REVIEWANALYSIS & EVALUATION

ARTICLE TITLE ANDBIBLIOGRAPHICINFORMATION

Systematic review and meta-analysis on the use of honey toprotect from the effects of radiation-induced oral mucositis.

Song JJ, Twumasi-Ankrah P, Salcido R.

Adv Skin Wound Care 2012;25(1):23-8.

REVIEWER

Tim Van den Wyngaert, MD, PhD

PURPOSE/QUESTION

Does the use of topical honeyprevent the occurrence of severeradiation-induced oral mucositis inhead and neck cancer patients?

SOURCE OF FUNDING

Information not available

TYPE OF STUDY/DESIGN

Systematic review with meta-analysis

LEVEL OF EVIDENCE

Level 2: Limited-quality, patientoriented evidence

STRENGTH OFRECOMMENDATION GRADE

Grade B: Limited-quality, patient-oriented evidence

J Evid Base Dent Pract 2012;12:203-2051532-3382/$36.00� 2012 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.jebdp.2012.09.011

Topical Honey Application to ReduceRadiation-Induced Oral Mucositis:ATherapy too Sweet to Ignore?

SUMMARY

Selection CriteriaThe authors performed a systematic review of the literature and meta-analysis of randomized controlled trials investigating the protective effectsof honey on radiation-induced oral mucositis. The MEDLINE, EMBASE, CI-NAHL, and Cochrane databases were queried, excluding non-human stud-ies, non-randomized trials, or studies with patients without head and neckcancers. This search strategy yielded 15 publications, of which 5 trials fulfilledthe selection criteria after careful review. From these, one study was excludedbecause of reporting only pain relief outcomes. The remaining 4 studies hadan identical design, with 20 patients receiving honey rinse therapy. An equalnumber of patients were used as controls and received no intervention in 3 ofthe 4 reports, or were treated with topical lignocaine in one study. However,none of the trials blinded the patients in the control group with the use ofa matching placebo, and only in one study were the assessors unaware ofthe treatment allocation. Patients with systemic illness or prior chemother-apy were excluded in all 4 studies, and prior irradiation was not allowed in3 of the 4 studies. Only one study permitted the use of concurrent chemora-diotherapy. Finally, one additional study was excluded from themeta-analysisbecause it used an averaged mucositis scoring system that could not bepooled with the discrete grading system used in the other 3 trials.

Key Study FactorThe intervention of interest was the use of topical honey before, after, andseveral hours after each session of radiation therapy.

Main Outcome MeasureThe World Health Organization (WHO) or Radiation Therapy OncologyGroup (RTOG) criteria were used for scoring acute oral mucosal toxicity.The WHO system accounts for both anatomical and functional changes(ie, food intake) and is graded on a 5-point scale. The RTOG system alsoconsists of a 5-point scale but only considers anatomical changes. For theoutcome analysis, grades 3 and 4 were considered symptomatic, whereasgrades 0 to 2 were considered non-symptomatic. One excluded studyused the Oral Mucositis Assessment Scale (OMAS), which is based onboth the size of ulceration (scored from 0 to 3) and the size of erythema(scored from 0 to 2), measured at 9 different sites in the oral cavity. Patientswere assessed for up to 7 weeks.

Main ResultsThree of the identified studies with a total of 120 subjects met the inclusionand exclusion criteria. Overall, the pooled relative risk of developing severemucositis was almost 80% lower (risk ratio 0.19; 95% CI 0.098-0.371;P< 0.0001) in patients treated with honey compared to patients in the con-trol groups. This treatment benefit was consistent across the 3 includedstudies, with no apparent heterogeneity other than chance (I2 = 0%;

JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE

P = 0.39). However, an assessment of the risk of bias withinthe individual studies raised important concerns on thesefindings. Indeed, all studies were prone to detection biasdue to the lack of blinding, and 2 of the 3 trials may nothave been free of selection bias because of unclear alloca-tion concealment.

ConclusionsDespite these promising results, the weaknesses of theindividual studies highlight the need for further, morerigorous, randomized controlled trials.

COMMENTARYANDANALYSIS

Severe oral mucositis is an important acute toxicity of ra-diation therapy when used for treating head and neckcancer, with WHO grade 3 or 4 oral mucositis occurringin up to 85% of patients.1 Considering that oral mucositisis the leading reason for treatment interruptions, it isnoteworthy that in a recent review none of the currentguidelines and position statements issued by professionalorganizations were able to provide specific pharmaco-logic interventions for reducing the severity of mucositisin this patient population.2 This lack of clinical practicerecommendations, aside from basic oral hygiene, high-lights the unmet need for effective therapies forradiation-induced oral mucositis.

Within this context, the systematic review and meta-analysis by Song and colleagues provides a useful assess-ment of the evidence on the use of honey as potentiallyinteresting therapeutic agent. Unfortunately, just 4 smallrandomized trials were identified, only 3 of which couldbe used for meta-analysis, and each had importantmethodological concerns that raise questions on the indi-vidual trial’s findings. Even though the meta-analysis in it-self was carefully performed and well reported, thevalidity of the results can be questioned given the verysmall number of study patients (n = 120) and the encoun-tered quality issues regarding study design and conduct.It is equally striking that these limitations appear ubiqui-tous in the field of mucositis research. Indeed, in a recentreview of 30 different interventions to prevent or treatoral mucositis in cancer patients, 11 showed some benefit,but the improvement was often weak, and most studieshad a limited sample size or other fundamental designlimitations.3 In addition, the authors of this review notethat comparing outcomes from different studies was ham-pered by the use of various methods of assessing mucosi-tis. This same difficulty was encountered by Song et al.,who had to drop one of the 4 trials from their analysisfor this reason. Briefly, this study compared the mean ofindividual patient OMAS mucositis scores in preventionand control groups without reporting the proportion ofpatients with severe mucositis in each group, precludinga pooled analysis. However, the confidence intervals ofthe mean scores at each assessment point in both groups

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were reported, allowing calculation of group means andvariances.4 Although Song and colleagues were correctto exclude this study from their analysis, an exploratoryestimate of the proportion of severe mucositis patientsin both groups can be made, assuming a normal distribu-tion of mucositis scores and using an empirical cut-off of20 (out of a theoretical maximum of 45). This would yieldan estimated 1 and 5 patients with severe mucositis in thetreatment and control groups, respectively. With thesenumbers, the resulting relative risk ratio would be 0.20(95% CI 0.03-1.56; P = 0.076), which is nearly identicalto the pooled result reported in the meta-analysis ofSong et al. Therefore, it appears that excluding this onestudy did not alter the estimate of overall benefit ofhoney, with all 4 studies showing a treatment effect of sim-ilar magnitude.

Another important issue raised by the work of Song andcolleagues is the lack of understanding of the mechanismof action by which honey would prevent mucositis. Al-though various hypotheses are explored, including ananti-microbial effect, a better understanding of the activeingredient responsible for the observed effect is requiredto improve clinical trial design, and in particular, creatinga suitable placebo undistinguishable from the active agent.A recent example of mechanism-driven development ofa therapeutic agent to prevent oral mucositis is palifermin,a recombinant human keratinocyte growth factor. In 2 well-designed randomized placebo controlled trials in patientswith head and neck cancer, the incidence of severe oralmucositis was significantly lower for palifermin than forplacebo, both in patients receiving definitive (54% versus69%; P = 0.041) or post-operative (51% versus 67%;P = 0.027) chemoradiotherapy.5,6 However, theseencouraging results did not translate into a reducednumber of treatment interruptions, causing some toquestion the routine use of palifermin in patients withhead and neck cancer.2

In conclusion, it appears that honey is one of manytreatments with some promising evidence of efficacy,but it is currently surrounded with equal amounts ofdoubt and concern due to well-intended but sub-optimally performed clinical trials. Likewise, there is ap-parently no gold-standard treatment that is prominentlybetter over any other. In light of these considerations,the conclusions of Song and colleagues are valid, and un-til more rigorous evidence becomes available, the jury isstill out on the true role of honey in the prevention ofradiation-induced oral mucositis.

REFERENCES

1. Peterson DE, Bensadoun RJ, Roila F. Management of oral and gastro-intestinal mucositis: ESMO Clinical Practice Guidelines. Ann Oncol2011;22(suppl 6):vi78-84.

2. Li E, Trovato JA. New developments in management of oral mucositisin patients with head and neck cancer or receiving targeted anticancertherapies. Am J Health Syst Pharm 2012;69:1031-7.

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JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE

3. Rodriguez-Caballero A, Torres-Lagares D, Robles-Garcia M, Pach�on-Ib�a~nez J, Gonz�alez-Padilla D, Guti�errez-P�erez JL. Cancer treatment-induced oral mucositis: a critical review. Int J Oral Maxillofac Surg2012;41:225-38.

4. MotallebnejadM,AkramS,Moghadamnia A,Moulana Z,Omidi S. Theeffect of topical application of pure honey on radiation-inducedmuco-sitis: a randomized clinical trial. J Contemp Dent Pract 2008;9:40-7.

5. Henke M, Alfonsi M, Foa P, Giralt J, Bardet E, Cerezo L, et al. Palifer-min decreases severe oral mucositis of patients undergoing postoper-ative radiochemotherapy for head and neck cancer: a randomized,placebo-controlled trial. J Clin Oncol 2011;29:2815-20.

6. Le QT, Kim HE, Schneider CJ, Murak€ozy G, Skladowski K, Reinisch S,et al. Palifermin reduces severe mucositis in definitive chemoradio-

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therapy of locally advanced head and neck cancer: a randomized,placebo-controlled study. J Clin Oncol 2011;29:2808-14.

REVIEWER

Tim Van den Wyngaert, MD, PhDAntwerp University HospitalDepartment of Nuclear Medicine, Wilrijkstraat 102650 Edegem, BelgiumPhone: þ32 3 821 34 97; fax: þ32 3 825 33 08tim.van.den.wyngaert@uza.be

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