596570

research-article2015
ICTXXX10.1177/1534735415596570Integrative Cancer TherapiesAghamohammadi and Hosseinimehr

Article
Integrative Cancer Therapies

Natural Products for Management of Oral

2016, Vol. 15(1) 60­–68
© The Author(s) 2015
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DOI: 10.1177/1534735415596570

Chemotherapy ict.sagepub.com

Azar Aghamohammadi, MS1,2,3 and Seyed Jalal Hosseinimehr, PhD1,2

Abstract
Oral mucositis is a common side effect of systemic chemotherapy and radiotherapy of head and neck in patients with
cancer. Severe oral mucositis is painful and affects oral functions, including intake of food and medications and speech.
Prevention of oral mucositis affects the life quality of patients. Recent studies have been focused on natural products to
improve or reduce this complication. Many clinical trials have been performed to assess natural products for treatment of
mucositis and their results are promising. The authors reviewed the evidence for natural products in the prevention and
treatment of oral mucositis induced by radiation therapy and chemotherapy.

Keywords
mucositis, xerostomia, radiation therapy, chemotherapy, cancer, natural products

Introduction used as protective agents against oral mucositis caused by

radiation or chemotherapy.
Radiotherapy and chemotherapy are the main strategies for
treatment of head and neck cancers.1,2 Ionizing radiation
generates reactive oxygen species (ROS) when it is passing Radiotherapy- and/or Chemotherapy-
through biological systems. ROS are very reactive, attack Induced Mucositis
the critical macromolecules in the cells such as DNA, and
Mucosal tissue covers respiratory and gastrointestinal tracts.
lead to cell damage and death. In head and neck cancer ther-
The part of this tissue that covers the mouth is called the oral
apy, radiation and anticancer drugs are not only effective on
mucosa. The oral mucosa is one of the most sensitive tissues
tumor cells but are also absorbed by the buccal and peribuc-
to chemotherapy and radiation. Mucositis is a condition
cal tissues.3,4 Since the mucosal cells of the gastrointestinal
characterized by pain and inflammation of the surface of the
tract have high proliferation rates, tumor cells in this region
mucous membrane. Almost 80% of patients with head and
of body are sensitive to radiation and anticancer agents.
neck cancer treated by radiotherapy suffer from oral mucosi-
Although radiotherapy and chemotherapy are effective in
tis. About 15% of patients who receive high doses of radio-
treatment of cancers, they have several short- and long-term
therapy in the mouth region must be hospitalized because of
side effects on normal tissues.5,6
these side effects. Younger people, because of their high cell
Mucositis is an acute injury to the mucosal barrier fol-
proliferation rate, are at high risk of oral mucositis induced
lowing head and neck cancer treatment with radiotherapy
by chemotherapy and radiotherapy.3,9 Various factors that
and/or chemotherapy. Oral mucositis is painful and patients
have difficulty swallowing food, and may require feeding
tubes. Mouth ulcers can become infected by bacteria; this 1
Traditional and Complementary Medicine Research Center, Mazandaran
sepsis can be a life-threatening condition for patients. There University of Medical Sciences, Sari, Iran
2
Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran
is no current Food and Drug Administration–approved
University of Medical Sciences, Sari, Iran
medication for the prevention of radiation-induced oral 3
Department of Midwifery, Sari Branch, Islamic Azad University, Sari,
mucositis.7,8 The protective effect of natural products Iran
against toxicity caused by radiation or anticancer agents is
Corresponding Author:
probably one of the most promising preventive strategies in Seyed Jalal Hosseinimehr, Department of Radiopharmacy, Faculty of
patients during therapy. In this review, we have concen- Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
trated on the preventive agents in natural products that are Email: [email protected]
Aghamohammadi and Hosseinimehr 61

affect the incidence of oral mucositis include mouth hygiene Mucosal changes like redness, ulceration with functional
condition before treatment, radiotherapy dosage and plan, outcomes such as inability to eat and pain have been
the type of treatment used (radiotherapy alone or combina- assessed in these scales. Based on clinical examination, 4
tion with chemotherapy), and the type of chemotherapy distinct grades can be determined for mucositis from 0 to 4
drug administered.10 scores. Higher grades of mucositis (grade 3-4) are associ-
Oral mucositis is an acute mucosal inflammation that ated with loss of taste, hemorrhage, decreased intake of
starts as redness and progresses to an increased ulceration food and fluids, ulceration, pain, loss of voice, and low
and pseudomembrane formation, which provides a tempo- quality of life.19-21
rary barrier until cellular repair promotes healing.11,12 The Several studies performed on natural product for
impaired mucosal tissue often permits bacteria and fungi to preventing or reducing chemotherapy- and radiotherapy-
penetrate into damaged mucosa and cause infections.12 induced oral mucositis. Information on their ability to
Mucositis is divided into 4 phases: an initial inflammatory/ reduce the incidence, severity or the period of oral mucosi-
vascular phase, an epithelial phase, an ulcerative/bacterio- tis was studied in this article. Most points of clinical results
logical phase, and a wound healing phase.13 are summarized in Table 1.
In the initial stage, irradiation or chemotherapy, by pro-
ducing free radicals and ROS, harmfully influences cells
and strands of DNA in the basal epithelium and the submu- Natural Products for Prevention and
cosa and leads to lesions. ROS also activate transcription Treatment of Mucositis
factors and leads to cell destruction in later stages. In the
next stage, not only ROS but also damaged cells and DNA
Calendula officinalis
start a cascade of reactions. During these reactions, pro- Calendula officinalis is a medicinal plant belonging to the
inflammatory cytokines produce and lead to lesions and Asteraceae family. Extracts of the flower of C. officinalis
basal cell apoptosis. These products have a positive reaction have been used as topical and oral herbal remedies for its
as well, and strengthen the lesions. In this stage, the tissue bactericidal, antiseptic, anti-inflammatory, antioxidant,
appears to be normal, with only with slight erythema. In the hepatoprotective properties, and antimetastatic effects.42
third stage, painful lesions appear and are colonized by bac- Several studies reported that C officinalis flower extract can
teria. Bacterial colonization can lead to the release of new reduce the severity of radiation-induced wounds.43,44 Daily
pro-inflammatory cytokines. application of C officinalis extract in gel form considerably
After stopping cancer treatment, oral mucositis vanishes reduces the oral mucositis induced by 5-fluorouracil in
little by little. In the healing process, symptoms decrease mucosa cheek pouches of hamsters.42 In a clinical trial
and the mucosa become normal, but outstanding neovascu- study, Babaee et al35 reported that calendula extract was
larization remains. effectively used to decrease the intensity of radiotherapy-
This tissue is easily broken and it is susceptible to che- induced oral mucositis. Considering the fact that calendula
motherapy and/or radiotherapy in future periods of cancer has antioxidant properties, it may act against ROS and pre-
treatments.14 Oral complications remain a major problem vent or delay the initiation phase of mucositis.35
despite the use of protective or treatment agents for them.6 Biological effects of this medicinal plant are mostly
Apoptosis or programmed cell death is responsible for the related to its chemical compositions such as polyphenols,
extension of oral mucositis induced by radiotherapy and carotenoids, triterpenes and essential oils. Anti-inflammatory,
chemotherapy.15 The responsibility of oral fungal and bac- antitumorigenic, antioxidant, and antimicrobial activities are
terial colonization for the extension of chemotherapy- and proposed for calendula to prevent oral mucositis.45,46
radiotherapy-induced oral mucositis is not clear but it is Quercetin is the main flavonoid of this plant. Antioxidant
supported by researchers.16 There is a relationship between activities of quercetin were demonstrated in recent studies.35
neutropenia caused by cancer treatment and existence of When quercetin encounters a free radical, it becomes a radi-
oral mucositis, which aggravates the severity or prolongs cal by giving a proton, but the quercetin radical has very low
duration of it in these patients17. But other studies have not energy because the unpaired electron is delocalized by reso-
found the correlation between severity or recovery of neu- nance. The B ring o-dihydroxyl groups, the 4-oxo group in
tropenia and grade and recovery of mucositis.18 Assessments conjugation with the 2,3-alkene and the 3- and 5-hydroxyl
of mucositis are varied in different studies. This diversity in groups are in quercetin’s structure and can donate electrons
scoring systems may lead to controversies among studies. to the rings, leading to quercetin’s antioxidant activity.47
The most widely used measurements for oral mucositis are
the World Health Organization and Radiation Therapy Drug interaction: Synergism with sedatives and
Oncology Group (RTOG) scales. Also, the Oral Mucositis antihypertensives.48
Assessment Scale, and a Visual Analog Pain Scale (patient Clinical outcome: Herbs that can be safely consumed
reporting scale of 0-10) are used for grading of mucositis. when used appropriately.48
62 Integrative Cancer Therapies 15(1)

Table 1.  Summary of Treatments With Natural Products for Mucositis in Cancer Patients.

Product No. Patients Type of use Treatment Results Reference

Honey 40 Topical and swallow R Significant reduction in the frequency of 22
mucositis; Risk of developing intolerable
mucositis was 0.05 and 0.75 for honey and
lignocaine groups, respectively
Honey 40 Topical and swallow CH-R Significant reduction in grade 4 mucositis, 23
Candida colonization and positive cultures
for aerobic pathogenic bacteria in honey
group
Honey 40 Topical and swallow R Significant reduction in mucositis scales but 24
no significant weight change was found
Honey 40 Topical and swallow R Significant reduction in symptomatic grade 25
3/4 mucositis but no significant weight
change was found
Honey 131 Topical and swallow R No improvement in mucositis, but 12
associated with a reduction in bacterial
infections
Honey 81 Topical and swallow CH-R No statistically significant difference between 26
the honey and placebo was reported
Propolis (bee glue) 40 Topical and swallow CH Not statistically significant 27
Coffee plus honey 75 Topical and swallow CH The best reduction in severity was achieved 28
in coffee plus honey group. Honey group
and steroid group ranked second and third
Matricaria recutita 52 Topical (mouthwash) CH Significant reduction in frequency of 29
mucositis
Matricaria recutita 1 (case Topical (mouthwash) CH Treated case 30
report)
Matricaria recutita 40 Topical (mouthwash) R 1% extract associated with reduced incidence, 31
intensity, and duration of mucositis
Matricaria recutita 164 Topical (mouthwash) CH No difference in frequency of mucositis 32
Peppermint 40 Topical (mouthwash) CH Significant reduction in frequency of 33
mucositis
Aloe vera 61 Oral juice R Significant reduction in frequency of 34
mucositis
Calendula officinalis 40 Topical (mouthwash) CH-R Significantly decreased the intensity of 35
mucositis
Olive leaf extract 30 Topical (mouthwash) CH Significantly decreased the intensity of 36
mucositis
Glycyrrhiza glabra 45 Topical (mouthwash) R Result showed better outcome for mucositis 37
Curcuma longa 7 Topical (mouthwash) CH Reduction in the WHO, OMAS, and VAS 38
scores of oral mucositis
Extract of human 60 Intramuscular R Decrease in pain and progression to grade 39
placenta 3 mucositis and improvement in difficulty
with swallowing was observed
Indigowood root 20 Topical (mouthwash) R Reduction in the severity of mucositis, 40
anorexia and swallowing difficulty
Dead Sea product 54 Topical (mouthwash) R Significantly decreased the intensity of 41
mucositis

Abbreviations: R, radiotherapy; CH, chemotherapy; WHO, World Health Organization; OMAS, Oral Mucositis Assessment Scale; VAS, Visual Analog
Pain Scale.

Matricaria chamomilla as chamazulene, alpha-bisabolol, bisaboloxides, spiro-

ethers, and flavonoids that have anti-inflammatory, antibac-
The flowers of Matricaria chamomilla (Chamomile) have terial, spasmolytic, sedative, and antifungal activities.49,50 It
been widely used in traditional and herbal medicine for a has been claimed to promote granulation and epithelializa-
long time.30 The plant contains chemical compositions such tion, which leads to normalization of the oral environment
Aghamohammadi and Hosseinimehr 63

and accelerates reepithelialization of oral tissue.51 Recent with head and neck cancer, who were under conventional
studies evaluated its effect on prevention and treatment of radiation therapy and received oral Aloe vera juice or pla-
oral mucositis induced by chemotherapy and radiotherapy.52 cebo. The incidence of severe mucositis was significantly
Carl and Emrich49 showed that chamomile (Kamillosan lower in the Aloe vera group compared with the placebo
Liquid oral rinse) can prevent or delay onset and reduce group. In this study, researchers used a fresh Aloe vera juice
occurrence and severity of mucositis induced by radiother- prepared under a well-controlled technique of enzyme deac-
apy and chemotherapy. Sixty-six patients with head and tivation. For this reason, their solution could preserve more
neck cancer received drops of chamomile in water 3 times a essential active compounds, such as glycoprotein, which are
day. Kamillosan Liquid oral rinse delayed the onset of radia- powerful substances to promote healing and anti-inflamma-
tion mucositis and in most patients reduced its the intensity. tory effects.34 However, more experiments are needed to
Prophylactic use of the oral rinse prevented the occurrence validate this process. Yagi et al61 examined the antioxidant
of severe mucositis in most patients who received systemic activity of Aloe vera. They indicated that isorabaichromone
chemotherapy.49 Despite these studies, in the phase III, dou- exhibited a strong antioxidative activity.
ble-blind, placebo-controlled clinical trial, chamomile Choi et al62 showed that other compounds in Aloe vera,
mouthwash did not reduce the stomatitis and inflammation including β-sitosterol improved the appearance of proteins
of the mouth and lips induced by 5-fluorouracil in patients.32 related to angiogenesis, namely von Willebrand factors,
Matricine and its transformation product chamazulene are vascular endothelial growth factor (VEGF), VEGF receptor
the main compounds of M chamomilla. Chamazulene may Flk-1, and blood vessel matrix laminin. They suggested that
contribute to the anti-inflammatory activity of chamomile β-sitosterol has curative angiogenic effects on injured blood
extracts by inhibiting leukotriene synthesis and additional vessels.62
antioxidative effects.53
Drug interaction: Synergism with insulin, topical hydro-
Drug interaction: There is a report of an interaction cortisone, and zidovudine.63
between warfarin and M recutita.54 Clinical outcome: Potassium depletion, hypokalemia,
Clinical outcome: Herbs that can be safely consumed increased hypoglycemic effect.63
when used appropriately.48
Isatis indigotica
Aloe vera Isatis indigotica Fort. (Indigowood root) belongs to the
Aloe vera is widely used to remedy some skin difficulties, Brassicaceae family. Indigowood root is used in Chinese
for example dry and burned skin and radiation-induced traditional medicine.64 You et al40 studied the effect of indi-
dermatitis.55,56 The use of Aloe vera in the treatment of irri- gowood root on patients with head and neck malignancy
tant contact dermatitis has been reported in the literature under radiotherapy. Twenty patients were randomly divided
since 70 years. Some studies suggested the beneficial effects into 2 groups. Group 1 served as controls with only normal
of Aloe vera on prevention and treatment of radiation- saline and the second group received indigowood root.
induced ulcers and mucositis.57 Preclinical studies showed They showed that indigowood root significantly reduced
that Aloe vera enhanced wound healing by reducing vaso- the severity of radiation induced mucositis, anorexia, and
constriction and platelet association at the wound place, swallowing difficulty. This extract increased the patients’
increasing collagen formation and wound oxygenation, appetite and swallowing ability and finally their quality of
scavenging free radicals, inhibiting collagenase and metal- life. The authors suggested that anti-inflammation was the
loproteinase, and activating macrophages.9,58-60 Also Aloe main mechanism for preventive effect of indigowood on
vera has anti-inflammatory property through the inhibition mucositis induced by radiation.40 Chemical analysis of
of cyclooxygenase.60 In a double-blind randomized clinical indigowood root illustrated that it contains indirubin and
trial study, significant benefits were not statistically found indigotone which have anti-inflammmatory activity.64
when adding Aloe vera to the standard oral care in the man- Most studies have shown that the particular structure of
agement of radiation mucositis.9 Radiation-induced mucosi- indirubin gives it the ability to inhibit cyclin-dependent
tis is recognized by exposure of a large region of basal kinases and glycogen synthase kinases, triggering cell
membrane and innervated mesenchymal tissue after erosion cycle arrest and apoptosis. Kinase inhibitor activity of indi-
of the mucosal layer. Treatment of oral ulcers is needed to rubin is a main cause of cellular proliferation and immune
regenerate and replace the basal membrane clonogens rather functions. Indirubin is also a strong aryl hydrocarbon
than to inhibit the mediators of inflammation and this maybe receptor (AhR) agonist. The AhR is a cytosolic protein,
one reason for noneffectiveness of Aloe vera for radiation- which, on ligand binding, is translocated to the nucleus and
induced mucositis.9 Puataweepong et al34 studied a phase III, acts as a transcription factor for genes engaged in oxidative
double-blind, placebo-controlled clinical trial on 61 patients stress.53
64 Integrative Cancer Therapies 15(1)

Drug interaction: None reported.65 and randomly divided into 2 equal placebo and peppermint
Clinical outcome: A classic textbook in traditional essential oils groups. Patients received 10 drops of oral rinse
Chinese medicine points out that Isatis root is not indi- peppermint essential oils 3 times a day. The incidence of oral
cated for feeble patients.66 mucositis was 15% for the essential oils group, while it was
50% in the placebo group. Mean scores of oral mucositis were
0.2 and 0.8 in essential oils– and placebo-treated groups,
Leptospermum scoparium respectively. Peppermint essence is an effective, safe,
Leptospermum scoparium, commonly called manuka, is a and well-tolerated products for prophylactic treatment of
species of flowering plant in the myrtle family. The chemotherapy-induced oral mucositis.33
Myrtaceae are native to New Zealand and southeast
Australia. This herb contains sesquiterpene hydrocarbons.
Human Placenta
These compounds have antifungal, antibacterial, and anti-
inflammatory activity.67,68 In a randomized placebo- Human placental extract contains a complex mixture of dif-
controlled trial study, 19 adult patients used a gargle con- ferent materials such as polydeoxyribonucleotides, RNA,
taining 2 drops of a 1:1 mix of the essential oils of manuka. DNA, peptides, amino acids, enzymes, and other scarce
Overall, the active gargle was well tolerated by patients ingredients. These products have anti-inflammatory func-
with no evidence of toxic or side effects relating to its swal- tion and have been used as a remedy for untreatable foot sore
lowing. Patients in the essential oil gargle group had a and appeared to be effective in the prevention and treatment
delayed onset of mucositis and reduced pain and oral symp- of chemotherapy- and radiotherapy-induced oral/oropharyn-
toms relative to placebo. Small sample size was a limitation geal mucositis and especially in controlling symptoms.75
of this study. They suggested that essential oils had the role Placentrex is a drug containing peptides (FNP-III, CRF),
in improving oral health by causing lysis of oral bacteria and nucleotides (PDRN, NADPH), and glutamate and is derived
helping to reduce the bacterial load. As a consequence of the from an extract of fresh term, healthy, and human placenta.
small data in their study, recommendation to using it for Each milliliter contains 0.1 g fresh human placenta.
mucositis needs large randomized clinical trials to confirm.69 Placentrex is used for a number of inflammatory skin
Recent studies showed that the antimicrobial activity of the diseases.3 Recent studies have demonstrated that Placentrex
manuka oil was related to flavesone and leptospermone.70,71 stimulates the pituitary and the adrenal cortex and normal-
izes the tissues metabolism. According to theory, it increases
Drug interaction: There is potential synergistic effect the vascularity of tissues.47 There are not many studies on
with bacitracin, cefadroxil, cephradin, and meropenem the assessment of the effect of human placenta on
but an antagonist effect with ofloxacin, enoxacin, and chemotherapy- and radiotherapy-induced oral mucositis. In
sparfloxacin.72 L scoparium contains a lipophilic flavo- a clinical trial study, 120 patients with head and neck cancer
noid that specifically interacts with benzodiaze- under radiation therapy were equally divided into 2 groups.
pine receptors (GABA-A receptor-chloride channel Patients received either Placentrex treatment or standard
complex).73 treatment. Placentrex was given as 2 mL intramuscular
Clinical outcome: Avoid using it during pregnancy injection, 5 days a week for 3 consecutive weeks. The con-
because of spasmolytic activity.68 trol group received common treatment of aspirin gargles and
betamethasone oral drops. A decrease of pain was observed
in 80% of patients in the Placentrex group compared with
Essential Oils 36.7% in the control group. The progression to grade 3 radi-
Essential oils have antibacterial and antifungal effects and ation mucositis was 40% in the Placentrex group compared
these natural compounds have been applied to treat the skin with 86.7% in the control group. Improvement in swallow-
and mucosa infections. In a clinical trial, Gravett74 assessed ing difficulty was seen in 93% of patients in the Placentrex
mixed essential oils as mouthwash for oral mucositis. group compared with 15% of patients in the control group.
Gravett74 combined a mixture of Melaleuca alternifolia (1 Human placental extract thus reduced the symptoms of
drop), Citrus bergamia (1 drop), and Pelargonium graveolens mucositis, and the study group had less severe mucositis
(1 drop) with half of a glass of boiled warm water to gargle for than standard treatment group.39 Some studies have sug-
5 times a day. Although few benefits were found when this gested that anti-inflammatory effect of this drug was caused
mouthwash was added to the routine oral care in the treatment by membrane stabilization and reduction of adenosine triphos-
of radiation mucositis, patients preferred to use this plant phate (ATP) synthesis.76 Investigations about the effect of
mouthwash because of less burning discomfort in comparison human placental extract on chemotherapy- and radiotherapy-
with routine mouthwash for managing oral mucositis.74 In a induced oral mucositis are not sufficient, and the results of
double-blind clinical trial study, 40 patients with colon or rec- this research should to be confirmed by other studies in the
tum cancers were admitted to chemotherapeutic management future.
Aghamohammadi and Hosseinimehr 65

Honey and Bee Products A randomized and uncontrolled study was done in 2008.
They swished and swallowed 20 mL honey from bees fed
Honey and propolis (bee glue) have been used in the man- primarily on Egyptian clover (Trifolium alexandrinum) 3
agement of mucositis.25 Golder77 indicated that propolis is times per day. Only 3 (15 %) of the honey-treated group had
beneficial for the treatment of mucositis induced by radia- RTOG ≥3 mucositis as compared with 12 (60%) in the con-
tion therapy. Honey has been used to heal burns, surgical trol group.23 A double-blind randomized placebo-controlled
wounds, and oral infections because of its antibacterial and trial investigation was done by Hawley et al26 in 2014. In
analgesic agents and epithelialization boosting effect.78,79 this study, 81 patients were randomized to swish, hold, and
The efficacy of pure natural honey for the treatment of swallow either 5 mL of irradiated organic manuka honey or
mucositis was reported in patients under radiation therapy a placebo gel, 4 times a day throughout radiation treatment,
and/or chemotherapy in several clinical trials. We have plus 7 more days. Sixty-two percent of subjects received
found many clinical trials associated with the preventive concurrent chemotherapy. They reported that manuka
and therapeutic effects of honey and its relative products for honey was not tolerated well by patients and did not have a
management of radiation- and chemotherapy-induced significant impact on the severity of radiation-induced oral
mucositis. In a randomized single blind clinical trial, 40 mucositis.26
patients who suffered from head and neck cancer and There are a number of probable reasons why the results
required radiation to the oropharyngeal mucosa were ran- of different studies might be different, including differences
domly divided into 2 groups. Patients received 20 mL pure in the source of honey, patient characteristics, study design,
natural honey from bees fed on thyme and astragale in the anticancer treatment protocols, and oral mucositis assess-
Alborz Mountains of Iran, 15 minutes before, then 20 mL ment tools.
doses again at 15 minutes and 6 hours after radiation ther- In 2012, Song et al81 reported a systematic and meta-
apy. They washed their mouths with honey and engorged analysis review on the use of honey for reduction of radia-
slowly to cover the oral and pharyngeal mucosa. A signifi- tion-induced oral mucositis. They concluded that the results
cant reduction in mucositis in patients treated with honey of clinical trials are promising and further studies are needed
was observed as compared with controls.24 The same results to strengthen the current evidence prior to a firm clinical
in reduction of mucositis were observed in another study, in recommendation being given,81 and Van den Wyngaert82
which 40 patients received topical applications of 20 mL confirmed it.
pure honey before and after radiation therapy.25 In a clinical Recent studies have reported that Iranian propolis has
trial, the effect of natural honey and 0.15% benzydamine flavonoids and phenolic compounds and can manage the
hydrochloride on onset and severity of radiation mucositis radiation-induced mucositis. It found that it postpones the
was assessed and compared with control. The patients were appearance of lesions and substantially reduces the severity
randomized into three groups of 20 patients. Group 1 of mucositis.24,83 Because honey is not a generic drug,
patients received topical application of natural honey; description of the composition of honey is not easy. The
groups 2 and 3 received topical application of 0.15% benzy- components depend on the plants of the geographical region
damine hydrochloride and 0.9% normal saline, respectively. where honeybees collect pollen. Honey naturally includes
The onset of mucositis and the severity of mucositis were <20% water, vitamins, enzymes, proteins, and a high con-
graded during the course of the radiotherapy and 2 weeks centration of sugars. Invertase, diastase, and glucose oxi-
after radiotherapy. A significant reduction of mucositis in dase are the honey enzymes. It is not clear whether the
patients treated with honey was compared with 0.15% ben- antimicrobial activity of honey is the result of its delay of
zydamine hydrochloride, 0.9% normal saline applied to hydrogen peroxide on exposure to catalase or the result of
patients was observed. The differences between the groups its high osmolarity.22
were statistically significant.80 Results of other studies Some researchers are worried about using honey in irra-
showed that prophylactic use of natural honey was effective diated patients. Their concern is that the topical use of
in reduction of mucositis subjective symptoms from radio- honey in the oral mucosa of patients with low motivation
therapy and/or chemotherapy. Honey reduces wound pain for oral hygiene could act in synergy with the other risk fac-
by postponing tissue oxygenation through blocking expo- tors for radiation-related caries. Honey can be highly cario-
sure of the damaged mucosa to oxygen.3,22-24 Biswal et al25 genic and certainly should be avoided in certain patients
suggested that the effectiveness of honey on wound healing undergoing radiotherapy.84
might be because of the hygroscopic nature of honey, its
viscosity, its acidic pH, which prevents bacteria growth on
the mucosa, inhibin (hydrogen peroxide) converted from
Conclusion
glucose oxidase and gluconic acid, enzymes which proba- Radiation- and anticancer treatment–induced oral mucositis
bly are growth factors and tissue nutritive minerals and vita- are severe complications in patients with head and neck
mins that help repair the tissue directly. cancers. Inflammation and ROS are cellular mechanisms
66 Integrative Cancer Therapies 15(1)

related to mucositis. Natural products such as herbal medi- 9. Su CK, Mehta V, Ravikumar L, et al. Phase II double-blind ran-
cine have potential to reduce oral mucositis in patients. domized study comparing oral aloe vera versus placebo to pre-
Many clinical trials have been performed to assess natural vent radiation-related mucositis in patients with head-and-neck
products for treatment of mucositis, and the results have neoplasms. Int J Radiat Oncol Biol Phys. 2004;60:171-177.
10. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence,
been promising. Nowadays, a standard preventive agent for
severity and associated outcomes in patients with head and
mucositis is not available from natural products that are
neck cancer receiving radiotherapy with or without chemo-
well documented with several multicenter clinical trials. therapy: a systematic literature review. Radiother Oncol.
These natural products were mostly evaluated only once, 2003;66:253-262.
with small number of patients. Honey has been widely 11. Scully C, Epstein J, Sonis S. Oral mucositis: a challenging
assessed in clinical studies. Several clinical studies support complication of radiotherapy, chemotherapy, and radioche-
honey for reduction of mucositis in patients during radia- motherapy: part 1. Pathogenesis and prophylaxis of mucosi-
tion therapy, although a recent trial found no effect of honey. tis. Head Neck. 2003;25:1057-1070.
There is, however, a lack of strong evidence for natural 12. Bardy J, Molassiotis A, Ryder WD, et al. A double-blind,
products to prevent or treat oral mucositis. Properly placebo-controlled, randomised trial of active manuka honey
designed clinical trials are required to understand and standard oral care for radiation-induced oral mucositis. Br
J Oral Maxillofac Surg. 2012;50:221-226.
natural product efficacy for controlling radiotherapy- and
13. Sonis S. Mucositis as a biological process: a new hypothesis
chemotherapy-induced oral mucositis.
for the development of chemotherapy-induced stomatotoxic-
ity. Oral Oncol. 1998;34:39-43.
Declaration of Conflicting Interests 14. Bensadoun R-J, Le Page F, Darcourt V, et al. Radiation-
The author(s) declared no potential conflicts of interest with induced mucositis of the aerodigestive tract: prevention and
respect to the research, authorship, and/or publication of this treatment. MASCC/ISOO mucositis group’s recommenda-
article. tions [in French]. Bull Cancer. 2006;93:201-211.
15. Debatin K-M. Cytotoxic drugs, programmed cell death, and
Funding the immune system: defining new roles in an old play. J Natl
Cancer Inst. 1997;89:750-751.
The author(s) received no financial support for the research,
16. Martin M. Irradiation mucositis: a reappraisal. Eur J Cancer
authorship, and/or publication of this article.
Part B Oral Oncol. 1993;29:1-2.
17. Eissner G, Lindner H, Behrends U, et al. Influence of bacterial
References endotoxin on radiation-induced activation of human endo-
1. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human thelial cells in vitro and in vivo: protective role of IL-101.
papillomavirus types in head and neck squamous cell carci- Transplantation. 1996;62:819-827.
nomas worldwide: a systematic review. Cancer Epidemiol 18. Chi K-H, Chen C-H, Chan W-K, et al. Effect of granulocyte-
Biomarkers Prev. 2005;14:467-475. macrophage colony-stimulating factor on oral mucositis in
2. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation head and neck cancer patients after cisplatin, fluorouracil, and
Therapy Oncology Group (RTOG) and the European leucovorin chemotherapy. J Clin Oncol. 1995;13:2620-2628.
Organization for Research and Treatment of Cancer 19. Eilers J, Million R. Prevention and management of oral muco-
(EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341-1346. sitis in patients with cancer. Semin Oncol Nurs. 2007;23:
3. Rodríguez-Caballero A, Torres-Lagares D, Robles-García 201-212.
M, Pachón-Ibáñez J, Gonzalez-Padilla D, Gutierrez-Perez J. 20. Epstein JB, Epstein JD, Epstein MS, Oien H, Truelove EL.
Cancer treatment-induced oral mucositis: a critical review. Int Management of pain in cancer patients with oral mucositis:
J Oral Maxillofac Surg. 2012;41:225-238. follow-up of multiple doses of doxepin oral rinse. J Pain
4. Levi F, Maisonneuve P, Filiberti R, La Vecchia C, Boyle P. Symptom Manage. 2007;33:111-114.
Cancer incidence and mortality in Europe. Sozi Präventivmed. 21. Biswal BM. Current trends in the management of oral

1989;34(suppl 2):S3-S83. mucositis related to cancer treatment. Malays J Med Sci.
5. Hosseinimehr SJ. Trends in the development of radioprotec- 2008;15(3):4-13.
tive agents. Drug Discov Today. 2007;12:794-805. 22. Khanal B, Baliga M, Uppal N. Effect of topical honey on
6. Clarkson JE, Worthington HV, Eden OB. Interventions for limitation of radiation-induced oral mucositis: an intervention
treating oral mucositis for patients with cancer receiving treat- study. Int J Oral Maxillofac Surg. 2010;39:1181-1185.
ment. Cochrane Database Syst Rev. 2007;(2):CD001973. 23. Rashad U, Al-Gezawy S, El-Gezawy E, Azzaz A. Honey
7. Rosenthal DI, Trotti A. Strategies for managing radiation- as topical prophylaxis against radiochemotherapy-induced
induced mucositis in head and neck cancer. Semin Radiat mucositis in head and neck cancer. J Laryngol Otol.
Oncol. 2009;19:29-34. 2009;123:223-228.
8. Kostler WJ, Hejna M, Wenzel C, Zielinski CC. Oral mucosi- 24. Motallebnejad M, Akram S, Moghadamnia A, Moulana Z,
tis complicating chemotherapy and/or radiotherapy: options Omidi S. The effect of topical application of pure honey on
for prevention and treatment. CA Cancer J Clin. 2001;51: radiation-induced mucositis: a randomized clinical trial. J
290-315. Contemp Dent Pract. 2008;9(3):40-47.
Aghamohammadi and Hosseinimehr 67

25. Biswal BM, Zakaria A, Ahmad NM. Topical application of in radiation-induced mucositis. J Alter Complement Med.
honey in the management of radiation mucositis. A prelimi- 2009;15:771-778.
nary study. Support Care Cancer. 2003;11:242-248. 41. Matceyevsky D, Hahoshen NY, Asna N, Khafif A, Ben-Yosef
26. Hawley P, Hovan A, McGahan CE, Saunders D. A ran-
R. Assessing the effectiveness of Dead Sea products as pro-
domized placebo-controlled trial of manuka honey for phylactic agents for acute radiochemotherapy-induced skin
radiation-induced oral mucositis. Support Care Cancer. and mucosal toxicity in patients with head and neck cancers:
2014;22:751-761. a phase 2 study. Chemotherapy. 2007;9:12.
27. Tomaževič T, Jazbec J. A double blind randomised placebo 42. Tanideh N, Tavakoli P, Saghiri MA, et al. Healing accelera-
controlled study of propolis (bee glue) effectiveness in the tion in hamsters of oral mucositis induced by 5-fluorouracil
treatment of severe oral mucositis in chemotherapy treated with topical Calendula officinalis. Oral Surg Oral Med Oral
children. Complement Ther Med. 2013;21:306-312. Pathol Oral Radiol. 2013;115:332-338.
28. Raeessi MA, Raeessi N, Panahi Y, et al. “Coffee plus honey” 43. Salvo N, Barnes E, van Draanen J, et al. Prophylaxis and man-
versus “topical steroid” in the treatment of chemotherapy- agement of acute radiation-induced skin reactions: a system-
induced oral mucositis: a randomised controlled trial. BMC atic review of the literature. Curr Oncol. 2010;17:94-112.
Complement Altern Med. 2014;14:293. 44. Chandran PK, Kuttan R. Effect of Calendula officinalis

29. Renani HA, Keikhai B, Mahani HG, Latifi M. Effect of
flower extract on acute phase proteins, antioxidant defense
chamomile mouthwash for preventing chemotherapy- mechanism and granuloma formation during thermal burns. J
induced ostomatitis in children. J Mazandaran Univ Med. Clin Biochem Nutr. 2008;43(2):58-64.
2012;21(86):19-25. 45. Loke WM, Proudfoot JM, Stewart S, et al. Metabolic trans-
30. Mazokopakis E, Vrentzos G, Papadakis J, Babalis D,
formation has a profound effect on anti-inflammatory activity
Ganotakis E. Wild chamomile (Matricaria recutita L.) of flavonoids such as quercetin: lack of association between
mouthwashes in methotrexate-induced oral mucositis. antioxidant and lipoxygenase inhibitory activity. Biochem
Phytomedicine. 2005;12:25-27. Pharmacol. 2008;75:1045-1053.
31. Braga FT, Santos AC, Bueno PC, et al. Use of Chamomilla 46. Duran V, Matic M, Jovanovć M, et al. Results of the clinical
recutita in the prevention and treatment of oral mucositis in examination of an ointment with marigold (Calendula offi-
patients undergoing hematopoietic stem cell transplantation: cinalis) extract in the treatment of venous leg ulcers. Int J
a randomized, controlled, phase II clinical trial. Cancer Nurs. Tissue React. 2004;27:101-106.
2015;38:322-329. 47. Anil S, Beena V. Oral submucous fibrosis in a 12-year-old
32. Fidler P, Loprinzi CL, O’Fallon JR, et al. Prospective
girl: case report. Pediatr Dent. 1993;15:120-122.
evaluation of a chamomile mouthwash for prevention of 48. Li TSC. Medicinal Plants: Culture, Utilization and
5-FU-induced oral mucositis. Cancer. 1996;77:522-525. Phytopharmacology. Boca Raton, FL: CRC Press; 2000:66-120.
33. Ashktorab T, Yazdani Z, Mojab F, Majd H, Madani H.
49. Carl W, Emrich LS. Management of oral mucositis during
Preventive effects of an oral rinse peppermint essence on che- local radiation and systemic chemotherapy: a study of 98
motherapy-induced oral mucosistis. Koomesh. 2010;12:8-13. patients. J Prosthet Dent. 1991;66:361-369.
34. Puataweepong P, Dhanachai M, Dangprasert S, et al. The 50. Avallone R, Zanoli P, Puia G, Kleinschnitz M, Schreier P,
efficacy of oral Aloe vera juice for radiation induced mucosi- Baraldi M. Pharmacological profile of apigenin, a flavonoid
tis in head and neck cancer patients: a double-blind placebo- isolated from Matricaria chamomilla. Biochem Pharmacol.
controlled study. Asian Biomed. 2009;3:375-382. 2000;59:1387-1394.
35. Babaee N, Moslemi D, Khalilpour M, et al. Antioxidant
51. Plevova P. Prevention and treatment of chemotherapy- and
capacity of Calendula officinalis flowers extract and preven- radiotherapy-induced oral mucositis: a review. Oral Oncol.
tion of radiation induced oropharyngeal mucositis in patients 1999;35:453-470.
with head and neck cancers: a randomized controlled clinical 52. Kührer I, Kuzmits R, Linkesch W, Ludwig H. Topical PGE2
study. Daru. 2013;21:18. enhances healing of chemotherapy associated mucosal
36. Al-Jaf HNHF, Ahmed KM, Najmuldeen HH. A microbio- lesions. Lancet. 1986;327:623.
logical study for evaluating olive leaf extract as a new topi- 53. Babcock AS. The Effects of Indirubin Derivatives on Gene
cal management for oral mucositis following chemotherapy Expression and Cellular Functions in the Murine Cell Line,
[abstract]. Bull UASVM. 2011;1(68):391 RAW 264.7 [dissertation]. Clemson, South Carolina: Clemson
37. Ismail AA, Behkite AA, Badria FM, Guemei AA. Licorice University; 2008.
in prevention of radiation induced mucositis. J Clin Oncol. 54. Segal R, Louise P. Warfarin interaction with Matricaria

2004;22:8268. chamomilla. CMAJ. 2006;174:1281-1282.
38. Elad S, Meidan I, Sellam G, et al. Topical curcumin for the 55. West DP, Zhu YF. Evaluation of aloe vera gel gloves in the
prevention of oral mucositis in pediatric patients: case series. treatment of dry skin associated with occupational exposure.
Altern Ther Health Med. 2013;19(3):21-24. Am J Infect Control. 2003;31:40-42.
39. Kaushal V, Verma K, Manocha S, Hooda H, Das B. Clinical 56. Visuthikosol V, Chowchuen B, Sukwanarat Y, Sriurairatana
evaluation of human placental extract (Placentrex) in S, Boonpucknavig V. Effect of aloe vera gel to healing of
radiation-induced oral mucositis. Int J Tissue React. 2000;23: burn wound a clinical and histologic study. J Med Assoc Thai.
105-110. 1995;78:403-409.
40. You WC, Hsieh CC, Huang JT. Effect of extracts from indi- 57. Williams MS, Burk M, Loprinzi CL, et al. Phase III double-
gowood root (Isatis indigotica Fort.) on immune responses blind evaluation of an aloe vera gel as a prophylactic agent for
68 Integrative Cancer Therapies 15(1)

radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys. 71. Porter NG, Wilkins AL. Chemical, physical and antimicrobial
1996;36:345-349. properties of essential oils of Leptospermum scoparium and
58. Heggie S, Bryant GP, Tripcony L, et al. A phase III study on Kunzea ericoides. Phytochemistry. 1999;50:407-415.
the efficacy of topical aloe vera gel on irradiated breast tissue. 72. Kim EH, Rhee GJ. Activities of ketonic fraction from

Cancer Nurs. 2002;25:442-451. Leptospermum scoparium alone and synergism in combina-
59. Barrantes E, Guinea M. Inhibition of collagenase and metal- tion with some antibiotics against various bacterial strains and
loproteinases by aloins and aloe gel. Life Sci. 2003;72: fungi. J Pharm Soc Korea. 1999;43:716-728.
843-850. 73. Häberlein H, Tschiersch KP. 2,5-Dihydroxy-7-methoxy-6,

60. Wynn RL. Aloe vera gel: update for dentistry. Gen Dent. 8-dimethylflavan-3-one a novel flavonoid from Leptospermum
2005;53:6-9. scoparium: in vitro affinity to the benzodiazepine bind-
61. Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa S, ing site of the GABAA receptor-chloride channel complex.
Khalifa T. Antioxidant, free radical scavenging and anti- Pharmazie. 1994;49:860.
inflammatory effects of aloesin derivatives in Aloe vera. 74. Gravett P. Aromatherapy treatment of severe oral mucositis.
Planta Med. 2002;68:957-960. Int J Aromather. 2000;10:52-53.
62. Choi S, Kim KW, Choi JS, et al. Angiogenic activity of beta- 75. Ngeow WC, Chai WL, Zain RB. Management of radiation
sitosterol in the ischaemia/reperfusion-damaged brain of therapy-induced mucositis in head and neck cancer patients.
Mongolian gerbil. Planta Med. Apr 2002;68(4):330-335. Part II: supportive treatments. Oncol Rev. 2008;2:164-182.
63. Posadzki P, Leala W, Edzard E. Herb-drug interactions:
76. Banerjee K, Bishayee A, Chatterjee M. Anti-inflammatory
an overview of systematic reviews. Br J Clin Pharmacol. effect of human placental extract: a biochemical mechanistic
2013;75:603-618. approach. Riv Eur Sci Med Farmacol. 1991;14:361-366.
64. Gilbert KG, Maule HG, Rudolph B, et al. Quantitative
77. Golder W. Propolis. The bee glue as presented by the Graeco-
analysis of indigo and indigo precursors in leaves of Isatis Roman literature [in German]. Wurzbg Medizinhist Mitt.
spp. and Polygonum tinctorium. Biotechnol Prog. 2004;20: 2003;23:133-145.
1289-1292. 78. Alam F, Islam MA, Gan SH, Khalil MI. Honey: a potential
65. Gardner Z, Michael M. American Herbal Products
therapeutic agent for managing diabetic wounds. Evid Based
Association’s Botanical Safety Handbook. Boca Raton, FL: Complement Alternat Med. 2014;2014:169130.
CRC Press; 2013. 79. Belcher J. Dressings and healing with honey. Br J Nurs.
66. Cassileth BR, Lucarelli CD. Herb-Drug Interactions in
2014;23(6):S22.
Oncology. Hamilton, Ontario, Canada: BC Dekker; 2003. 80. Jayachandran S, Balaji N. Evaluating the effectiveness of
67. Lis-Balchin M. Aromatherapy Science: A Guide for topical application of natural honey and benzydamine hydro-
Healthcare Professionals. London, England: Pharmaceutical chloride in the management of radiation mucositis. Indian J
Press; 2006. Palliat Care. 2012;18:190-195.
68. Lis-Balchin M, Hart S, Deans S. Pharmacological and anti- 81. Song JJ, Twumasi-Ankrah P, Salcido R. Systematic review
microbial studies on different tea-tree oils (Melaleuca alter- and meta-analysis on the use of honey to protect from the
nifolia, Leptospermum scoparium or Manuka and Kunzea effects of radiation-induced oral mucositis. Adv Skin Wound
ericoides or Kanuka), originating in Australia and New Care. 2012;25:23-28.
Zealand. Phytotherapy Res. 2000;14:623-629. 82. Van den Wyngaert T. Topical honey application to reduce
69. Maddocks-Jennings W, Wilkinson JM, Cavanagh HM,
radiation-induced oral mucositis: a therapy too sweet to
Shillington D. Evaluating the effects of the essential oils ignore? J Evid Based Dent Pract. 2012;12:203-205.
Leptospermum scoparium (manuka) and Kunzea ericoides 83. Ghassemi L, Zabihi E, Mahdavi R, Seyedmajidi M, Akram
(kanuka) on radiotherapy induced mucositis: a random- S, Motallebnejad M. The effect of ethanolic extract of prop-
ized, placebo controlled feasibility study. Eur J Oncol Nurs. olis on radiation-induced mucositis in rats. Saudi Med J.
2009;13:87-93. 2010;31:622-626.
70. Reichling J, Koch C, Stahl-Biskup E, Sojka C, Schnitzler 84. Santos-Silva AR, Rosa GB, Eduardo CP, Dias RB, Brandao
P. Virucidal activity of a β-triketone-rich essential oil of TB. Increased risk for radiation-related caries in cancer
Leptospermum scoparium (manuka oil) against HSV-1 and patients using topical honey for the prevention of oral muco-
HSV-2 in cell culture. Planta Med. 2005;71:1123-1127. sitis. Int J Oral Maxillofac Surg. 2011;40:1335-1336.