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European Journal of Integrative Medicine 5 (2013) 217–225

Review article

The effectiveness of honey for the management of radiotherapy-induced oralmucositis in head and neck cancer patients: A systematic review of clinical

trials

Melanie Charalambous a, Vasilios Raftopoulos b, Ekaterini Lambrinou a, Andreas Charalambous c,∗a Cyprus University of Technology, Nursing Department, Limassol, Cyprus

b Cyprus University of Technology, Nursing Department, Mediterranean Research Centre for Public Health and Quality of Care, Limassol, Cyprus1

c Cyprus University of Technology, Nursing Department, Euro-Mediterranean Research Centre for Oncology and Palliative Care, Cyprus2

Received 26 November 2012; received in revised form 16 January 2013; accepted 16 January 2013

bstract

im: To evaluate the effectiveness of honey in the management of oral mucositis in head and neck cancer patients undergoing radiotherapy.ethods: The review of the literature was based on a keyword strategy and pre-determined inclusion and exclusion criteria. The keywords

head and neck cancer”, “radiotherapy”, “oral mucositis”, “controlled trial” and “honey” were used as search terms in the EMBASE, CINAHL,OCHRANE and PUBMED databases. The citation and reference list of the eligible articles were also screened for potentially relevant articles.he methodological quality of the selected trials was assessed by the JADAD scale.esults: In total, 5 studies met the criteria and were included in the systematic review. Three studies assessed the effectiveness of honey againstther products including golden syrup, lignocaine and saline and two studies assessed the effectiveness of honey against standard treatment regimes.our out of the five studies demonstrated significant reduction in the mucositis levels and one study reported that honey had no statistical associationith less severe mucositis. Methodologically the quality of most studies was moderate due to the small sample size, which might impact upon the

ignificance of the findings.

onclusions: Although honey appears to be a simple, affordable, available and cost-effective treatment for the management of radiation-inducedral mucositis, there is a need for further multi-centre randomized trials to validate these findings.

2013 Elsevier GmbH. All rights reserved.

eywords: Clinical trials; Honey; Oral mucositis; Radiation therapy; Head and neck cancer

apofc

ntroduction

An estimated 36,500 new cases of and 7900 deaths from oralavity and pharyngeal cancers occurred in 2010 in the Unitedtates [1]. Squamous cell carcinoma or a variant is the histologic

ype in more than 90% of these tumours [2,3]. The three maininds of treatment that may be given independently or in combi-ation, for head and neck cancers include surgery, chemotherapy

∗ Corresponding author at: Nursing Department, Cyprus University of Tech-ology, Cyprus. Tel.: +357 25002011; fax: +357 25002822.

E-mail address: andreas.charalambous@cut.ac.cy (A. Charalambous).1 www.cut.ac.cy/medyp.2 http://www.euro-mediterraneancenter.com.

Seccmmiet

876-3820/$ – see front matter © 2013 Elsevier GmbH. All rights reserved.ttp://dx.doi.org/10.1016/j.eujim.2013.01.003

nd radiation therapy (RT). The treatment plan for an individualatient depends on a number of factors including the locationf the tumour, the stage and the pathologic findings. Theseactors consecutively guide the appropriate radiation protocol,hemotherapy regime or surgical procedure to be followed [4].ingle-modality treatment with surgery or radiotherapy is gen-rally recommended for 30–40% of stage I–II head and neckancer patients [5]. In addition to its desired effect on cancerells, radiation therapy often causes acute toxicities althoughost of them are temporary. Most side effects occur towards theiddle and the end of the course of treatment and continue dur-

ng the first couple of weeks after the treatment has finished. Theffects can be mild or severe, depending on the dose of RT andhe length of the treatment. Oral mucositis is one of the most

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ommon, severe and persistent side effects that patients withead and neck cancer confronted during and after radiotherapy.

Molecular and cell biology in oral mucositis is a multi-tep process. Sonis [6] has described a five phase model toharacterize the theory for the pathogenesis of oral mucosi-is. These phases include initiation, signalling, amplification,lceration and healing [6]. According to this theory, reactivexygen species generated by exposure to radiation therapy orhemotherapy result in DNA strand breaks and that causesamage to the cells, tissues and blood vessels. These damagesctivate transcription factors which cause increased productionf pro-inflammatory cytokines like interleukin that lead to tissuenjury and apoptosis. The cytokines cause further tissue damagehich amplifies the signalling cascade that lead to ulceration and

nflammation. A signal send by the submucosal tissue initiateshe healing process which in turn stimulates epithelial prolifer-tion and cellular differentiation restoring the lining of the oralavity [6].

The development of oral mucositis is an expected accompa-iment of radiation therapy applied to the head and neck regions.evere radiation mucositis leads to ulceration and painful dys-hagia that can negatively influence the quality of life andorce the discontinuation of treatment. At least 50% of patientsill experience some grade of oral mucositis as well as grade

mucositis when 66–70 Gy radiation are delivered to largeucosal surfaces in 6–7 weeks with 1.8–2 Gy per fraction [7].A variety of treatments are used for the prevention and the

anagement of oral mucositis and the choice of the treatmentepends on the patient’s condition and needs. The most usualategories of these agents include topical cytoprotective agentse.g. sucralfate), anti-inflammatory agents (e.g. benzydamineydrochloride), antibacterial agents (e.g. chlorhexidine) topicalr systemic anti-oxidants (e.g. amifostine, vit. E) and sialo-ogues [8–10]. Cryotherapy and low-level laser therapy foundo be helpful in reducing the severity of chemotherapy andadiation-induced oral mucositis [11,12]. Keratinocyte growthactor (KGF-1, palifermin), G-CSF and GM-CSF factors andlutamine (nonessential amino acid) are some of the therapieshich have recently been evaluated for preventing and manag-

ng oral mucositis [13–15]. Despite the availability of treatmentptions for oral mucositis, these do not seem to provide anffective and comprehensive management method [16].

In the light of the ineffectiveness of these conventional means,ealth-care professionals and the public alike turned to comple-entary and alternative medicine (CAM) in order to find ways

o better manage oral mucositis. However, a dilemma emergedegarding the use of such methods (i.e. honey) due to the lackf consistent scientific evidence in relation to their efficacy andafety. Nevertheless, an increasing number of cancer popula-ions use CAM as adjunct therapies whether prescribed or not17,18]. Despite the increased attention on such methods in dif-erent cancer populations there has been a disproportional studyor their use in head and neck cancer patients [19]. The avail-

ble preceding studies emphasized the management of variousreatments related side-effects experienced by head and neckancer patients through the use of CAM [20–23]. Among thesereatments that have been explored is that of natural honey.

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Integrative Medicine 5 (2013) 217–225

Some studies refer to honey as one of the traditionaledicines that have beneficial properties to health [24,25]

ncluding its ability to facilitate the healing process. Molan,tressed that honey facilitates an increase in lymphocytes andhagocytes and aids monocytes to release cytokines and inter-eukins, thus stimulating the healing process [24]. Hence theres a reasonable justification that honey can enhance phase 3f oral mucositis’ pathogenesis which involves signalling andmplification.

Honey is acidic with a pH ranging from 3.2 to 4.5, whicherves to inhibit the growth of pathogens as the majority thrivest a pH between 7.2 and 7.4 [24,25]. High sugar content ofoney draws water from the wound, reducing the availability ofater to the pathogens, which further impedes microbial growth

26]. It also contains the enzyme glucose-oxidase that stimulateshe release of hydrogen peroxide after contact with body tissue,hich has an antiseptic effect [27,28] and within some types ofoney there are phytochemicals which are known to have bac-ericidal properties [28,29]. These properties may help phase 4ulceration and inflammation) of the biologic process of mucosi-is and thus minimize more severe mucositis and colonizationy oral bacteria and the risk of sepsis.

Honey contains numerous compounds such as organiccids, proteins, aminoacids, minerals, polyphenols, vitamins androma compounds [29] and its composition depends greatlyn the botanical origin [30]. Despite the fact that the contri-ution of honey to the recommended daily intake is small, it canelp head and neck cancer patients undergoing radiation therapynd chemotherapy who suffer from malnutrition and increasedeight loss [31]. Studies have also shown that honey applied toounds reduced and relieved pain, a symptom that accompaniesatients with oral mucositis [21,31,32].

Although several studies explored the effectiveness of honeyn different side-effects, there is a need for further researchooking at the use of honey explicitly for the management ofadiation-induced oral mucositis. This is strengthened by theact that to date, there is only one systematic review by Bardyt al. [31] exploring the use of honey and its potential valueithin oncology care, but it does not fully explore its effective-ess in radiotherapy induced-oral mucositis in head and neckancer patients.

The aim of this study is to retrieve and review the availableandomized Control Trials (RCTs) that have a clear focus on

he effectiveness of honey in the management of radiotherapynduced-oral mucositis in head and neck cancer patients.

aterials and methods

EMBASE, CINAHL, COCHRANE and PUBMED elec-ronic databases were thoroughly searched from 1977 to date.he search was undertaken from January to March 2012 in

rder to identify the articles that met the inclusion and exclusionriteria.

The search strategy was identical for each of these electronicatabases and was undertaken with the use of the following key

nal of Integrative Medicine 5 (2013) 217–225 219

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5 studies included in systematic rev iew

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ords: “clinical trials”; “honey”; “oral mucositis”; “radiationherapy” and “head and neck cancer”.

nclusion/exclusion criteria

The inclusion criteria were as follows: (a) RCTs that useoney as a sole intervention (rinses in oral cavity) or as an adjuncto another standard treatment for the treatment of oral mucositis,b) adult participants (>18+ years old), (c) head and/or neckancer populations, and (d) written in English or Greek language.rticles were excluded if: (a) the trials were in progress, (b)

he trials were published in the form of dissertations, abstracts,ingle case studies, reviews or meta-analyses, (c) the trials didot focus solely on head and neck cancer patients, and (d) oralucositis was not the side-effect of radiotherapy.

alidity assessment

Walji and Boon [33], state that RCTs are widely recognizeds the gold standard for evaluating the efficacy of a new interven-ion or treatment. However, it is common in the literature that theoorly designed RCTs may suffer from methodological prob-ems which impact the quality, generalizability and acceptabilityf their findings. Furthermore, any variations in their method-logical quality can affect the conclusions about the existingvidence [34] and this is the reason why their quality assessmentecomes essential.

As part of the current review, all potentially relevant RCTsere independently read by three authors (MC, AC, VR) andere scored for methodological quality following the JADAD

cale scoring system [35]. This scale assigns points rangingrom poor (=0) to high (=5) methodological quality. The itemsf the JADAD score assess randomization (maximum points:), blinding (maximum points: 2) and reporting of withdrawalsnd dropouts (maximum points: 1) [35]. The decision to usehe JADAD scoring scale lays on the following reasons: TheADAD scale has been adapted for use in many health carereas and it was found to be the most frequently cited and theost commonly used scale by the health care community [36].urthermore, it was tested for construct validity [24], test-retesteliability in different areas and it presented the best validityvidence compared to other scales [35].

earch outcome

The literature search was carried out by the three researchersMC, AC, VR). The researchers screened independently all ref-rences from each database. The total number of referenceserived from the searched strategy was 528 and included stud-es on the general management of radiation-induced mucositisFig. 1). Fifteen articles were retrieved from EMBASE, 18 arti-les from CINAHL, 70 from COCHRANE and another 425 fromUBMED.

Following this, a hand search was performed in all articlesnd their citation list in order to ensure that no relevant articlesere overlooked or duplicated. During this phase 52 studiesere removed due to duplication. All articles went through

a(t

Fig. 1. Flow diagram of reviewed studies.

title screening by the three researchers and the titles thatere irrelevant with the aim of the review were excluded. With

his approach 428 articles were removed and 48 articles wereelected. The selected articles were forwarded to the next phase.heir abstracts were read and checked by the researchers accord-

ng to the inclusion and exclusion criteria. Forty three studiesere excluded during this phase. The full text of the retrieved

rticles was read and examined by the reviewers (MC, AC, VR)o decide whether the information on the topic of interest wasncluded, according to the predefined criteria additionally to aourth reviewer who acted as a moderator (EL). Five articlesere included in the final review (Table 1).

esults

All five trials were published between 2003 and 2011 andere conducted in different countries. All studies used oral

ssessment scales for research data collection with predomi-antly that of Radiation Therapy Oncology Group (RTOG) andhe population examined involved only patients with head andeck cancer. Each study was assessed independently and dataere collected on the clear wording of the purpose, design,

ize and characteristics of the sample, the methodology and theesults. One of the methodological weaknesses identified was themall sample size with the majority being small in both groups20 participants in each group). The total number of participantsncluded in this systematic literature review was 309.

The methodological quality of the majority of the studies

ccording to JADAD score was moderate ranging from 2 to 5Table 1). Although these studies were RCT’S, only 2 out of the 5horoughly discussed how the randomization of the participants

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Table 1List of reviewed studies.

Authors Study design Scales-tools Type of honey Analysis Results JADADscore

[39] • 20 patients in study arm –rinses of 20 ml pure honey before,after and 6 h after radiotherapy

• Clinical andmirror examination ofthe mucosa.

Tea plant(Camelliasinensis)

• Demographic,treatment, morbidityscores – Microsoft-Excelsoftware differencebetween variousparameters was comparedusing chi-squared test

• 16 patients in the s/a showed some form ofradiation mucositis/19 patients in c/a

3

• 20 patients in control arm(without intervention)

• RTOG gradingsystem scale

• Difference in grade 3–4 was 20% in the s/aand 75% in c/a (p < 0.00058)

• The allocation was equallyby computer-generated randomnumbers

• Median mucositis grade was grade 2 in c/aand grade 1 in s/a

[37] • 20 patients in study arm –rinses of 20 ml pure honey before,after and 6 h after radiotherapy

• Clinicalevaluation every weekfor radiation mucositis

Clove (Trifoliumalexandrinum)

• Microsoft-Excelsoftware

• In the s/a no patients developed grade fourmucositis and 3 developed grade three mucositis(15%)/in the c/a 3 patients developed grade fourmucositis and 9 patients developed grade threemucositis (45%)

2

• 20 patients in control arm(without intervention)

(WHO) • Descriptive analysisand Yates correctedchi-square analysis

• 5 c/a patients (25%) was interrupted as aconsequence of radiation mucositis, comparedwith none in the treatment group.

[38] • A single-blinded,randomized controlled trial

• Clinicalevaluation every weekfor radiation mucositis

Forest honey • SPSS Version 11.5was used to performed allstatistical analysis

• In the honey group 1 of 20 developed 3–4mucositis grade and in the lignocaine group 15of 20 patients developed mucositis grade 3–4

• 20 patients in honeygroup(s/a) – rinses of 20 ml purehoney 15′ before and 15′ afterradiotherapy and before going tobed

• RTOG (Gratingsystem)

• Descriptive analysiswas used

• The relative risk of a patient in the testgroup developing mucositis grate 3–4 was0.05/0.75 which is 0.7 or 70%

4

• 20 patients in lignocainegroup (c/a) rinses of 20 mllignocaine gel 15′ before and 15′after radiotherapy and beforegoing to bed

• To determine whetherthere was a statisticallysignificant difference inproportions of patients inthe groups withintolerable mucositis thechi-squared test wasapplied

• The number needed to treat (NNT derivedfrom the inverse of the risk difference) was 1.43,implying that treating 14 patients would benefit10.

• A low relative risk of 0.067 and NNT of1.43 indicated that honey has a strong protectiveeffect in lessening the severity ofradiation-induced oral mucositis

• Honey and lignocaine groups werecompared using the chi-squared test todetermine whether choice of intervention had astatistically significant association with lesssevere mucositis (p = < 0.0001)

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221

Table 1 (Continued)

Authors Study design Scales-tools Type of honey Analysis Results JADADscore

• Honey had a statistically significantassociation with less severe mucositis.

[40] • A single-blinded,randomized controlled trial

• Clinicalevaluation every weekfor radiation mucositis

• Thyme andastragale(Astragalusmembranaceus)

• T-test • In the study group 4 patients (20%) showedno evidence of mucositis during the radiotherapycourse leading to refusal of treatment or takingthe medication

• 20 patients in honey group(s/a) – rinses of 20 ml pure honey15′ before and 15′ afterradiotherapy and 6 h afterradiation

• (OMAS scale) • Mann–Whitney test • The mucositis score of OMAS at the end ofweek in the study group was significantly lowerthan the control group (Mann–Whitney test)(p < 0.001)

3

• 20 patients (c/a) rinses of20 ml saline 15′ before, 15′ afterand 6 h after radiotherapy

• Friedman test • The mucositis score changes for the twogroups during the 6 weeks were compared usingthe Friedman test and showed significantdifferences in the OMAS during the 6 weeks(p < 0.001)

[41] • 130 patients were randomlyallocated by acomputer-generated list ofrandom numbers

• Clinicalevaluation every weekfor radiation mucositisRTOG scale to assessmucositis was used

• Manuka • Chi-squared test withYates’ correction to assessthe significance ofdifferences in the primaryoutcome (the incidence ofgrade 3 or 4 mucositis)between the two arms ofthe trial.

• 127 patients were available for analysis. Thedistribution of oral and oropharyngeal cancersdid not differ significantly between the honeyand the syrup arms, and the diagnostic groupsand treatment regimens were equallyrepresented between the 2 arms.

• 66 patients in active manukahoney group

• The median areasunder the curve werecompared usingWilcoxon’s rank sum test.

• The primary analysis revealed no difference(p = 0.64) in the incidence of grade 3 mucositisbetween AMH 51/64 (80%) and placebo 47/63(75%). There was also no significant difference(p = 0.79) in the severity or duration of mucositisin the AMH group and the golden syrup group

5

• Ninety-eight patients managed at least 1week of the intervention, and 67 patientsmanaged more than 2 weeks. The mediancompliance was 2 weeks (range 1–42 days forboth groups).

• 64 patients in placebo(golden syrup) rinses of 20 ml ofthe allocated substance, and toswallow it slowly, 4 times a dayfor the duration of theradiotherapy (4 weeks) and for 2weeks after treatment (42 days intotal).

RTOG, Radiation Therapy Oncology Group; WHO, World Health Organization; OMAS, Oral Mucositis Assessment Scale.

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as done. One of the studies [37] scored 2 points as it onlyentioned some details about randomization and blinding, 3

tudies had a score equal to 3 or more [38–40] and only onetudy scored 5 [41].

ral mucositis and honey

The main purpose of all RCTs was to evaluate the effective-ess of honey on radiation- induced mucositis. The majority ofhe studies except that of Bardy et al. [41], seem to suggest thatoney can provide a distinct benefit by limiting the severity ofucositis (reduction in grades three and four mucositis) [37,38]

nd a delayed onset of mucositis [39,40].The first single blinded research was conducted by Biswal

t al. [39] in a sample of 40 patients diagnosed with head andeck cancer requiring radiation to the oropharyngeal mucosalrea. Patients were allocated in two arms to either receive radi-tion alone or radiation additionally to topical application of0 ml pure honey three times a day (15′ before radiotherapy,5′ after radiotherapy and 6 h from the time of radiotherapy).he duration of the honey treatment was undertaken throughout

he course of radiation. Patients were assessed weekly for theevelopment of radiation-induced mucositis using the Radia-ion Therapy Oncology Group (RTOG). The results showed thathe number of subjects in the control arm who developed someorm of radiation-induced mucositis was higher than the numbern the intervention arm. The two arms also demonstrated differ-nces on the grade of mucositis. These findings were statisticallyignificant (p < 0.00058).

Motallebnejad et al. [40] assessed the effect of pure naturaloney on radiation-induced mucositis in a sample of 40 patientsivided into two groups. The control group received radiationlus 20 ml of saline rinses before and after radiation and thentervention group received radiation and topical application ofure honey using the same protocol as Biswal et al. [39]. Patientsere evaluated weekly for progression of mucositis using theral Mucositis Assessing Scale (OMAS). The findings pointed

owards a statistically significant reduction in mucositis amonghe patients who received honey compared to the control groupp < 0.001).

Similarly, another RCT study [37] enrolled 40 head and neckancer patients who were randomized to either the treatmentroup to receive concomitant radio-chemotherapy plus topicalpplication of honey, or the control group to receive only theoncomitant radio-chemotherapy. The oral cavity was weeklyssessed for the development of radiation-induced mucositissing the World Health Organization (WHO) oral mucositisrading. The findings of this study showed that honey canarkedly reduce the incidence of radio-chemotherapy-induced

ral mucositis of grade three and four. The significant reduc-ion of oral mucositis in the treatment group strengthens theypothesis that the prophylactic use of pure honey is effec-ive in reducing oral mucositis in head and neck cancer patients

ndergoing radio-chemotherapy.

Another single-blinded RCT was carried out by Khanalt al. [38] and compared the mucositis-limiting qualities ofoney with lignocaine. Subjects were head and neck cancer

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Integrative Medicine 5 (2013) 217–225

atients undergoing radiotherapy and were randomized into tworoups, the intervention group receiving oral rinses of 20 mlure honey three times a day and the control group receivingral rinses of 20 ml lignocaine three times a day. Assessmentsere done according to the RTOG oral assessment scale. The

esults showed that the proportion of patients with intolerableral mucositis was lower in the honey group and this was sta-istically significant (p < 0.001). Therefore, these results suggesthat honey appears to provide a distinct benefit by limiting theeverity of oral mucositis in head and neck patients undergoingadiotherapy.

The last double-blind, placebo-controlled randomized trialssessed the effectiveness of honey on the grade and duration ofadiation-induced oral mucositis [41]. This trial had a high qual-ty score and was the largest study in terms of the sample used131 head and neck cancer patients). Patients were receivingadiotherapy and were randomly allocated to take either 20 mlf manuka honey (n = 67) or 20 ml of placebo (n = 64 goldenyrup), 4 times a day. The assessment of oral mucositis was per-ormed weekly during radiotherapy and twice thereafter until theral mucositis resolved using the RTOG criteria. The study had

poor compliance among the patients receiving honey (medianompliance was 2 weeks) which affected the potential impact ofhe intervention and any safe conclusions drawn on the results.ccording to the researchers, the poor compliance was attributed

o problems with the taste and texture of the products and citedhe effort required to take them as reason for discontinuation.ompliance might have been hampered by the use of the car-

ier (sodium alginate). This trial found no statistical differencesetween the honey and placebo group, failing to show that honeyan ameliorate radiation-induced oral mucositis. These resultsre in contrast with those reported by the other trials in this sys-ematic review which supported that honey had a positive effectn oral mucositis. However, the results demonstrated a notableeduction in the incidence of bacterial infections which can pos-tively influence the onset and severity of oral mucositis. Thisnding should be read in the light of poor compliance and highrop-out rate which were found to affect the potential impact ofhe intervention.

Although most of the results are in agreement with theypothesis that honey can be effective in oral mucositis in headnd neck cancer patients undergoing radiotherapy, most of theCTs were pilot studies which failed to provide valid data on

he effectiveness of honey application.

iscussion

The aim of this review was to critically evaluate the effec-iveness of honey for the management of oral mucositis. Thisystematic review provides encouraging evidence for the role ofoney in the management of oral mucositis for head and neckancer patients undergoing radiotherapy. Previous reviews inther cancer populations support that honey is an effective inter-

ention regarding wound healing, oral pain and oral infectionsesulting from radiation therapy [24–28].

Honey was found to promote faster wound healing, mini-ize scarring tissue, alleviate pain and fight infections [42–45].

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olan [46] and Sela [47] in their studies identified the potentialositive role of explicit properties of honey in oral health. Aommon finding in these two studies supports that the supposedolubility-reducing factor present in honey, which accordingo literature, remains active in the absence of saliva, but wille inactivated by salivary enzymes, gives some support to theypothesis that honey is less cariogenic in dry-mouth subjects47].

The majority of the studies examined have a small numberf individuals in both arms and as a consequence these findingsust be treated with caution as it might have a negative impact on

heir significance (i.e. generalizability). The researchers do notiscuss the rationale underlying the sample sizes and whetherhese had sufficient statistical power.

In these studies the researchers have used different typesf honey and therefore this might have biased the findingseported. The researchers have used Manuka honey [41], forestoney [40], honey from clover (Trifolium alexandrenum) [37]nd tea honey (Camellia sinsesis) [39]. In the study of Khanalt al. [38], the authors only mentioned that the honey was pureithout specifying its’ origin. Different types of honey (i.e. thy-us honey) have fortified specific qualities that may cause a

reater effect on the amelioration of oral mucositis whilst oth-rs (i.e. Manuka honey) can be more effective in wound healing.lthough it has been determined that the antimicrobial and heal-

ng activity of each kind of honey varies [47,48] there are notnough clinical studies that compare or consider the honey’source (i.e. plants origin) as an indicator of its effectiveness. Inight of this aspect, findings are comparable only in those caseshere the same type of honey was tested.In addition to the type, the classification and quality of the

oney must also be taken to consideration. Honey can be sub-ected to a variety of processing methods (i.e. pasteurization),hat determine its classification. Based on these processing meth-ds, honey can be classified as crystallized, pasteurized, raw,trained, ultra filtered, ultrasonicated, whipped, dried, comb andhunk. Only two of the reviewed studies clarified the classifica-ion of honey used [37,39]. In both studies the honey used waslassified as “raw”. This means that the honey was as it existedn the beehive or as obtained by extraction, settling or strainingithout adding heat. The honey was subjected to chemical anal-sis in four out of the five studies [37,39–41] in order to verify itsuality. Particularly, three of the studies [37,39,40] mentionedhat honey subjected to chemical analysis, microbial, pH, den-ity and viscosity measurements while in one was reported thatoney underwent stringent quality control testing [41].

Contrary to the varied types of honey assessed, the protocolsamount and frequency) used by the researchers in the 5 trials isather consistent. This potentially allows for cross-studies com-arisons at least on the basis of the amount and the solutionensity of the honey used in the intervention groups.

Also, notable were the variety of oral mucositis assessmentcales, the frequency and the duration of assessments used in

ach of the reviewed trials. A number of scoring systems haveeen defined to assess the severity of oral mucositis includinghe World Health’s organization scale (WHO) [49], the Nationalancer Institute’s Common Toxicity Criteria (NCI CTC version

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Integrative Medicine 5 (2013) 217–225 223

and 4) [50], the Oral Mucositis Assessment Scale (OMAS)hich has been proposed by Sonis [52] and a scale devised byadiation Therapy Oncology Group (RTOG) [51]. It has becomelear that there is a lack of a definitive technique to appropriatelyeasure oral mucositis. The WHO scale has integrated objec-

ive mucosal changes like redness and ulceration with functionalutcomes like ability to eat. In contrast, NCI CTC scale haseen developed to classify oral mucositis in patients undergoinghemotherapy, radiation therapy and bone marrow transplanta-ion and has common features with RTOG scale. The OMAScale separates objective and subjective findings with primarynd secondary indicators. In the majority of the reviewed stud-es, patients were weekly clinically evaluated in order to detecthe onset or changes in the grade of the developed radiation-nduced mucositis using the RTOG grading system [38,39,41].ther assessment tools used included the World Health Organi-

ation (WHO) oral scale [37] and the OMAS scale [40]. Givenhat the assessment scales used in the reviewed studies were nothe same, any conclusions with regards to the correlations ofheir results or comparisons between the scales should be madeith caution.A related aspect to the assessment tools that emerged from the

eviewed studies was the time period of the oral mucosa assess-ents. The review revealed the variability of the frequency of

he assessments making it difficult to assess the duration or/andnset of any positive effect deriving from the use of honey. Twof the studies [37,39] did not mention the frequency and dura-ion of the oral assessments. In the study of Motallebnejad et al.40] it was reported that all patients were examined weekly upo the end of radiotherapy whereas in the study of Bardy et al.41] oral assessments were undertaken during radiotherapy (4eeks in total) and every 2 weeks thereafter until the mucositis

esolved. Khanal et al. [38] reported that the assessment of oralucositis was done weekly for 6 weeks. Therefore, based on

he findings from this review the effect (if any) of honey on oralucositis is not evident beyond the 6 week period.There is scarcity regarding the details reported on who actu-

lly assessed the patients’ oral cavities during these studies. Inwo studies [37,39] the researchers did not clarify who actuallyarried out the assessments while in the other studies [38,40,41]linded researchers performed the visuals examinations. How-ver, no detailed explanations (i.e. physician, nurse) about theackground of each evaluator were provided. This may havenfluenced the outcome measures and consequently biased thendings placing a thread on the validity of the results.

An aspect that deserves consideration was the doses of radio-herapy, fraction size, volume of irradiated tissue, fractionationcheme and the type of ionizing irradiation (depending on TNMlassification) given to the patients and the areas of the body thatere irradiated. This information is important as these can influ-

nce the degree of acute radiation morbidities like oral mucositis39]. In the studies included in this review, the participantsad oropharynx or oral carcinoma and the radiation protocol

ncluded doses of 50–70 Gy in total. To an extent this allows forhe necessary cross-studies comparisons.

The degree and extent of oral mucositis that develops inach patient appears to depend on factors such as age, gender,

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24 M. Charalambous et al. / European Jour

nderlying systemic disease and race, as well as tissue specificactors [40] Although the effects of patients’ age, cancer stagend gender on the oral mucositis of head and neck cancer areot clear, these are some of the characteristics that have to beollated to this systematic review. In three of the studies [39–41]he mean age of the participants ranged from 54 to 60 years, inne study it was 48 years [39] while one study only mentionedn overall age division which covered > or < 40 years [38]. Apartrom age, the number of male patients seemed outweigh femalesn four out of the five studies. In the study of Khanal et al., thereas no mention about gender. Further, the exact type of cancerf the participants was only reported by Bardy et al. [41] andhilst there is missing information about the stage of cancer forost studies, staging is one of the determinants that can affect

he severity of the radiation-induced oral mucositis.Further to these aspects, most studies investigated the effec-

iveness of honey in patients receiving radiotherapy alone.owever, the review stressed the need for more studies to

xplore honey’s effectiveness in head and neck patients also inases where patients were treated with chemo-radiotherapy. Thiseview has highlighted the need for further high quality random-zed clinical trials especially in head and neck cancer patientsegarding the management of oral complications through com-lementary and alternative means. The results of this systematiceview cannot be compared with other reviews as there are noimilar systematic reviews or meta-analyses focused on headnd neck cancer patients and the effect of honey in the treatmentf oral mucositis.

onclusions

The scarcity of trials in this field and group of patients, theesign, the methodological quality, and the small samples muste taken into consideration before advocating in favour of orgainst honey in the management of radiotherapy-induced oralucositis. The sample sizes were relatively small; while theirethodological quality was medium to low affecting the validity

nd generalization of the results.The majority of studies showed that honey can have a positive

ffect on the management of radiation-induced oral mucositis.t the same time though, this review highlights the need for fur-

her investigation through high quality blinded RCTs regardingoney’s potential value in oncology, especially in head and neckancer patients receiving radiotherapy.

The anti-inflammatory, antimicrobial and healing propertiesf honey enhance the potentially positive effective managementf head and neck cancer patients, as this population is proneo oropharyngeal infections as a result of aggravation of pre-xisting mucositis. The fact that the conventional therapies haveailed to offer a comprehensive and effective management forral complications, calls for studies to support the effectivenessf honey in various cancer populations receiving radiotherapyr chemo-radiotherapy.

onflict of interest

The authors declare that they have no conflicts of interest.

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eferences

[1] American Cancer society. Cancer facts & figures Atlanta: AmericanCancer Society. Available at: http://www.cancer.org./downloads/STT/Cancer-Facts-and-Figures-2010 (accessed 12.04.11).

[2] De Vita Jr V, Lawrence T, Rosenberg S. Cancer: principles & practice ofoncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

[3] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA: A Cancer Journalfor Clinicians 2010;60:277–300.

[4] Scully C, Epstein JB. Oral health care for the cancer patient. Oral OncologyEuropean Journal of Cancer 1996;32B:281–92.

[5] National Comprehensive Cancer Network. Head and Neck Cancers:Clinical Practice Guidelines in Oncology 2011;9(6). Available at:www.NCCN.org

[6] Sonis ST. The pathobiology of mucositis. Nature Reviews of Cancer2004;4:277–84.

[7] Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. Accel-erated fractionation (AF) compared to conventional fractionation (CF).Improve loco-regional control in the radiotherapy of advanced head andneck cancer: results of the EORTC 22851 trial. Radiotherapy and Oncology1997;44:123–36.

[8] McGuire DB, Correa ME, Johnson J, Wienandts P. The role of basicoral care and good clinical practice principles in the management of oralmucositis. Support Care Cancer 2006;14:541–7.

[9] Shieh SH, Wang ST, Tsai ST, Tseng CC. Mouth care for nasopharyngealcancer patients undergoing radiotherapy. Oral Oncology 1997;33:36–41.

10] Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti-inflammatoryagents in themanagement of alimentary mucositis. Support Care Cancer2006;14(6):558–65.

11] Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, TherneauTM, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy.Journal of Clinical Oncology 1991;9:449–52.

12] Barasch A, Peterson DE, Tanzer JM, D’Ambrosio JA, Nuki K, Schu-bert MM, et al. Helium–neon laser effects on conditioning-induced oralmucositis in bone marrow transplantation. Cancer 1995 Dec 15;76(12):2550–6.

13] Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T,et al. Palifermin for oral mucositis after intensive therapy for hematologiccancers. New England Journal of Medicine 2004;351:2590–8.

14] Wyminga AN, van der Graaf WT, Hofstra LS, Spijkervet FKL, Timens W,Timmer-Bosscha H, et al. Phase I study of transforming growth factor-beta3mouthwashes for prevention of chemotherapy-induced mucositis. ClinicalCancer Research 1999;5:1363–8.

15] Foncuberta MC, Cagnoni PJ, Brandts CH, Mandanas R, Fields K, DerigsHG, et al. Topical transforming growth factor-beta3 in the prevention oralleviation of chemotherapy-induced oral mucositis in patients with lym-phomas or solid tumors. Journal of Immunotherapy 2001;24:384–8.

16] Clarkson JE, Worthington HV, Eden OB. Interventions for treating oralmucositis for patients with cancer receiving treatment. Cochrane Databaseof Systematic Reviews 2007:CD001973.

17] Ernst E. Prevalence of use of complementary/alternative medicine: a sys-tematic review. Bulletin of the World Health Organization 2000;78:393–6.

18] Molassiotis A, Fernadez-Ortega, Pud D, Ozden G, Scott JA, Pandeli V,et al. Use of complementary and alternative medicine in cancer patients: aEuropean survey. Annals of Oncology 2005;16:655–63.

19] Simon L, Prebay D, Beretz A, Bagot A, Lobstein A, Rubinstein I, et al.Complementary and alternative medicines taken by cancer patients. Bul-letin du Cancer 2007;94:483–8.

20] Cavanagh D, Beazley J, Ostapowicz F. Radical operation for carcinomaof the vulva. A new approach to wound healing. Journal of Obstetrics andGynaecology of the British Commonwealth 1970;77:1037–40.

21] Chiba M, Idobata K, Kobayashi N, Sato Y, Muramatsu Y. Use of honey toease the pain of stomatitis during radiotherapy. Kangogaku Zasshi JapaneseJournal of Nursing 1985;49:171–6.

22] Smirnova II, Filatova EI, Suvorov AN, Bylinskaia EN. The use of thera-peutic/prophylactic dragee ‘honey laminolact’ in radiotherapy of uterinetumors. Voprosy Onkologii 2000;46:748–50.

nal of

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

M. Charalambous et al. / European Jour

23] Simon A, Sofka K, Wiszniewsky G, Blaser G, Bode U, Fleischhack G.Wound care with antibacterial honey (Medihoney) in pediatric hematology-oncology. Supportive Care in Cancer 2006;14:91–7.

24] Molan PC. Honey as a topical antibacterial agent for the treatment ofeffected wounds. Worldwide wounds available at: http://www.worldwidewounds.com/2001/november/molan/honey-as-topical-agent.html(accessed 11/2001).

25] Stephen-Haynes J. Evaluation of a honey-impregnated tulle dressingin primary care. British Journal of Community Nursing Supplement2004;9:S21–7.

26] Lusby PE, Coombes A, Wilkinson JM. Honey: a potent agent forwound healing? Journal of Wound, Ostomy and Continence Nursing2002;29:295–300.

27] Hyslop PA, Hinshow DB, Scraufstatter IU, Cochrane CG, Kunz S, VosbeckK. Hydrogen peroxide as a potent bacteriostatic antibiotic: implications forhost defense. Free Radical Biology and Medicine 1995;19:31–7.

28] Anderson I. Honey dressings in wound care. Nursing Times2006;102:40–2.

29] White JW. Composition of honey. In: Crane E, editor. Honey. A compre-hensive survey. London: Heinemann Edition; 1975. p. 157–206.

30] Persano Oddo L, Piro R. Main European unifloral honeys: descriptivesheets. Apidologie 2004;35:S38–81.

31] Bardy J, Slevin JN, Mais LK, Molassiotis A. A systematic review of honeyuses and its potential value within oncology care. Journal of Clinical Nurs-ing 2008;17:2604–23.

32] Subrahmanyam M, Sahapure A, Nagane N. Effects of topical applica-tion of honey on burn wound healing. Annals of Burns and Fire Disasters2001;14:143–5.

33] Walji R, Boon H. Redefining the randomized control trial in the contextof acupuncture research. Complementary Therapies in Clinical Practice2006;12:91–6.

34] Verhagen APDE, Vet HC, de Bie RA, Kessels AG, Boers M, KnipschildPG. Balneotherapy and quality assessment: interobserver reliability of theMaastricht criteria list and the need for blinded quality assessment. Journalof Clinical Epidemiology 1998;51:335–41.

35] Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds DJM, GavaghanDJ, et al. Assessing the quality of reports of randomized clinical trials – isblinding necessary? Controlled Clinical Trials 1996;17:1–12.

36] Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ. Scalesto assess the quality of randomized controlled trials: a systematic review.Physical Therapy 2007;88(2):156–75.

37] Rashad UM, Al-Gezawy SM, El-Gezawy E, Azzaz AN. Honey as top-ical prophylaxis against radiochemotherapy-induced mucositis in headand neck cancer. The Journal of Laryngology and Otology 2009;123:

223–8.

38] Khanal B, Baliga M, Uppal N. Effect of topical honey on limitation ofradiation-induced oral mucositis: an intervention study. International Jour-nal of Oral and Maxillofacial Surgery 2010;39:1181–5.

[

Integrative Medicine 5 (2013) 217–225 225

39] Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in themanagement of radiation mucositis: a preliminary study. Supportive Carein Cancer 2003;11:242–8.

40] Motallebnejad M, Akram S, Moghadamnia A, Moulana Z, Omidi S. Theeffect of topical application of pure honey on radiation-induced mucosi-tis: a randomized clinical trial. Journal of Contemporary Dental Practice2008;9:40–7.

41] Bardy J, Molassiotis A, Ryder WD, Kathleen M, Sykes A, Yap P, et al. Adouble-blind, placebo-controlled, randomized trial of active manuka honeyand standard oral care for radiation-induced oral mucositis. Journal of Oraland Maxillofacial Surgery 2011;(3):221–6.

42] English HK, Pack AR, Molan PC. The effects of manuka honey on plaqueand gingivitis: a pilot study. Journal of the International Academy of Peri-odontology 2004;6:63–7.

43] Al-Waili NS. Topical application of natural honey, beeswax and oliveoil mixture for atopic dermatitis or psoriasis: partially controlled, single-blinded study. Complementary Therapies in Medicine 2003;11:226–34.

44] Fox C. Honey as a dressing for chronic wounds in adults. British Journalof Community Nursing 2002;7:530–4.

45] Tahmaz L, Erdemir F, Kibar Y, Cosar A, Yalcyn O. Fournier’s gangrene:report of thirty-three cases and a review of the literature. InternationalJournal of Urology 2006;13:960–7.

46] Molan PC. The potential of honey to promote oral wellness. General Den-tistry 2001;49:584–9.

47] Sela M, Maroz D, Gedalia L. Streptococcus mutans in saliva of normalsubjects and head and neck irradiated cancer subjects after conception ofhoney. Journal of Oral Rehabilitation 2000;27:269–70.

48] Maddocks-Jennings W, Wilkinson JM, Cavanagh HM, Shillington D. Eval-uating the effects of the essential oils Leptospermum scoparium [manuka]and Kunzea ericoides (kanuka) on radiotherapy induced mucositis: arandomized, placebo controlled feasibility study. European Journal ofOncology Nursing 2009;13:87–93.

49] World Health Organization. WHO handbook for reporting the results ofcancer treatment. Geneva, Switzerland: WHO Offset Publications; 1979.p. 15–22.

50] Cox JD, Stetz J, Pajak TF. Toxicity criteria of Radiation Therapy OncologyGroup (RTOG) and European Organization for Research and Treatment ofCancer (EORTC). International Journal of Radiation Oncology, Biology,Physics 1995;31:1341–6.

51] National Cancer Institute. Common Terminology Criteria forAdverse Events (CTCAE) Version4.0 Published: May 28, 2009(v4.03: June 14, 2010) U.S. Department of health and humanser-vices, National Institutes of Health (NIH) Publication No. 09-5410http://evs.nci.nih.gov/ftp1/CTCAE/About.html

52] Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett Jr WH, Mulagha MT,et al. Validation of a new scoring system for the assessment of clinical trialresearch of oral mucositis induced by radiation or chemotherapy. Mucositisstudy group. Cancer 1999;85(10):2103–13.