,
further research is needed to assess the efficacy of antioxi-
dants in clinical practice.
Conclusions
Though oral and topical antioxidants provided a significant
improvement in mucositis severity scores in individual stud-
ies, only one study was found for each intervention, and the
quality of the evidence was low due to the small number of
studies and unclear or high-risk bias. Additional studies are
needed to confirm these results.
Supplementary information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00520-0​ 22-0​ 7190-4.
Author contribution Drs. Raza, Karimyan, Emperumal, Al-Eryani, and
Enciso contributed to the study conception and design. Material prepa-
ration and data collection were performed by Drs. Raza, Karimyan,
and Emperumal under the supervision of Drs. Enciso and Al-Eryani.
Dr. Enciso performed all data analyses. Drs. Raza, Karimyan, Empe-
rumal, Al-Eryani, Waters, and Enciso contributed to the first draft of
the manuscript and multiple revisions of the manuscript. All authors
read and approved the final manuscript.
Availability of data and material Results of the search and the meta-
analyses are presented in tables and figures. Any intermediate data is
available by email to renciso@usc.edu.
Code availability Not applicable.
Declarations
Ethics approval This systematic review did not require any approval
as it did not include any human or animal subjects.
8701
Consent to participate Not applicable.
Consent for publication Not applicable.
Conflict of interests The authors declare no competing interests.
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