Interventions for Preventing Oral Mucositis for Patients With

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Interventions for preventing oral mucositis for patients with

cancer receiving treatment (Review)

Worthington HV, Clarkson JE, Eden TOB

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 4http://www.thecochranelibrary.com

Interventions for preventing oral mucositis for patients with cancer receiving treatment (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com/

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Active treatment versus placebo/no treatment, Outcome 1 Mucositis (absent versus present). 96 Analysis 1.2. Comparison 1 Active treatment versus placebo/no treatment, Outcome 2 Mucositis (0-1 versus 2+). . 100 Analysis 1.3. Comparison 1 Active treatment versus placebo/no treatment, Outcome 3 Mucositis (0-2 versus 3+). . 105 Analysis 2.1. Comparison 2 Comparisons between active interventions, Outcome 1 Mucositis (absent versus present). 109 Analysis 2.2. Comparison 2 Comparisons between active interventions, Outcome 2 Mucositis (0-1 versus 2+). . . 110 Analysis 2.3. Comparison 2 Comparisons between active interventions, Outcome 3 Mucositis (0-2 versus 3+). . . 110 Analysis 3.1. Comparison 3 Side effects, Outcome 1 Amifostine. . . . . . . . . . . . . . . . . . . 111

112 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117 WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iInterventions for preventing oral mucositis for patients with cancer receiving treatment (Review)




[Intervention Review]

Interventions for preventing oral mucositis for patients withcancer receiving treatment

Helen V Worthington1, Jan E Clarkson2, Tim OB Eden3

1Cochrane Oral Health Group, MANDEC, School of Dentistry, The University of Manchester, Manchester, UK. 2Dental HealthServices Research Unit, University of Dundee, Dundee, UK. 3 Young Oncology Unit, Christie Hospital NHS Trust, Manchester, UK

Contact address: Helen V Worthington, Cochrane Oral Health Group, MANDEC, School of Dentistry, The University of Manchester,Higher Cambridge Street, Manchester, M15 6FH, UK. [email protected] .

Editorial group: Cochrane Oral Health Group.Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008.Review content assessed as up-to-date: 20 August 2007.

Citation: Worthington HV, Clarkson JE, Eden TOB. Interventions for preventing oral mucositis for patients with cancer receivingtreatment. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD000978. DOI: 10.1002/14651858.CD000978.pub3.


A B S T R A C T

Background

Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain amajor source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers).

Objectives

To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with otherpotentially active interventions, placebo or no treatment.

Search strategy

The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE andEMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information.

Date of most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2).

Selection criteria

Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancerreceiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes -prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life.

Data collection and analysis

Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in dupli-cate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carriedout. The Cochrane Collaboration statistical guidelines were followed and risk ratios (RR) calculated using random-effects models.

1Interventions for preventing oral mucositis for patients with cancer receiving treatment (Review)


mailto:[email protected]

mailto:[email protected]



Main results

Two hundred and seventy-seven studies were eligible. One hundred and eighty-eight were excluded for various reasons, usually asthere was no useable information on mucositis. Of the 89 useable studies all had data for mucositis comprising 7523 randomisedpatients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, antibiotic pastille or paste, benzydamine, betacarotene, calcium phosphate, camomile, Chinese medicine, chlorhexidine, etoposide, folinic acid, glutamine, granulocyte/macrophagecolony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole,pilocarpine, pentoxifylline, povidone, prednisone, propantheline anticholinergic, prostaglandin, sucralfate, systemic antibiotic clar-ithromycin, traumeel, zinc sulphate. Of the 33 interventions included in trials, 12 showed some evidence of a benefit (albeit sometimes

weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysisfinding a significant difference when compared with a placebo or no treatment were:

- amifostine which provided minimal benefit in preventing mild and moderate mucositis RRs = 0.95 (95% confidence interval (CI)0.92 to 0.98) and 0.88 (95% CI 0.80 to 0.98);

- Chinese medicine showed a benefit at all three dichotomies of mucositis with RR values of 0.44 (95% CI 0.20 to 0.96), 0.44 (95%CI 0.33 to 0.59) and 0.16 (95% CI 0.07 to 0.35) for increasing levels of mucositis severity;

- hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52);and

- ice chips prevented mucositis at all levels RRs = 0.64 (95% CI 0.50 to 0.82), 0.38 (95% CI 0.23 to 0.62), and 0.24 (95% CI 0.12to 0.48).

Other interventions showing somebenefitwith onlyone studywere: benzydamine, calcium phosphate,etoposidebolus, honey, iseganan,oral care, zinc sulphate.

The general reporting of RCTs, especially concealment of randomisation, was poor. However, the assessments of the quality of therandomisation improved when the authors provided additional information.

Authors’ conclusions

Several of the interventions were found to have some benefit at preventing or reducing the severity of mucositis associated with cancertreatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specificfor certain cancer types and treatment. There is a need for well designed and conducted trials with sufficient numbers of participantsto perform subgroup analyses by type of disease and chemotherapeutic agent.

P L A I N L A N G U A G E S U M M A R Y

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Several therapies appear to either prevent or reduce the severity of mouth ulcers caused by chemotherapy or radiotherapy for cancer.

Treatment for cancer (including bone marrow transplant) can cause oral mucositis (severe ulcers in the mouth). This can cause

discomfort, pain, difficulties in eating, and a longer stay in hospital. Different strategies are used to try and prevent this condition, andthe review of trials found that some of these may be effective. Four interventions showed some promise. For patients with head andneck cancer these are amifostine and hydrolytic enzymes. For patients undergoing chemotherapy with 5-FU, ice chips may be effective.Chinese medicine was found to be effective on patients with head and neck cancer and other solid cancers.





B A C K G R O U N D

Treatment of solid malignant tumours and the leukaemias withcytotoxic chemotherapy or radiotherapy or both is becoming in-creasingly more effective but it is associated with short and longterm side effects. Among the clinically important acute side ef-fects is the disruption in the function and integrity of the mouth.The consequences of this include severeulceration (mucositis) andfungal infection of the mouth (oral candidiasis, thrush). Thesedisease and treatment induced complications may also produceoral discomfort and pain, poor nutrition, delays in drug admin-istration, increased hospital stays and costs and, in some patients,life threatening infection (septicaemia).

Oral complications remain a major source of illness despite theuse of a variety of agents to prevent them. There are variations in

usage between cancer centres in terms of the mouth care regimenused. Compliance with recommended use of product is variableand there are conflicting reports of the effectiveness of prophy-lactic agents. The qualitative and quantitative benefits, side ef-fects and costs of oral therapies are of importance to the cancerteams responsible for the treatment of patients. Mucositis presentsa particular challenge due to its complex biological nature and therange of interventions tested have targeted specific pathways andinclude mucosal surface protectants, anti-inflammatory, antimi-crobials, growth factors and agents difficult to classify.

There have been several traditional reviews published and mostof these present a general discussion for both chemotherapy and

radiotherapy induced oral side effects ( Andreassen 2003; Chang2003; De Pauw 1997; Denning 1992; Duncan 2003; Lortholary 1997; Savarese 2003; Stevens 1995; Symonds 1998; Verdi 1993;

White 1993).Theconclusionsdrawnandrecommendationsmadevary from advocating a particular therapy to recommending oralcareprocedures thathavenot beensystematically investigated.Twosystematic reviews have focused on the prevention of oral mucosi-tis in patients with cancer. One older review published in 1998concluded that for most strategies reviewed there is insufficientevidence to draw any conclusions regarding their effectiveness (Kowanko 1998).Theothermorerecentreviewfocusedonpatients

with head and neck cancer only and the main analysis combinedall the interventions in one meta-analysis and found a beneficial

effect of prophylactic interventions (Sunderland 2001). Since theprevious update of this review the most significant developmenthas been the publication of a review of evidence and developmentof clinical practice guidelines by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer andthe International Society for Oral Oncology (Rubenstein 2004;Sonis 2004). This undertaking highlights the importance of thissubject within the profession but also the potential for duplicationof effort internationally. This was highlighted further in a review looking at the prevention of mucositis in patients with head andneck cancer undergoing radiotherapy or chemotherapy or bothpublished in 2006 which failed to reference this Cochrane review (Stokman 2006).

A previous version of this Cochrane review looked at the use of

oral and prophylactic agents for the prevention of oral mucositisand oral candidiasis in patients with cancer treated by chemother-apy (Clarkson 2000). The review concluded that there was someevidence that using ice chips during the chemotherapy treatment

was effective in preventing mucositis. The review was updated in2003 (Clarkson 2003a) and this update broadened the oral mu-cositis part of the initial review and looked at the prevention of oral mucositis in patients receiving any treatment for cancer, in-cluding patients with all types of cancer, including head and neck cancer, and including comparisons between any interventions forprevention. A second review update was carried out in 2006 (

Worthington 2006) and reviews on the prevention of oral can-didiasis has also beenpublishedin The Cochrane Library (Clarkson

2007a; Worthington 2004a). These reviews form part of a se-ries of four Cochrane reviews on the prevention and treatment of oral mucositis and oral candidiasis (Clarkson 2007b; Worthington2007).

O B J E C T I V E S

To evaluate the effectiveness of interventions (which may includeplacebo or no treatment) for the prevention of oral mucositis inpatients with cancer receiving chemotherapy or radiotherapy orboth.

The following primary null hypothesis was tested for comparisonsbetween groups receiving interventions to prevent oral mucositisduring cancer treatment:

There is no difference in the proportion of patients acquiring oralmucositis during cancer treatment.

In this review we proposed to address the hypothesis of no differ-ence between groups treated for oral mucositis for the followingoutcomes if data were available and provided there was a signifi-cant benefit based on three or more trials or one trial with morethan 100 participants, otherwise we would record outcomes re-ported:

• Relief of pain/use of analgesia

• Duration or severity of dysphagia and the use of parenteralnutrition or feeding tube

• Incidence of infection

• Treatment interruption

• Days of stay in hospital

• Toxicity

• Cost of care

• Patient quality of life





• Death

• Weight loss.

The following subgroup analyses were proposed:

• Cancer type (leukaemia, head and neck, other solidtumours and mixed)

• Cancer treatment (specific, for example 5-fluorouracil (5-FU))

• Age group (adults, children or both).

M E T H O D S

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials (RCTs) were eligible for inclu-sion in this review, including both cross-over and parallel groupstudies.

Types of participants

Anyone with cancer who received chemotherapy or radiotherapy or both.

Types of interventions

(This review did not include studies of different cancer treatments when the primary outcome was survival or cure with mucositis asa toxicity.)

Active agents: any agent prescribed prophylactically for oral mu-cositis.

Control: may be placebo or no treatment, or another active inter-vention.

Types of outcome measures

Primary outcome

• Mucositis (at all levels of severity) (ulcers). Mucositismeasured on a 0 to 4 point scale (none to severe) was used andthis was dichotomised as 0 versus 1+, 0 to 1 versus 2+, 0 to 2versus 3+.

Secondary outcomes

• Relief of pain/use of analgesia• Duration or severity of dysphagia and the use of parenteral

nutrition or feeding tube• Incidence of infection• Treatment interruption• Days of stay in hospital• Toxicity • Cost of care• Patient quality of life• Death• Weight loss.

Search methods for identification of studies

This review is part of a series of four reviews on the preventionand treatment of oral candidiasis and oral mucositis in patients

with cancer, and the same search strategies were used for all fourreviews.The searches attempted to identify all relevant trials irrespectiveof language. Papers not in English were translated by members of The Cochrane Collaboration.Electronic searching - the databases searched were:Cochrane Oral Health Group Trials RegisterPain, Palliative Care, and Supportive Care (PaPaS) Group Trials

RegisterCochrane Central Register of ControlledTrials (CENTRAL) (The Cochrane Library 2006, Issue 2)MEDLINE (from 1966) and MEDLINE Pre-indexedEMBASE (from 1980)CINAHLCANCERLIT via PubMedSIGLE (1980-2003) (no longer have access)LILACS.Sensitive search strategies were developed for each database usinga combination of free text and MeSH terms. These are describedin detail in Appendix 1; Appendix 2; Appendix 3; Appendix 4;

Appendix 5; Appendix 6; Appendix 7; and Appendix 8.

Only handsearching carried out by The Cochrane Collaborationis included in the search (see master list www.cochrane.org).The controlled trials database ( www.controlled-trials.com) wasalso searched to identify ongoing and completed trials and to con-tact trialists for further information about these trials.The reference list of relatedreview articles and all articles obtained

were checked for further trials. Authors of trial reports and spe-cialists in the field known to the review authors were written toconcerning further published and unpublished trials.The review will be updated every 2 years using the CochraneOralHealth Group TrialsRegister, CENTRAL, MEDLINE, EM-BASE, CINAHL, CANCERLIT, SIGLE, and LILACS.Date of most recent searches June 2006:



http://www.cochrane.org/

http://www.controlled-trials.com/



http://www.cochrane.org/



CENTRAL (The Cochrane Library 2006, Issue 2)

MEDLINE, EMBASE, CINAHL, LILACS (limit 2004-2006(June)).

Data collection and analysis

The titles and abstracts (when available) of all reports identifiedthrough the searches were scanned by two review authors (He-len Worthington (HW) and Jan Clarkson (JC)). Full reports wereobtained for trials appearing to meet the inclusion criteria, orfor which there was insufficient information in the title and ab-stract to make a clear decision. The full reports obtained from all

the electronic and other methods of searching were assessed inde-pendently, in duplicate, by these two review authors to establish whether the trials met the inclusion criteria or not. Disagreements were resolved by discussion.The quality assessment of included trials was undertaken indepen-dently and in duplicate by two review authors as part of the dataextraction process. Included trials were assessed on three criteria:concealed allocation of treatment (A = adequate, B = unclear, C= inadequate); blinding of patients (0 = no, 1 = yes, 2 = unclear),carers and outcome assessors (0 = no, 1 = yes, 2 = unclear); andinformation on reasons for withdrawals by trial group (0 = no, 1= yes). The agreement between the review authors was assessed by calculating the kappa score.

Risk of bias was assessed for each study. Studies were consideredto be at low risk of bias if there was adequate concealment of allocation, blinded outcome assessment and information on thereason for withdrawals provided by trial group. If one of thesecriteria werenot met a study would be considered at moderate risk of bias, otherwise at high risk of bias.Data were extracted by two review authors independently usingspecially designed data extraction forms. The characteristics of thetrial participants, interventions andoutcomes in the included trialsare presented in the study tables. Mucositis may be dichotomisedat different levels of severity. In order to maximise the availability of similar outcome data we recorded the number of patients ineach category of mucositis. We planned to form three dichotomies

of mucositis: absent versus present (0 versus 1+), mild versus mod-erate/severe (0 to 1 versus 2+) and moderate versus severe (0 to 2versus 3+). Pain was assessed on visual analogue scales (0 to 100),the means and standard deviations for each group were recorded.The duration of trials and timing of assessments were recorded inorder to make a decision about which to include for commonality.

We also recorded the country where the trial was conducted and whether a dentist was involved in the investigation. Some of theauthors were contacted for clarification or for furtherinformation.

Data synthesis

For dichotomous outcomes, the estimates of effect of an interven-

tion were expressed as risk ratios together with 95% confidenceintervals.

We planned to investigate clinical heterogeneity by examining thedifferent cancer types and age groups, however there were insuf-ficient trials looking at the same intervention to undertake this.Meta-analyses were done only with studies of similar compar-isons reporting the same mucositis outcome measures. Risk ratios

were combined for dichotomous data using random-effects mod-els. The significance of any discrepancies in the estimates of thetreatment effects from the different trials was assessed by meansof Cochran’s test for heterogeneity and quantified by I2 statistics.

Cross-over trialsItis possible to conduct cross-over trials in this area as patients may be receiving several chemotherapy sessions, any mucositis com-pletely healing in the periods between the sessions. The treatmenteffects from cross-over trials were combined with those from par-allel group trials where appropriate, using the data from both peri-ods of the cross-over studies (Elbourne 2002). The generic inversevariancemethodincorporatedin RevMan wasusedfor all analyses.

Where data for the cross-tabulation of pairs were not available, allpossible paired comparisons for each study were calculated, givingrise to the same risk ratios values with different confidence inter-vals. The widest confidence interval was used in the analysis.It was planned to undertake a sensitivity analysis to examine the

effectofriskofbiasontheoverallestimatesofeffect.Howeverthere were insufficient trials for any specific intervention to undertakethis.

We proposed a priori to conduct subgroup analyses for differentcancer types (leukaemia, head and neck, other solid tumours andmixed), cancer treatment (for example 5-fluorouracil (5-FU)) andage groups (children, adults and both). However there were insuf-ficient trials by intervention type to do this.

R E S U L T S

Description of studies

See: Characteristicsof includedstudies; Characteristicsof excludedstudies; Characteristics of ongoing studies.

Characteristics of the trial settings and investigators

See Characteristics of included studies table.See Characteristics of excluded studies table.There were 277 trials eligible for inclusion in the review. Onehundred and eighty-eight of these trials were excluded for thefollowing reasons:





• Abstracts and reports giving insufficient information (58trial reports: Adamietz 1997; Antonadou 1998; Bensadoun1995; Buentzel 1999; Calais 1998; Collova 2004; Colombat1995; Costa 1999; Crawford 1994; Crispino 1997; Cruz 1997;Epstein 1999; Etiz 1998; Evans 1990; Ferretti 1985; Gabison1995; Goldberg 2003; Gujral 1999; Harris 1995; Hartmann1999; He 2004; Kante 1995; Klocke 2006; Labar 1990; Leong1995; Levendag 1998; Lozada 1998; Marcial 1994; Merte 1999;Minn 1999; Okuno 1998; Papas 1984; Peterson 2003; Pfeiffer1989; Porta 1994; Pouli 1999; Radmard 2002; Robustelli 1999;Scarantino 2001a; Scarantino 2001b; Schwerkkoske 1999;Spadaro 1991; Staar 2001; Su 2004a; Su 2004b; Suc 1999;Svanberg 2004; Symonds 1995; Teshima 1986; Throuvalas

1995; Valcárcel 1997; Valcarcel 2002a; Valcarcel 2002b; Vesole1999; Vitello 2000; Wagner 2002; Wymenga 1999a; Zalcberg1995)• Mucositis data presented in the form of mean scores, which

were not in an appropriate form for this review (24 trial reports: Apaydin 1996; Barasch 1995; Bensadoun 1999; Braaksma 2002;Cowen 1997; Dudjak 1987; Epstein 1989; Epstein 1992;Epstein 1994; Etiz 2000; Feber 1996; Grotz 2001; Hanson1997; Jebb 1995; Kenny 1990; Lievens 1998; Lopez 1994;McGaw 1985; Prada 1985; Raether 1989; Rutkauskas 1993;Samaranayake 1988; Verdi 1995; Weisdorf 1989)• Mucositis data not in appropriate form for other reasons

than that given above (21 trial reports: Anderson 1998b; Cella

2003; Cheng 2004a; Chi 1995; Decker-Baummann 1999;Epstein 1986; Epstein 2001; Evensen 2001; Ferreira 2002;Ferreira 2004; Hanson 1995; Lin 2006; Loprinzi 1997;Mantovani 2003; Nicholl 1995; Niibe 1985b; Piccirillo 2003;Pytlik 2002; Vacha 1999; Vacha 2003; Weiss 1990)• Data presented as episodes rather than patients, where

patients were re-entered into the study, so data not independent(six trials: Awidi 2001; Hickey 1982; Karthaus 1998; Lorusso2003; Mahmoud 1996; Rojas 2001)• Major change to protocol half way through study (one trial:

Okuno 1997)• No recruitment (one trial: Kasten-Sportes 2003)• Comparing different cancer treatments including

radiotherapy regimens (17 trials: Andersen 1987; Ardizzoni2002; Awada 2002; Awwad 2002; Bensadoun 2006; Bentzen2001; Bleehen 1996; Bourhis 2006; Cassidy 2002; Cunningham1995; De Boer 2002; Denham 1999; Dobrowsky 1998;Doroshow 1987; Falcone 2001; Giles 2003b; Levi 1997)• Qualitative assessment of mucositis (one trial: McIlroy

1996)• Randomised controlled trial (RCT) design fault (four trials:

Antin 2002; Cheng 2003; Cheng 2004b; Erkisi 1996)• Not RCT (38 trials: Altmann 1999; Awada 2004; Calais

2004; Cheng 2001; Cheng 2002; Costa 2003; Edelman 1998;Eisen 2003; El-Sayed 2000; El-Sayed 2002b; Fahlke 1999; Fay 1994; Foncuberta 2001; Gutierrez 1996; Howell 1983; Hu

2003; Ito 2002; Johnson 2002; Labbate 2003; Madero 1999;

Malaker 1991; Matejka 1990; Mills 1995; Okutomi 2000; Peters1993; Phillips 2002; Sato 1997; Stokman 2004; Sykes 2004;Thieblemont 2002; Toubai 2003; Uchiyama 2005; Wang2002b; Whelan 2002; Whelan 2004; Wollina 2002; Wymenga1999b; Yokomizo 2004)• No useful outcomes (nine trials: Aquino 2005; Bergmann

1995; Feber 1995; Kokkonen 2002; Ohnmacht 2001; Rades2004; Rocci 2005; van Zaanen 1994; Warde 2002)• Mucositis not primary outcome (five trials: Bolwell 2004;

Calais 2000; Ezzat 2005; Pyrhonen 1995; Rabinovitch 2006)• Some mucositis present at baseline (two trials: Djuric 2006;

Masucci 2005)• Design flaw (one trial: Nikoletti 2005).

Of the 89 included trials83 were designed as parallel group studiesand six as cross-over studies ( Anderson 1998; Dozono 1989; Jebb1994; Loprinzi 1990; Mahood 1991; Pfeiffer 1990). None of thepublished reports gave the ’paired’ data in an appropriate formto be used in a meta-analysis. All the authors were contacted andreplies were received supplying data for three studies ( Anderson1998; Loprinzi 1990; Mahood 1991). Other data had to be ex-tracted as outlined in the methods section.Ofthe 89includedtrials allincludeddataon assessment of mucosi-tis. Seventy-four (83%) of the 89 included trials were conductedat a single site. Thirty of these trials were conducted in Europe,24 in the USA, three in both China and Japan, two in Canada,

India and Israel and one in each of the following countries: Ar-gentina, Hong Kong, Malaysia, Mexico, Singapore, South Africa,Taiwan and Uruguay. The remaining 15 trials were multicentrestudies. Five of these were conducted in the USA (Freytes 2004;Giles 2004; Meropol 2003; Scarantino 2006; Spielberger 2004),three in the USA and European countries (Brizel 2000; Buentzel2006; Giles 2003a), two in the USA and Canada (Foote 1994;Nemunaitis 1995), two in European countries alone (Castagna2001; Vokurka 2005) and one in the USA, Canada and Europe (Trotti 2004), one in Australia (Spencer 2005) and one in Canada (El Sayed2002a). Fifty (56%) trials received external funding, withthis being unclear ina further22 (25%) trials and with no externalfunding evident in 17 (19%) trials. A dentist was involved in 21

(24%) of the trials and in 11 (12%) trials the patient was involvedin the clinical outcome measure, eight of these being placebo con-trolled.

Characteristics of the participants

Seventy-eight (88%) of the included trials recruited only adult pa-tients, nine included both adults and children (with a differencein age as large as 1 to 70 years) and only one trial was conductedsolely on paediatric patients (Shenep 1988), the age group beingunclear in one trial (Mahood 1991). The type of cancer for whichpatients were being treated was exclusively head and neck cancerin 41 trials (56%), leukaemia in six trials, solid tumours in 15





trials and a combination of haematological and solid tumours in

22 trials, the cancer type being unclear in five trials. The radio-therapy and/or chemotherapy regimen was described in most of the trials though the chemotherapeutic agents were not alwaysdescribed in full detail. Twenty-two trials included patients who

were undergoing a bone marrow transplant. The chemotherapy regimen included 5-fluorouracil (5-FU) in 11 trials, in eight of these the patients had solid tumours, and in three trials the cancertype was unclear. It was not always clear if the dose was in a bolusor continuous form. Trials in which patients received radiother-apy generally gave information about the total and daily or weekly dose. Total radiotherapy for head and neck cancer was generally 60 to 74 Gy and the Karnofsky performance > 60.

Characteristics of the interventions

All of the 89 trials provided a clear description of theinterventionsincluding the dose and method of administration for the test andcontrol groups. The dosage of the test agents varied for similarproducts. Eighty-four trials used either a placebo (57 trials), or ano treatment control (27 trials). A true placebo was not alwaysused, and the following interventions were used and described asplacebo: water, albumin, glycine, sugar solution, polycal, saline.Two trialsincludedin the no treatment controlgrouptesteddiffer-ent oral care protocols and in each case one group received limitedoral hygiene (Borowski 1994; Shieh 1997). Two trials comparedChinese medicine to a control described as Dobell’s solution (

Huang 2003; Wang 2002a). Four trials compared two active inter-ventions: ice chips sucked for different time periods (30 minutesversus 60 minutes) (Rocke 1993), etoposide (bolus versus contin-uous infusion) (Damon 2004), granulocyte/macrophage colony-stimulating factor (GM-CSF) versus sucralfate (Saarilahti 2002),and keratinocyte (50 mg versus 25 mg) (Freytes 2004).The interventions for the 89 studies assessing oral mucositis were:

• acyclovir (Bubley 1989)• allopurinol mouthrinse (Dozono 1989; Loprinzi 1990)• aloe vera (Su 2003)• amifostine ( Antonadou 2002; Bourhis 2000; Brizel 2000;

Buentzel 2006; Buntzel 1998; Hartmann 2001; Hwang 2004;

Karacetin 2004; Koukourakis 2000; Niibe 1985; Spencer 2005)• antibiotic pastille or paste (El Sayed 2002a; Stokman 2003;

Symonds 1996; Trotti 2004; Wijers 2001)• benzydamine (Prada 1987)• beta carotene (Mills 1988)• calcium phosphate (Papas 2003)• camomile (Fidler 1996)• Chinese medicine (details of herbs used is given in

’Characteristics of included studies’ table) (Huang 2003; Wang2002a)• chlorhexidine (Dodd 1996; Ferretti 1988; Ferretti 1990;

Foote 1994; Pitten 2003; Spijkervet 1989; Wahlin 1989)• etoposide (Damon 2004)

• folinic acid (Erlichman 1988)

• glutamine ( Anderson 1998; Cerchietti 2006; Dickson2000; Huang 2000; Jebb 1994; Okuno 1999)• GM-CSF (Cartee 1995; Crawford 1999; Dazzi 2003; Ifrah

1999; Katano 1995; Makkonen 2000; Nemunaitis 1995;Saarilahti 2002; Schneider 1999; van der Lelie 2001)• histamine gel (Elad 2006)• honey (Biswal 2003)• hydrolytic enzymes (Gujral 2001; Kaul 1999)• ice chips (Cascinu 1994; Lilleby 2006; Mahood 1991;

Rocke 1993)• iseganan (Giles 2003a; Giles 2004; Trotti 2004)• keratinocyte GF (Freytes 2004; Meropol 2003; Spielberger

2004)• misonidazole (Lee 1989)• oral care (Borowski 1994; Shieh 1997; Trotti 2004)• pilocarpine (Lockhart 2005; Scarantino 2006)• pentoxifylline ( Attal 1993)• povidone (Rahn 1997; Vokurka 2005)• prednisone (Leborgne 1997)• propantheline anticholinergic ( Ahmed 1993)• prostaglandin (Duenas 1996; Labar 1993; Pillsbury 1986)• sucralfate (Carter 1999; Castagna 2001; Cengiz 1999;

Franzen 1995; Makkonen 1994; Nottage 2003; Pfeiffer 1990;Saarilahti 2002; Scherlacher 1990; Shenep 1988)• systemic antibiotic clarithromycin ( Yuen 2001)• traumeel (Oberbaum 2001)• zinc sulphate (Ertekin 2004).

Characteristics of outcome measures

Mucositis

All trials used a graded scale to record the severity of mucositis.Most described the index used or referred to published criteria,mainly World Health Organization (WHO) or European Orga-

nization for Research and Treatment of Cancer (EORTC). Scales were similar to the 5-point WHO scale ranging from 0 (normal)to 4 (severe). The categories initially relate to visible changes inthe mucosa and gradually record pain and inability to eat solidfoods. Forty-six studies provided information for an absent versuspresent dichotomy, 42 trials provided information dichotomisingat grade 1 and 49 trials dichotomising at grade 2. The duration of the trials varied from a few days up to a year after treatment. Theinterval during which mucositis was recorded varied from 5 to 90days or until the end of the radiotherapy, or the leukocyte count

was above 8000 mm³. Several studies presented data at differenttime points, with the median time point being 28 days. The near-est assessment to 28 days was used for all studies.





Secondary outcomes

There was little consistency on the other outcome measures re-ported:

• Oral hygiene measures (Borowski 1994; Lockhart 2005; Wahlin 1989)

• Relief of pain/use of analgesia (morphine) ( Attal 1993;Carter 1999; Cengiz 1999; Cerchietti 2006; Dazzi 2003; ElSayed 2002a; Ertekin 2004; Ferretti 1988; Franzen 1995; Freytes2004; Giles 2003a; Giles 2004; Karacetin 2004; Lilleby 2006;Lockhart 2005; Makkonen 2000; Nottage 2003; Papas 2003;Pfeiffer 1990; Saarilahti 2002; Scarantino 2006; Spencer 2005;Spielberger 2004; van der Lelie 2001; Vokurka 2005; Wijers2001)

• Duration or severity of dysphagia ( Antonadou 2002;Bourhis 2000; Buntzel 1998; Cengiz 1999; Franzen 1995;Freytes 2004; Giles 2003a; Giles 2004; Gujral 2001; Pfeiffer1990; Prada 1987; Scarantino 2006; Spielberger 2004; Symonds1996)• Use of parenteral nutrition or feeding tube (Bourhis 2000;

Carter 1999; Cerchietti 2006; Damon 2004; Dickson 2000;Lilleby 2006; Spencer 2005; Spielberger 2004; Yuen 2001)• Incidence of systemic infection or use of antibiotics ( Attal

1993; Borowski 1994; Crawford 1999; Ferretti 1990; Shenep1988; van der Lelie 2001; Yuen 2001)• Febrile episodes ( Ahmed 1993; Attal 1993; Borowski 1994;

Duenas 1996; Giles 2003a; Hwang 2004; Katano 1995; Labar

1993; Shenep 1988; Spielberger 2004; van der Lelie 2001;Vokurka 2005; Wahlin 1989; Yuen 2001)• Blood changes ( Ahmed 1993; Antonadou 2002; Buntzel

1998; Cartee 1995; Crawford 1999; Meropol 2003; Saarilahti2002; van der Lelie 2001)• Treatment interruption ( Antonadou 2002; Carter 1999; El

Sayed 2002a; Makkonen 1994; Saarilahti 2002; Trotti 2004 )• Days of stay in hospital ( Attal 1993; Cerchietti 2006;

Damon 2004; Dickson 2000; Duenas 1996; Lilleby 2006;Saarilahti 2002; van der Lelie 2001)• Toxicity - nausea/vomiting/constipation/diarrhoea (

Antonadou 2002; Bourhis 2000; Brizel 2000; Buentzel 2006;Castagna 2001; Cengiz 1999; Dickson 2000; Duenas 1996; El

Sayed 2002a; Freytes 2004; Hartmann 2001; Hwang 2004;

Karacetin 2004; Labar 1993; Lee 1989; Meropol 2003; Nottage2003; Shenep 1988; Spencer 2005; Yuen 2001)• Toxicity - skin changes (Bourhis 2000; Buntzel 1998; Giles

2004; Gujral 2001; Karacetin 2004; Lee 1989 (numbness);Shenep 1988; Spielberger 2004; Yuen 2001)• Toxicity - unspecific (Buentzel 2006; Cerchietti 2006;

Damon 2004; El Sayed 2002a; Fidler 1996; Giles 2003a; Giles2004; Karacetin 2004; Makkonen 1994; Makkonen 2000;Okuno 1999)• Xerostomia (Brizel 2000; Buentzel 2006; Buntzel 1998;

Cengiz 1999; Karacetin 2004; Lockhart 2005; Scarantino 2006)• Cost (Dodd 1996, Hartmann 2001)• Patient quality of life (Nottage 2003)• Death ( Ahmed 1993; Attal 1993; Brizel 2000; Buentzel

2006; Damon 2004; Ferretti 1988; Labar 1993; Makkonen2000).• Weight loss/gain (Biswal 2003; Cerchietti 2006; El Sayed

2002a; Lilleby 2006; Nottage 2003; Stokman 2003)• Caloric intake by oral nutrition (Castagna 2001; Freytes

2004; Lilleby 2006)• Eating/drinking difficulty (Lockhart 2005; Nottage 2003;

Stokman 2003)• Overall health (Su 2003)• Recurrence of cancer (Buentzel 2006; Cerchietti 2006;

Damon 2004; Spencer 2005).

Risk of bias in included studies

There was excellent agreement between the scores assigned by the two review authors, with kappa values for concealment 0.88,patient blind 0.85, carer blind 0.90, outcome assessor blind 0.68and clear description of withdrawals 0.72.The results of the quality assessment for concealment of randomi-sation, blindingof outcome assessor andwhether there is a clear ex-planation of drop outs by study groupare given in Additional Table1, using the criteria outlined in the methods section. Changes inthe quality assessment due to information from authors are shownby putting the initial assessment in parenthesis.

Table 1. Quality assessment of trials

Study Concealed alloca-

tion

Outcome blinded Explanation of

drop outs

Risk of bias Withdrawals %

Ahmed 1993 B yes yes M 0

Anderson 1998 B yes yes M 46

Antonado 2002 B no yes H 10













2002a) and we wrote to/e-mailed 17 authors requesting further

information. All authors replied and data were supplied by onetrialist (Damon 2004). Of the 17 replies six changes were madefor the allocation concealment from uncertain to adequate. Fiveauthors clarified that the providerwasblinded, one author clarifiedthat the outcome assessor was blinded, and two authors clarified

withdrawals.

We assessed each study for risk of bias and 33% of trials weredeemed at low risk of bias, 32% at medium risk of bias and 36%high risk of bias (Additional Table 1).

Effects of interventions

Two hundred andseventy-sevenreports of trials wereinitiallyiden-tified as eligible according to the defined criteria for study design,participants, interventions and outcomes. The total number of included trials was 89, there were 10 duplicate reports and 188studies were excluded, as the data presented were not in an acces-sible form for this review. See Characteristics of excluded studiestable for further information on this.Of the 89 included studies all had data for mucositis appropriatefor this review comprising 7523 randomised patients.The results section presents the results relatingto each interventionin alphabetical order.

• Acyclovir versus placebo (Comparison 1, Outcome 1.1)

One trial compared acyclovir with a placebo (Bubley 1989). Data

wereprovidedforthedichotomyofmucositisabsentversuspresent(0 versus 1+). No statistically significant differences were foundand therefore there is insufficient evidence to support or refuteacyclovir as more or less effective than placebo.

• Allopurinol versus placebo/no treatment (Comparison 1,Outcome 1.1)

Two trials, both designed as cross-over studies, compared allopuri-nol mouthrinse with placebo or no treatment and had data for themucositis absent versus present (0 versus 1+) dichotomy (Dozono1989; Loprinzi 1990). This pooled meta-analysis was non-signif-icant.

• Aloe vera versus placebo (Comparison 1, Outcome 1.2)

One trial (Su 2003; n = 58) compared aloe vera with placebofor the mild versus moderate/severe mucositis (0 to 1 versus 2+)dichotomy. No statistically significant difference was found andtherefore there is insufficient evidence to support or refute aloevera as more or less effective than placebo.

• Amifostine versus placebo/no treatment (Comparison 1,Outcomes 1.1 to 1.3)

Eleven trials compared amifostine with a placebo (Buentzel 2006;Niibe 1985 ) or no treatment ( Antonadou 2002; Bourhis 2000;Brizel 2000; Buntzel 1998; Hartmann 2001; Hwang 2004;

Karacetin 2004; Koukourakis 2000; Spencer 2005). All trials re-

cruited adults with head and neck cancer being treated with ra-diotherapy. Seven trials provided data for mucositis at the level of absent versus present (0 versus 1+), five with estimable data be-cause every patient experienced mucositis in the other two. There

was a significant benefit for amifostine preventing mucositis inthis trial with risk ratio (RR) = 0.95 (95% confidence interval (CI)0.92 to 0.98, chi squared = 3.03, degrees of freeom (df) = 4, P= 0.55, I2 = 0%). At the dichotomy mild versus moderate/severemucositis (0 to 1 versus 2+) eight trials provided homogeneousdata demonstrating amifostine as more effective than placebo orno treatment at preventing moderate/severe mucositis RR = 0.88(95% CI 0.80 to 0.98, chi squared = 9.17, df = 7, P = 0.24, I 2

= 24%). Ten trials provided data for the dichotomy of mucositis

moderate versus severe (0 to 2 versus 3+) and the pooled meta-analysis was on the borderline of significance RR = 0.70 (95% CI0.49 to 1.00, chi squared = 26.6, df = 9, P = 0.0006, I2 = 69%),

with significant heterogeneity. This indicates that amifostine may prevent and reduce the severity of oral mucositis in adults withhead and neck cancer treated with radiotherapy. This is based onevidence from 11 trials with 845 participants. In five of the trialsthe allocation concealment was adequate, two had a blinded out-come assessment (Buentzel 2006; Niibe 1985) and eight had anadequate explanation of withdrawals, with withdrawals across the11 trials ranging from 0% in six trials to 21% in one trial.

• Antibiotic pastille or paste versus placebo (Comparison 1,

Outcomes 1.1 to 1.3)Three trials compared antibiotic pastilles with a placebo (El Sayed2002a; Stokman 2003; Symonds 1996) and one trial antibioticpaste PTA with a placebo ( Wijers 2001). Meta-analyses were con-ducted for each dichotomy however no statistically significant dif-ference was found and therefore there is insufficient evidence tosupport or refuteantibiotic pastille or paste as more or lesseffectivethan placebo.

• Benzydamine versus placebo (Comparison 1, Outcome 1.1)

One trial compared benzydamine with a placebo (Prada 1987)and for the outcome of mucositis 0 versus 1+ there was evidence

that it prevented mucositis compared to placebo RR = 0.67 (95%CI 0.47 to 0.96). This finding is based on a single trial of only 36 participants and is therefore considered weak and unreliableevidence of a benefit.

• Beta carotene versus no treatment control (Comparison 1,Outcome 1.3)

One trial (Mills 1988) provided useable data for beta caroteneversus no treatment control for the 0 to 2 versus 3+ mucositisdichotomy. No statistically significant difference was found andtherefore there is insufficient evidence to support or refute betacarotene as being more or less effective than no treatment.





• Calcium phosphate versus placebo (Comparison 1,

Outcomes 1.1 to 1.3)

One trial (Papas 2003) provided data comparing calcium phos-phate with placebo for allthree dichotomies of mucositis. All threecomparisons were significant with RR values of 0.75 (95% CI0.58 to 0.99), 0.63 (95% CI 0.42 to 0.94) and 0.42 (95% CI 0.23to 0.76) for increasing levels of severity. The trial of 94 patientshad adequate allocation concealment, blinding of outcome asses-sor and description of withdrawals and was considered at low risk of bias. As this finding is based on a single trial it is considered

weak evidence of a benefit.

• Camomile versus placebo (Comparison 1, Outcomes 1.1 to1.3)

One trial compared camomile with a placebo (Fidler 1996). Data were provided for all three dichotomies of mucositis. No statisti-cally significant differences were found therefore there is insuffi-cient evidence to support or refute camomile as being more or lesseffective than placebo.

• Chinese medicine versus control (Comparison 1, Outcomes1.1 to 1.3)

Two trials provided data for Chinese medicine versus control (Do-bell’ssolution)(Huang 2003; Wang 2002a). Huang 2003included11 herbs and Wang 2002b included fivedifferent herbs. Data were

for the three dichotomies of mucositis although all the patients inHuang 2003 had mucositis for the first dichotomy. All compar-isons were significant indicating that the Chinese medicine wasbeneficial with RR values of 0.44 (95% CI 0.20 to 0.96), 0.44(95% CI 0.33 to 0.59) and 0.16 (95% CI 0.07 to 0.35) for in-creasing levels of mucositis severity. Both trials were considered athigh risk of bias, so there is weak evidence of a benefit.

• Chlorhexidine versus placebo/no treatment (Comparison 1,Outcomes 1.1 to 1.3)

Seven trials compared chlorhexidine with either a placebo or notreatment control group. All trials provided data on the incidenceof mucositis which could be dichotomised at some level, along

the 5-point scale (0 to 4). Four trials (Dodd 1996; Ferretti 1988;Ferretti1990; Foote 1994)provideddataforthefirstdichotomy(0versus 1 to 4), two trials (Foote 1994; Pitten 2003) provided datacomparing mucositis dichotomised as 0 to 1 versus 2+, and threetrials (Foote 1994; Spijkervet 1989; Wahlin 1989) provided datafor the third dichotomy of mucositis 0 to 2 versus 3+ and none of these found significant differences between the two groups, onceagain this was not significant, and therefore there is insufficientevidence to support or refute that chlorhexidine is more or lesseffective than placebo/no treatment.

• Folinic acid versus no treatment (Comparison 1, Outcomes1.1 to 1.3)

One trial compared folinic acid with a no treatment control group

(Erlichman 1988). Participants in the no treatment group wereless likely to experience mucositis compared with those receivingfolinic acid. This difference was statistically significant for the di-chotomies of mucositis 0 versus 1+ RR = 3.65 (95% CI 2.39 to5.58) and mucositis 0 to 1 versus 2+, RR = 2.38 (95% CI 1.35 to4.21). This trial was published in 1988 and initially involved 130patients receiving 5-fluorouracil (5-FU) chemotherapy for solidtumours. It was unclear if the assessor was blinded to the treat-ment group and information on withdrawals was not provided. Itprovides weak evidence that folinic acid might induce mucositiscompared with no treatment. This would be expected as folinicacid potentiates 5-FU cytotoxic activity.

•

Glutamine versus placebo (Comparison 1, Outcomes 1.1 to1.3)

Six trials, two of which had a cross-over design, included the in-tervention glutamine compared with placebo ( Anderson 1998;Cerchietti 2006; Dickson 2000; Huang 2000; Jebb 1994; Okuno1999). None of the meta-analyses found any significant differencesbetween glutamine and placebo. This demonstrated that there isinsufficient evidence to support or refute that glutamine is moreor less effective than placebo for the prevention of mucositis for-mation at any level of severity.

• GM-CSF versus placebo/no treatment (Comparison 1,Outcomes 1.1 to 1.3)

Ninetrials compared granulocyte/macrophagecolony-stimulatingfactor (GM-CSF) with a placebo or no treatment control group.Seven trials wereplacebo controlled(Cartee 1995; Crawford1999;Dazzi 2003; Ifrah 1999; Nemunaitis 1995; Schneider 1999; vander Lelie 2001) of which three trials (Crawford 1999; Nemunaitis1995; Schneider 1999) compared recombinant human granulo-cyte-colony stimulating factor and two trials had a no treatmentcontrol group (Katano 1995; Makkonen 2000). Three trials pro-vided data for the dichotomies of mucositis 0 versus 1+ and 0 to1 versus 2+, with six trials providing data for the 0 to 2 versus 3+dichotomy. None of these comparisons were significant and there-fore there is insufficient evidence to support or refute the efficacy of GM-CSF.

• Histamine gel versus placebo (Comparison 1, Outcomes1.1 and 1.3)

One trial compared histamine gel with placebo (Elad 2006) fortwo dichotomies of mucositis. Neither of these comparisons weresignificant and therefore there is insufficient evidence to supportor refute the efficacy of histamine gel.

• Honey versus no treatment control (Comparison 1,Outcomes 1.1, 1.3)

One trial (Biswal 2003) compared honey with a no treatmentcontrol for the prevention of mucositis at the 0 versus 1+ and 0





to 2 versus 3+ dichotomies. There was no statistically significant

difference at the first dichotomy but the honey was shown to beeffective at reducing the prevalence of severe mucositis RR = 0.27(95% CI 0.11 to 0.66) in this trial on 40 patients. The trial wasconsidered at high risk of bias so there is weak unreliable evidencethat honey may prevent severe mucositis.

• Hydrolytic enzymes versus no treatment (Comparison 1,Outcomes 1.1 to 1.3)

Two trials compared hydrolytic enzymes with a no treatment con-trol group (Gujral 2001; Kaul 1999). Both trials provided datafor each of the meta-analyses. Individually the trials were signifi-cant for different levelsof mucositis. The pooled meta-analysis didnot find a difference for the dichotomy of mucositis absent versus

present, however, significant differences were found for mucositis0 to 1 versus 2+ RR = 0.52 (95% CI 0.36 to 0.74) and for mu-cositis 0 to 2 versus 3+, RR = 0.17 (95% CI 0.06 to 0.52). Forboth of these comparisons the data were homogeneous, based on149 adults treated for head and neck cancer in open trials, one

with adequate allocation concealment and unclear information on withdrawals in both, both being classified as at high risk of bias.The weak evidence suggests that hydrolytic enzymes may reducethe severity of mucositis associated with the treatment of head andneck cancer rather than prevent it.

• Ice chips versus no treatment (Comparison 1, Outcomes1.1 to 1.3)

Three trials (Cascinu 1994; Lilleby 2006; Mahood 1991), one of which was designed as a cross-over trial compared ice chips with ano treatment control group. Significant differences were found ateach of thethree dichotomies of mucositis, with RRs of 0.64 (95%CI 0.50 to 0.82), 0.38 (95% CI 0.23 to 0.62) and 0.24 (95% CI0.12 to 0.48) for increasing severity of mucositis. The evidenceis moderate from three trials with 178 patients treated with 5-FU chemotherapy. The quality of the reporting of the trials variedand none had a blinded outcome assessment, one was consideredat medium and two at high risk of bias. This indicated that icechips may be beneficial in preventing or reducing the severity of mucositis for patients treated with 5-FU.

• Iseganan versus placebo (Comparison 1, Outcomes 1.2,1.3)

Three studies (Giles 2003a; Giles 2004; Trotti 2004) comparediseganan with placebo for different dichotomies of mucositis. A singletrial (Giles2003a) compared mucositisabsent versus presentand showed a benefit for iseganan, RR 0.59 (95% CI 0.43 to0.80), and this trial was considered at high risk of bias. The meta-analyses at the other dichotomies of mucositis were not found tobe significant so there is weak unreliable evidence that isegananmay prevent mucositis based on one trial of 221 patients.

• Keratinocyte GF versus placebo (Comparison 1, Outcomes1.1 to 1.3)

Three trials compared keratinocyte GF with placebo (Freytes

2004; Meropol 2003; Spielberger 2004) at the 0 to 1 versus 2+and the 0 to 2 versus 3+ dichotomies of mucositis. No statistically significant difference was found and therefore there is insufficientevidence to support or refute keratinocyte GF as more or less ef-fective than placebo.

• Misonidazole versus control (Comparison 1, Outcomes 1.1to 1.3)

Onestudy(Lee1989) compared misonidazoleversus no treatmentcontrol and provided data for each of the three dichotomies of mucositis. No statistically significant differences were found andthereforethereis insufficient evidence to support or refutewhethermisonidazole is effective in preventing mucositis.

• Oral care versus no treatment or limited oral hygiene(Comparison 1, Outcomes 1.1 to 1.3)

Three trials compared oral care with no treatment or limited oralhygiene (Borowski 1994; Shieh 1997; Trotti 2004) and reportedoutcomes at different levels of mucositis. A significant difference

was found for the single trial comparing oral care versus no treat-ment (Shieh 1997) at the level of mucositis 0 versus 1+ with a RR of 0.60 (95% CI 0.42 to 0.85). The other comparisons were notstatistically significantly different. This indicates that oral care in-terventions may be beneficial in preventing mucositis however theevidence is weak and based on a single study of 30 adults treatedfor head and neck cancer with radiotherapy, although the study

was considered at low risk of bias.

• Pentoxifylline versus no treatment (Comparison 1,Outcome 1.3)

One trial compared pentoxifylline with a no treatment controlgroup ( Attal 1993). Data were provided at the dichotomy of mu-cositis 0 to 1 versus 2+. No statistically significant differences werefound therefore there is insufficient evidence to support or refutethat pentoxifylline is more or less effective than no treatment.

• Pilocarpine versus placebo (Comparison 1, Outcome 1.3)

Two trials compared pilocarpine versus placebo (Lockhart 2005;

Scarantino 2006). No statistically significant differences werefound and therefore there is insufficient evidence to support orrefute whether pilocarpine is effective in preventing mucositis.

• Povidone versus water (Comparison 1, Outcomes 1.1 to1.3)

Two trials compared povidone with water or saline (Rahn 1997;Vokurka 2005). No statistically significant differences were foundand therefore there is insufficient evidence to support or refute

whether povidone is effective in preventing mucositis.

• Prednisone versus placebo (Comparison 1, Outcomes 1.1to 1.3)





Onetrialcomparedprednisolone with a placebo (Leborgne 1997).

Data were provided at all three dichotomies of mucositis. No sta-tistically significant differences were found and therefore there isinsufficient evidence to support or refute that prednisone is moreor less effective than placebo.

• Propantheline versus placebo (Comparison 1, Outcome1.1)

One trial compared propantheline with a placebo ( Ahmed 1993).Data were provided at the dichotomy of mucositis 0 versus 1+. Nostatistically significant differences were found and therefore thereis insufficient evidence to support or refute that propantheline ismore or less effective than placebo.

•

Prostaglandin versus placebo (Comparison 1, Outcomes1.1, 1.3)

Threetrials comparedprostaglandinwith a placebo (Duenas 1996;Labar 1993; Pillsbury 1986). Useable data were provided for twoof the dichotomies of mucositis. No statistically significant differ-ences were found and therefore there is insufficient evidence tosupport or refute that prostaglandin is more or less effective thanplacebo.

• Sucralfate versus placebo (Comparison 1, Outcomes 1.1 to1.3)

Eight trials (Carter 1999; Castagna 2001; Cengiz 1999; Franzen1995; Makkonen 1994; Pfeiffer 1990; Scherlacher 1990; Shenep

1988) compared the intervention sucralfate with a placebo, oneof which had a cross-over design (Pfeiffer 1990). Data were pro-vided at threedichotomies of mucositis. No statistically significantdifferences were found and therefore there is insufficient evidenceto support or refute that sucralfate is more or less effective thanplacebo.

• Systemic antibiotic clarithromycin versus no treatment(Comparison 1, Outcome 1.2)

One trial compared clarithromycin with no treatment ( Yuen2001). Data were provided at the dichotomy of mucositis 0 to 1versus 2+. The difference was on the borderline of statistical sig-nificance RR = 0.69 (95% CI 0.47 to 1.01), but the trial of 70

patients was considered at high risk of bias. There is insufficientevidence to support or refute whether a systemic antibiotic is ef-fective in preventing mucositis.

• Traumeel versus placebo (Comparison 1, Outcome 1.1)

One trial compared traumeel with a placebo (Oberbaum 2001).Data were provided at the dichotomy of mucositis 0 versus 1+. Nostatistically significant difference was found and therefore there isinsufficient evidence to support or refute that traumeel is more orless effective than placebo.

• Zinc sulphate versus placebo (Comparison 1, Outcomes1.1 to 1.3)

One trial (Ertekin2004) compared zinc sulphate with placebo and

provided data at all three dichotomies of mucositis. The two moresevere levels of mucositis were statistically significant with RR =0.42 (95% CI 0.20 to 0.89) and 0.05 (95% CI 0.00 to 0.78).However although assessed as at low risk of bias, this result is basedon one trial of only 27 patients provides only weak evidence thatzinc sulphate may prevent more severe mucositis.

Comparisons between potentially active

interventions

• Cryotherapy: 30 minutes versus 60 minutes (Comparison2, Outcomes 2.1 to 2.3)

One study (Rocke 1993) compared sucking ice chips during bo-lus dose 5-FU treatment for 30 minutes or 60 minutes, and pro-vided data for the three dichotomies of mucositis. No significantdifferences were found and there is therefore insufficient evidenceto support or refute that sucking ice chips for 60 rather than 30minutes is more effective in preventing mucositis.

• Etoposide: bolus versus continuous infusion (Comparison2, Outcomes 2.1 to 2.3)

One trial compared bolus etoposide with continuous infusionetoposide (Damon 2004). A significant benefit for bolus prevent-ing mucositis was found for each of the three dichotomies withRR values of 0.43 (95% CI 0.30 to 0.62), 0.16 (95% CI 0.07to 0.38) and 0.06 (95% CI 0.00 to 0.95) for increasing levels of mucositis severity. This trial of 97 patients was considered at highrisk of bias, so there is weak evidence of a benefit.

• GM-CSF versus sucralfate (Comparison 2, Outcomes 2.1to 2.3)

One study (Saarilahti 2002) compared two possibly active inter-ventions GM-CSF and sucralfate. Useable data were presented fortwo dichotomies of mucositis, and no significant differences werefound. There is therefore insufficient evidence to support or refutethat GM-CSF is more or less effective than sucralfate.

• Keratinocyte: 50 mg versus 25 mg

One study compared 50 mg keratinocyte with 25 mg keratinocyte(Freytes 2004). No statistically significant differences were foundso there is no evidence to support or refute an increased benefit

with a higher dose.

Additional outcomes (Comparison 3, Outcome 3.1)

The information relating to additional outcomes and side effects was variable across the 89 included studies. To explore these fur-ther, for the intervention, amifostine, found to be beneficial atpreventing or reducing the severity of mucositis, the data werepooled and synthesised for side effects.





Of the 11 trials evaluating amifostine nine reported side effects

( Antonadou 2002; Bourhis 2000; Brizel 2000; Buentzel 2006;Hartmann 2001; Hwang 2004; Karacetin 2004; Koukourakis2000; Spencer 2005). For five of these side effects, data from morethan one study were available. No significant difference was foundbetween amifostine and no treatment control for survival at 24months, recurrence at 18 months after cancer treatment, incom-plete response to radiotherapy, hypotension and nausea. Delay toradiotherapy was on the borderline of significance with those re-ceiving amifostine less likely to have a delay to receiving radio-therapy for cancer however, it was based on a single study of 39patients RR = 0.44 (95% CI 0.19 to 1.01). The only significantfinding was for vomiting with no patients in the control groupcompared with 10/182 treated with amifostine experiencing this

side effect RR = 5.95 (95% CI 1.03 to 34.29, chi squared = 0.90,df = 2, P = 0.6). In two studies (Hartmann 2001; Hwang 2004)the side effects for nausea and vomiting were combined and wedid not include these with either of these outcomes. Hartmann2001 found a significant difference with higher levels of delay of vomiting/nausea in the control group. This study also comparedinpatient costs and those treated with amifostine were dischargedafter 16 days compared to 18 days in the control, on average.Somestudies reportedadverse events thought to be related to amifostinein these patients only; it was unclear if there were events in thecontrol arm (Karacetin 2004; Spencer 2005).

D I S C U S S I O N

The number and range of interventions included in this review indicates the uncertainty and importance of this clinical topic.This update has identified 18 more included trials which havebeen published in less than 2 years, bringing the total number of included studies up to 89. The number of excluded studies hasalso increased from 131 to 188 over the same period. The tri-als included in this review have evaluated 33 interventions andrecruited 7523 patients. The country of conduct, financial sup-port and the design of trials have varied and there have been sev-eral publications highlighting the need for a co-ordinated research

agenda (Cella 2003; Wright 2003). The 14 multicentre trials werethe largest with respect to patient recruitment. There is a lack of duplication of studies investigating the same interventions whichlimits the strength of evidence and generalisability, however thereis duplication in attempts to publish clinical guidance in this area.

The eligible trials for this review varied in their design and quality and it was especially unfortunate that many studies presented datain an unusable form. We feel that the use of structured abstractsand adherence to the CONSORT guidelines will greatly improvethe reporting and hopefully the conduct of randomised controlledtrials (RCTs) (Begg 1996; Moher 2001). With respect to publica-tion bias, several negative studies for mucositis have been reported

and we congratulate the authors and editors for doing so. It was

not possible to detect any existing publication bias, as there wereinsufficient studies in each meta-analysis investigating the sameinterventions.

The setting of the included trials varied with the majority beingconducted by medical teams who did not report any involvement

with a dentist (76%). An issue that was not considered in any of the trials was the reliability and validity of the outcome measuresassessed. The appearance of the mucositis and oral candidiasis canbe similar; therefore if the assessor is neither trained nor expe-rienced in the diagnosis of these oral lesions, the validity mightbe affected. Scores of mucositis were not always defined althoughthere was consistency in the number of categories of the indices

used, with the lowest indicating no mucositis. Since the last review publications have appeared in relation to the development of con-sensus methods for scoring oral mucositis. These scoring methodsneed validating and then using by trialists in studies.

This review was initially conducted in 1999 and the most impor-tant outcome was considered to be whether mucositis was presentor not, at different levels of severity. Trials also publish other mea-sures of mucositis such as mean values, which may be more sensi-tive to detecting differences in severity, however we still feel that itis important for both clinicians and patients to know how severethe mucositis became, and feel this should be reported.

The reporting of outcomes other than mucositis was variable and

they were reported more frequently in trials published within thelast5yearsthanbefore.Thetypeofoutcomesreportedhaschangedto reflect more the characteristics identified as clinically meaning-ful and important to patients (Bellm 2002; Cella 2003; Chang2003; Sonis 2004; Wright 2003). Some trials reported additionaloutcomes which are know to be side effects of the intervention.They only report these for the intervention group and it is un-clear if there were any events in the control group. We feel thatthese should still be measured on all patients andreported forbothgroups. For example for amifostine some trials which reportednausea and vomiting in both groups, indicated no evidence of adifference, harm or benefit between the study groups, however thetrials reporting these events on only the amifostine arm imply it

is a significant event for those patients, which is misleading forreaders. Only interventions to prevent mucositis were included inthis review however using a range of dichotomies for mucositis thefindings can be interpreted also as reduction in severity.

The findings of this review should be considered in context withthe general medical management of patientswithcancer.Outcomemeasures, other than clinical scores for mucositis, were predom-inantly reported in recent publications. Rarely did they considerclinically meaningful outcomes such as oral pain, use of opioidanalgesic, oral intake, quality of life, duration of hospital stay (Bellm 2002).

In addition to interventions specifically for presenting mucositis,





we have also included modifications to the cancer treatmentwhich

may also have this effect (amifostine, etoposide and folinic acid).The inclusion of these will be reconsidered before the next update.

Twelve of the 33 interventions were found to have some evidenceof a benefit (albeit sometimes weak) in preventing or reducing theseverity of mucositis. One intervention, folinic acid, was signifi-cantly worse than placebo. A summary of the 12 potentially effec-tive interventions is given below.

• Amifostine is an amino thiol free radical scavenger. Itappears to have small benefit in preventing (risk ratio (RR) =0.95 (95% confidence interval (CI) 0.92 to 0.98)) and reducingthe severity of mild mucositis (RR = 0.88 (95% CI 0.80 to

0.98)). This is based on the largest body of evidence found inthis review, from 11 trials with 845 participants. The side effectsof amifostine were not significantly different to no treatment forsurvival at 24 months, recurrence at 18 months after cancertreatment, incomplete response to radiotherapy, hypotensionand nausea. Delay to radiotherapy was on the borderline of significance with those receiving amifostine less likely toexperience a delay RR = 0.44 (95% CI 0.19 to 1.01). The only significant finding was for vomiting with no patients in thecontrol group compared with 10/182 treated with amifostineexperiencing this side effect RR = 5.95 (95% CI 1.03 to 34.29).

• Benzydamine, an indirect cytoprotectant with anti-inflammatory, analgesic and antimicrobial activity was comparedto placebo in one trial and was found to be significantly moreeffective for preventing mucositis RR = 0.67 (95% CI 0.47 to0.96). The evidence is weak based on one trial of 36 adultpatients with head and neck cancer, receiving radiotherapy.

• Calcium phosphate is thought to support the inflammatory process and provide a source of phosphate for cell repair. There is

weak evidence based on one trial based on 94 patients, which was assessed as at low risk of bias, that calcium phosphate may bebeneficial at preventing mucositis at all levels of severity. The RR

values ranged from 0.42 to 0.75.

• Chinese medicine is a mixture of herbs, different selectionsof herbs being included in the two trials, and we are unsure of the biological action of this. There is weak evidence of a benefitbased on two trials both assessed as of high risk of bias, with RR ranging from 0.16 (95% CI 0.07 to 0.35) to 0.44 (95% CI 0.33to 0.59).

• Etoposide bolus had a significant benefit over continuousinfusion, when given in the same amount. The evidence is weak

from a single trial of 97 patients which was assessed as at high

risk of bias. The RRs ranged from 0.06 to 0.43.

• Honey has antibacterial and wound healing properties and was shown to be effective at reducing the prevalence of severemucositis RR = 0.27 (95% CI 0.11 to 0.66) in this trial on 40patients. The trial was considered at high risk of bias so there is

weak unreliable evidence that honey may prevent severemucositis.

• Hydrolytic enzymes have analgesic and anti-inflammatory properties. Two trials provided evidence of moderate benefit at

reducing the severity if mucositis rather than preventing it withmucositis 0 to 1 versus 2+ RR = 0.52 (95% CI 0.36 to 0.74) andmucositis 0 to 2 versus 3+ RR = 0.17 (95% CI 0.06 to 0.52). Forboth of these comparisons the data were homogeneous, based on149 adults treated for head and neck cancer in open trials.

• Ice chips are thought to act by producing localvasoconstriction therefore limiting the cytotoxic effects of chemotherapy. The evidence is moderate from three trials with178 patients treated with bolus dose 5-FU chemotherapy.Significant differences were found at all dichotomies of mucositis, with risk ratios of 0.64 (95% CI 0.50 to 0.82), 0.38

(95% CI 0.23 to 0.62) and 0.24 (95% CI 0.12 to 0.48) forincreasing severity of mucositis. This therapy would not beexpected to work in patients receiving long infusions of 5-FU.

• Iseganan is an antimicrobial peptide with broad spectrumactivity. It is well tolerated and this is thought to be due to itslack of systemic absorption. There is weak evidence of a benefitin preventing mucositis from a single trial assessed as at high risk of bias, with RR 0.59 (95% CI 0.43 to 0.80).

• Oral care is thought to be important as it reduces the

impact of oral microbial flora and limits opportunistic infection.It is compared with no treatment in two trials, however only onetrial found a significant difference for oral care versus notreatment at the level of mucositis 0 versus 1+ with a risk ratio of 0.60 (95% CI 0.42 to 0.85). The evidence that oral careinterventions may be beneficial in preventing mucositis is weak,based on a single study of 30 adults treated for head and neck cancer with radiotherapy. Most interventions for preventingmucositis are tested with a background of standard oral careprotocols however it is unclear how important this is, and if so

what exact oral care regimen should be followed.





• Zinc sulphate is thought to act as an antioxidant and

stabilizer of membrane structure. One trial compared zincsulphate with placebo and the two more severe levels of mucositis were statistically significant with RR = 0.42 (95% CI0.20 to 0.89) and 0.05 (95% CI 0.00 to 0.78). However as thisresult is based on one trial of only 27 patients, although this wasassessed at low risk of bias, it provides only weak evidence thatzinc sulphate may prevent more severe mucositis.

In conclusion, four interventions were identified where there wasmorethan onetrialcontributingto a meta-analysis finding a signif-icant difference: amifostine, Chinese medicine, hydrolyticenzymeand ice chips. Three of these, amifostine, hydrolytic enzymes wereassessed in patients with head and neck cancer, and ice chips intwo studies were used on patients having chemotherapy treatment

with bolus dose 5-FU, and in the third patients were receiving thesingle-agent melphalan.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Several of the interventions (amifostine, benzydamine, calciumphosphate, Chinese medicine, bolus etoposide, honey, hydrolyticenzymes, ice chips, iseganan, oral care and zinc sulphate) werefound to have some benefit at preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice includeconsideration of the fact that benefits may be specific for certaincancer types and treatment.

Implications for research

There is a need for well designed and conducted trials reportedaccording to the CONSORT guidelines with sufficient numbersof participants to performsubgroup analyses by type of disease andchemotherapeutic agent. This review has highlighted several in-terventions for which further research into the benefits and harmsshould be conducted (benzydamine, calcium phosphate, Chinese

medicine, honey, hydrolytic enzymes, ice chips, iseganan, oral careandzincsulphate). There shouldbe continuedevaluation of agentsformucositis. Outcome measures of anyfuture trial shouldaddressthe link between oral and general health including the outcomesrelevant to the patient and as a minimum they should include the

reduction of oral pain, the use of opioid analgesics, improvement

in oral intake and quality of life, and reduction of hospitalisationduration. Collaboration between medical and dental teams is in-dicated with a consensus on the choice of objective oral indicesfor mucositis.

A C K N O W L E D G E M E N T S

Thanks go to Sylvia Bickley, Trials Search Co-ordinator for theCochrane Oral Health Group for carrying out the searches forthe review; Luisa Fernandez Mauleffinch, Co-ordinator for theCochrane Oral Health Group forher helpwith the administration

of the review; Phil Riley for his help in locating all the articles forthe review, sending out letters to authors and helping collate theinformation for the review.

The help and expertise of the following is gratefully acknowl-edged: Marco Esposito (Italian translations, The University of Manchester); Tatiana Macfarlane (Russian translations, Univer-sity of Aberdeen); Valeria Marinho (Spanish/Portuguese transla-tions, Queen Mary’s School of Medicine and Dentistry, London,UK); Shi Zongdao and Wu Jiapei (Chinese translations, SichuanUniversity); and Mikako Hayashi and Kumiko Kasashi (Japanesetranslations, University of Osaka) for providing translations of thetrial reports and completing the data extraction forms.

We wouldalso liketo thankthe followinginvestigators whorepliedto our request for additional information about their trials: Pro-fessors S Cascinu, D Cella, MJ Dodd, GA Ferretti, T Feyer-abend, P Gotzshe, CL Loprinzi, S Wang and Drs PM Anderson,B Bensinger, BM Biswal, C Bokemeyer, J Bourhis, H Brincker, JBuentzel, L Cerchietti, L Damon, C Dazzi, TC Dickson, P Di-etrich, A Duenas-Gonzalez, S El Sayed, S Elad, MV Ertkin, GA Ferretti, R Foote, L Frazen, Freytes, J Hartmann, M Heydt, R Haddad, E Huang, N Ifrah, SA Jebb, M Katano, J Leborgne, PLockhart, G Masucci, SH Okuno, N Piccirillo, HC Pillsbury, R Rahn, K Saarilahti, C Scarantino, JL Shenep, JA Sloan, A Spencer,Spielberger, C Sportes, M Stokman, C Su, RP Symonds, A Trotti,

YB Wahlin, H Whelan.

We would also like to thank those who have provided commentsand editorial input into this review.

The administration of this review has been aided by a USA NIDCR grant, reference 1 R03 DE0 16950-01.





R E F E R E N C E S

References to studies included in this review

Ahmed 1993 {published data only}

Ahmed T, Engelking C, Szalyga J, Helson L, Coombe N, Cook P,et al.Propantheline prevention of mucositis from etoposide. Bone

Marrow Transplantation1993;12(2):131–2.

Anderson 1998 {published and unpublished data}

Anderson PM, Schroeder G, Skubitz KM. Oral glutamine reducesthe duration and severity of stomatitis after cytotoxic cancerchemotherapy. Cancer 1998;83(7):1433–9.

Antonadou 2002 {published data only}

Antonadou D, Pepelassi M, Synodinou M, Puglisi M, ThrouvalasN. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer.International Journal of Radiation Oncology, Biology and Physics

2002;52(3):739–47.

Attal 1993 {published data only}

Attal M, Huguet F, Rubie H, Charlet J-P, Schlaifer D, Huynh A, etal.Prevention of regimen-related toxicities after bone marrow transplantation by pentoxifylline: A prospective, randomized trial.Blood 1993;82(3):732–6.

Biswal 2003 {published data only}

Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis. A preliminary study.Supportive Care in Cancer 2003;11(4):242–8.Biswal BM, Zakaria A, Nik Min A. Topical application of honey in

the management of radiation mucositis: A randomised study.International Journal of Cancer 2002;Supp 13:480 (Abs 1109).

Borowski 1994 {published data only}

Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP,Hayat M. Prevention of oral mucositis in patients treated withhigh-dose chemotherapy and bone marrow transplantation: arandomised controlled trial comparing two protocols of dental care.European Journal of Cancer Part B, Oral Oncology 1994;30B(2):93–7.

Bourhis 2000 {published data only}∗ Bourhis J, De Crevoisier R, Abdulkarim B, Deutsch E, Lusinchi A, Luboinski B, et al.A randomized study of very acceleratedradiotherapy with and without amifostine in head and neck squamous cell carcinoma. International Journal of Radiation

Oncology, Biology and Physics 2000;46(5):1105–8.Bourhis J, Rosine D. Radioprotective effect of amifostine inpatients with head and neck squamous cell carcinoma. Seminars inOncology 2002;29(6):Supp 19 61-2.

Brizel 2000 {published data only}

Brizel DM, Wasserman TH, Henke H, Strnad V, Rudat V,Monnier A, et al.Phase III randomized trial of amifostine as aradioprotector in head and neck cancer. Journal of Clinical Oncology

2000;18(19):3339–45.

Bubley 1989 {published data only}

Bubley GJ, Chapman B, Chapman SK, Crumpacker CS, SchnipperLE. Effect of acyclovir on radiation- and chemotherapy-inducedmouth lesions. Antimicrobial Agents and Chemotherapy 1989;33(6):862–5.

Buentzel 2006 {published data only}

Buentzel J, Micke O, Adamietz IA, Monnier A, Glatzel M, de Vries A. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study.International Journal of Radiation Oncology, Biology, Physics 2006;64

(3):684–91.

Buntzel 1998 {published data only}

Bennett CL, Lane D, Stinson T, Glatzel M, Buntzel J. Economicanalysis of amifostine as adjunctive support for patients withadvanced head and neck cancer: Preliminary results from arandomized phase II clinical trial from Germany. Cancer

Investigation 2001;19(2):107–13.Bourhis J, Rosine D. Radioprotective effect of amifostine inpatients with head and neck squamous cell carcinoma. Seminars inOncology 2002;29(6):Supp 19 61-2.Buntzel J, Glatzel M, Kuttner K, Weinaug R, Frohlich D. Amifostine in simultaneous radiochemotherapy of advanced headand neck cancer. Seminars in Radiation Oncology 2002;12(1 (Supp1)):4–13.Buntzel J, Kuttner K, Frohlich D, Glatzel M. Selectivecytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Annals of Oncology 1998;9(5):505–9.∗ Buntzel J, Schuth J, Kuttner K, Glatzel M. Radiochemotherapy with amifostine cytoprotection for head and neck cancer.Supportive Care in Cancer 1998;6(2):155–60.

Cartee 1995 {published data only}

Cartee L, Petros WP, Rosner GL, Gilbert C, Moore S, Affronti ML,et al.Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind,dose-ranging study. Cytokine 1995;7(5):471–7.

Carter 1999 {published data only}

Carter DL, Hebert ME, Smink K, Leopold KA, Clough RL, BrizelDM. Double blind randomized trial of sucralfate vs placebo radialradiotherapy for head and neck cancers. Head and Neck 1999;21

(8):760–6.

Cascinu 1994 {published and unpublished data}

Cascinu S, Fedeli A, Fedeli SL, Catalano G. Oral cooling(cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. European Journal of Cancer Part B,

Oral Oncology 1994;30B:234–6.

Castagna 2001 {published data only}

Castagna L, Benhamou E, Pedraza E, Luboinski M, Forni M,Brandes I, et al.Prevention of mucositis in bone marrow transplantation: a double blind randomised controlled trial of sucralfate. Annals of Oncology 2001;12(7):953–5.

Cengiz 1999 {published data only}

Cengiz M, Ozyar E, Ozturk D, Akyol F, Atahan IL, Hayran M.Sucralfate in the prevention of radiation-induced oral mucositis.

Journal of Clinical Gastroenterology 1999;28(1):40–3.

Cerchietti 2006 {published data only}

Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, et al.Double-blinded, placebo-controlled trial onintravenous L-alanyl-L-glutamine in the incidence of oral mucositis





following chemoradiotherapy in patients with head-and-neck

cancer. International Journal of Radiation Oncology, Biology, Physics 2006;65(5):1330–7.

Crawford 1999 {published data only}

Crawford J, Tomita DK, Mazanet R, Glaspy J, Ozer H. Reductionof oral mucositis by filgrastim (r-metHuG-CSF) in patientsreceiving chemotherapy. Cytokines, Cellular and Molecular Therapy

1999;5(4):187–93.

Damon 2004 {published data only}

Damon LE, Johnston LJ, Ries CA, Rugo HS, Case D, Ault K, etal.Treatment of acute leukemia with idarubicin, etoposide andcytarabine (IDEA). A randomized study of etoposide schedule.Cancer Chemotherapy and Pharmacology 2004;53(6):468–74.

Dazzi 2003 {published data only}∗

Dazzi C, Cariello A, Giovanis P, Monti M, Vertogen B, Leoni M,et al.Prophylaxis with GM-CSF mouthwashes does not reducefrequency and duration of severe oral mucositis in patients withsolid tumors undergoing high-dose chemotherapy with autologousperipheral blood stem cell transplantation rescue: a double blind,randomized, placebo-controlled study. Annals of Oncology 2003;14

(4):559–63.Dazzi C, Cariello A, Monti M, Giovanis P, Vertogen B, Nanni O, etal.Prophylaxis with GM-CSF mouthwash does not reducefrequency and duration of severe oral mucositis in patients withsolid tumors undergoing high dose chemotherapy with autogousPBPC rescue: A double blind randomized placebo-controlledstudy. Annals of Oncology 2002;13 (Supp 5):167 (Abs 617).

Dickson 2000 {published data only}

Coghlin Dickson TM, Wong RM, Offrin RS, Shizuru JA, JohnstonLJ, Hu WW, et al.Effect of oral glutamine supplementation duringbone marrow transplantation. Journal of Parenteral and Enteral

Nutrition 2000;24(2):61–6.

Dodd 1996 {published and unpublished data}

Dodd MJ, Larson PJ, Dibble SL, Miaskowski C, Greenspan D,MacPhail L, et al.Randomized clinical trial of chlorhexidine versusplacebo for prevention of oral mucositis in patients receivingchemotherapy. Oncological Nursing Forum 1996;23(6):921–7.

Dozono 1989 {published data only}

Dozono H, Nakamura K, Motoya T, Nakamura S, Shinmura R,Miwa K, et al.Prevention of stomatitis induced by anti-cancerdrugs. Gan-to-kagaku-ryoho 1989;16(10):3449–51.

Duenas 1996 {published and unpublished data}Duenas-Gonzalez A, Sobrevilla-Calvo P, Frias-Mendivil M,Gallardo-Rincon D, Lara-Medina F, Aguilar-Ponce L, etal.Misoprostol prophylaxis for high-dose chemotherapy-inducedmucositis: a randomized double-blind study. Bone Marrow

Transplantation 1996;17(5):809–12.

El Sayed 2002a {published data only}

Duncan GG, Epstein JB, Tu D, El Sayed S, Bezjak A, Ottaway J, etal.Quality of life, mucositis, and xerostomia from radiotherapy forhead and neck cancers: a report from the NCIC CTG HN2randomized trial of an antimicrobial lozenge to prevent mucositis.Head & Neck 2005;27(5):421–8.∗ El-Sayed S, Nabid A, Shelley W, Hay J, Balogh J, Gelinas M, etal.Prophylaxis of radiation-associated mucositis in conventionally

treated patients with head and neck cancer: a double-blind, phase

III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system.

Journal of Clinical Oncology 2002;20(19):3956–63.

Elad 2006 {published data only}

Elad S, Ackerstein A, Bitan M, Shapira MY, Resnick I, GesundheitB, et al.A prospective, double-blind phase II study evaluating thesafety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem celltransplantation. Bone Marrow Transplantation 2006;37(8):757–62.

Erlichman 1988 {published data only}

Erlichman C. Fluorouracil and leucovorin for metastatic colorectalcancer. Journal of Chemotherapy 1990;2(S1):38–40.∗ Erlichman C, Fine S, Wong A, Elhakim T. A randomized trial of fluorouracil and folonic acid in patients with metastatic colorectalcarcinoma. Journal of Clinical Oncology 1988;6(3):469–75.

Ertekin 2004 {published data only}

Ertekin MV, Koc M, Karslioglu I, Sezen O. Zinc sulfate in theprevention of radiation-induced oropharyngeal mucositis: aprospective, placebo-controlled, randomized study. International

Journal of Radiation Oncology, Biology, Physics 2004;58(1):167–74.

Ferretti 1988 {published and unpublished data}

Ferretti GA, Ash RC, Brown AT, Largent BM, Kaplan A, Lillich TT.Chlorhexidine for prophylaxis against oral infections and associatedcomplications in patients receiving bone marrow transplants.

Journal of American Dental Association 1987;114(4):461–7.∗ Ferretti GA, Ash RC, Brown AT, Parr MD, Romond EH, LillichTT. Control of oral mucositis and candidiasis in marrow

transplantation: a prospective, double-blind trial of chlorhexidinedigluconate oral rinse. Bone Marrow Transplantation 1988;3(5):483–93.

Ferretti 1990 {published and unpublished data}

Ferretti GA, Raybould TP, Brown AT, Macdonal JS, GreenwoodM, Maruyama Y, et al.Chlorhexidine prophylaxis forchemotherapy- and radiotherapy- induced stomatitis: a randomiseddouble-blind trial. Oral Surgery, Oral Medicine, Oral Pathology

1990;69(3):331–8.

Fidler 1996 {published data only}

Fidler P, Loprinzi CL, O’Fallon JR, Leitch JM, Lee JK, Hayes DL, etal.Prospective evaluation of a chamomile mouthwash for preventionof 5-FU-induced oral mucositis. Cancer 1996;77(3):522–5.

Foote 1994 {published data only}Foote RL, Loprinzi CL, Frank AR, O’Fallon JR, Gulavita S, Tewfik HH, et al.Randomized trial of a chlorhexidine mouthwash foralleviation of radiation-induced mucositis. Journal of Clinical Oncology 1994;12(12):2630–3.

Franzen 1995 {published data only}

Franzen L, Henriksson R, Littbrand B, Zackrisson B. Effects of sucralfate on mucositis during and following radiotherapy of malignancies in the head and neck region. Acta Oncologica 1995;34

(2):219–23.

Freytes 2004 {published data only}

Freytes CO, Ratanatharathorn V, Taylor C, Abboud C, Chesser N,Restrepo A, et al.Phase I/II randomized trial evaluating the safety and clinical effects of repifermin administered to reduce mucositis





in patients undergoing autologous hematopoietic stem cell

transplantation. Clinical Cancer Research 2004;10(24):8318–24.Giles 2003a {published data only}

Giles FJ, Miller CB, Hurd DD, Wingard JR, Fleming TR, SonisST, et al.A phase III, randomized, double-blind, placebo-controlled,multinational trial of iseganan for the prevention of oral mucositisin patients receiving stomatotoxic chemotherapy (PROMPT-CTtrial). Leukemia & Lymphoma 2003;44(7):1165–72.

Giles 2004 {published data only}

Giles FJ, Rodriguez R, Weisdorf D, Wingard JR, Martin PJ,Fleming TR, et al.A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis inpatients receiving stomatotoxic chemotherapy. Leukemia Research2004;28(6):559–65.

Gujral 2001 {published data only}

Gujral MS, Patnaik PM, Kaul R, Parikh HK, Conradt C,Tamhankar CP, et al.Efficacy of hydrolytic enzymes in preventingradiation therapy-induced side effects in patients with head andneck cancers. Cancer Chemotherapy Pharmacology 2001;47:S23–S28.

Hartmann 2001 {published data only}

Hartmann JT, von Vangerow A, Fels LM, Knop S, Stolte H, KanzL, et al.A randomized trial of amifostine in patients with high-doseVIC chemotherapy plus autologous blood stem cell transplantation.British Journal of Cancer 2001;84(3):313–20.

Huang 2000 {published data only}

Huang EY, Leung SW, Wang CJ, Chen HC, Sun LM, Fang FM, etal.Oral glutamine to alleviate radiation-induced oral mucositis: A

pilot randomized trial. International Journal of Radiation Oncology,Biology and Physics 2000;46(3):535–9.

Huang 2003 {published data only}

Huang GX, Zhao C, Han F, Zhang B, Qiu HJ, Xu BP, etal.[Clinical study in prophylactic use of chinese medicine to preventchemoradiotherapy induced mucositis in nasopharyngealcarcinoma]. Ai Zheng 2003;22(10):1084–7.

Hwang 2004 {published data only}

Hwang WY, Koh LP, Ng HJ, Tan PH, Chuah CT, Fook SC, et al.A randomized trial of amifostine as a cytoprotectant for patientsreceiving myeloablative therapy for allogeneic hematopoietic stemcell transplantation. Bone Marrow Transplantation 2004;34(1):51–6.

Ifrah 1999 {published data only}

Ifrah N, Witz F, Jouet JP, Francois S, Lamy T, Linassier C, etal.Intensive short term therapy with granulocyte-macrophage-colony stimulating factor support, similar to therapy for acutemyeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. American Cancer Society 1999;86(8):1496–505.

Jebb 1994 {published and unpublished data}

Jebb SA, Osborne RJ, Maughan TS, Mohideen N, Mack P, MortD, et al.5-fluorouracil and folinic acid-induced mucositis: no effectof oral glutamine supplementation. British Journal of Cancer 1994;70(4):732–5.

Karacetin 2004 {published data only}

Karacetin D, Yucel B, Leblebicioglu B, Aksakal O, Maral O,Incekara O. A randomized trial of amifostine as radioprotector in

the radiotherapy of head and neck cancer. Journal of B.U.ON.

2004;9(1):23–6.Katano 1995 {published data only}

Katano M, Nakamura M, Matsuo T, Iyama A, Hisatsugu T. Effectof granulocyte colony-stimulating factor (G-CSF) onchemotherapy-induced oral mucositis. Surgery Today 1995;25(3):202–6.

Kaul 1999 {published data only}∗ Kaul R, Mishra BK, Sutradar P, Choudhary V, Gujral MS. Therole of Wobe-Mugos in reducing acute sequele of radiation in headand neck cancers - a clinical phase-III randomized trial. Indian

Journal of Cancer 1999;36(2-4):141–8.Kaul RVC. To evaluate the effect of Wobe mugos hydrolyticenzyme therapy on inflammation induced by external radiotherapy in patients of head and neck cancers. Bahrain Medical Bulletin

2001;23(3):116–8.

Koukourakis 2000 {published data only}

Koukourakis MI, Kyria G, Kakolyris S, Kouroussis C, FrangiadakiC, Giatromonaolaki A, et al.Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase IIstudy. Journal of Clinical Oncology 2000;18(11 June):2226–33.

Labar 1993 {published data only}

Labar B, Mrsic M, Pavletic Z, Bogdanic V, Nemet D, Aurer I, etal.Prostaglandin E2 for prophylaxis of oral mucositis followingBMT. Bone Marrow Transplantation 1993;11(5):379–82.

Leborgne 1997 {published data only}

Leborgne JH, Leborgne F, Zubizarreta E, Ortega B, Mezzera J.Corticosteroids and radiation mucositis in head and neck cancer. A

double-blind placebo-controlled randomized trial. Radiotherapy and Oncology 1997;47(2):145–8.

Lee 1989 {published data only}

Lee DJ, Pajak TF, Stetz J, Order SE, Weissberg JB, Fischer JJ. A phase I/II study of the hypoxic cell sensitizer misonidazole as anadjunct to high fractional dose radiotherapy in patients withunresectable squamous cell carcinoma of the head and neck: aRTOG randomized study (#79-04). International Journal of Radiation Oncology, Biology, Physics 1989;16(2):465–70.

Lilleby 2006 {published data only}

Lilleby K, Garcia P, Gooley T, McDonnnell P, Taber R, HolmbergL, et al.A prospective, randomized study of cryotherapy duringadministration of high-dose melphalan to decrease the severity and

duration of oral mucositis in patients with multiple myelomaundergoing autologous peripheral blood stem cell transplantation.Bone Marrow Transplantation 2006;37(11):1031–5.

Lockhart 2005 {published data only}

Lockhart PB, Brennan MT, Kent ML, Packman CH, Norton HJ,Fox PC, et al.Randomized controlled trial of pilocarpinehydrochloride for the moderation of oral mucositis duringautologous blood stem cell transplantation. Bone Marrow Transplantation 2005;35(7):713–20.

Loprinzi 1990 {published and unpublished data}

Loprinzi CL, Cainflone SG, Dose AM, Etzell PS, Burnham NL,Therneau TM, et al.A controlled evaluation of an allopurinolmouthwash as prophylaxis against 5-fluorouracil-inducedstomatitis. Cancer 1990;65(8):1879–82.





Mahood 1991 {published data only}

Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM,Thereau TM, et al.Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. Journal of Clinical Oncology 1991;9(3):449–52.

Makkonen 1994 {published data only}

Makkonen TA, Bostrom P, Vilja P, Joensuu H. Sucralfate mouth washing in the prevention of radiation-induced mucositis: A placebo-controlled double-blind randomized study. International

Journal of Radiation Oncology, Biology and Physics 1994;30(1):177–82.

Makkonen 2000 {published data only}

Makkonen TA, Minn H, Jekunen A, Vilja P, Tuominen J, JoeensuuH. Granulocyte Macrophage-colony stimulating factor (GM-CSF)and sucralfate in prevention of radiation-induced mucositis: A prospective randomized study. International Journal of Radiation

Oncology, Biology and Physics 2000;46(3):525–34.

Meropol 2003 {published data only}

Meropol NJ, Somer RA, Gutheil J, Pelley RJ, Modiano MR,Rowinsky EK, et al.Randomized phase I trial of recombinanthuman keratinocyte growth factor plus chemotherapy: potentialrole as mucosal protectant. Journal of Clinical Oncology 2003;21(8):1452–8.

Mills 1988 {published data only}

Mills EE. The modifying effect of beta-carotene on radiation andchemotherapy induced oral mucositis. British Journal of Cancer

1988;57(4):416–7.

Nemunaitis 1995 {published data only}

Nemunaitis J, Rosenfeld CS, Ash R, Freedman MH, Deeg HJ,

Appelbaum F, et al.Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplantation 1995;15(6):949–54.

Niibe 1985 {published data only}

Niibe H, Takahashi I, Mitsuhashi N, Miyaishi K, Itoh J, Maehara Y, et al.An evaluation of the clinical usefulness of amifostine (YM-08310), radioprotective agent. A double-blind placebo-controlledstudy.1. Head and neck tumors. Nippon-gan-chiryo-gakkai-shi

1985;20(5):984–93.

Nottage 2003 {published data only}

Nottage M, McLachlan SA, Brittain MA, Oza A, Hedley D, FeldR, et al.Sucralfate mouthwash for prevention and treatment of 5-fluorouracil-induced mucositis: a randomized, placebo-controlledtrial. Supportive Care in Cancer 2003;11(1):41–7.

Oberbaum 2001 {published data only}∗ Oberbaum M, Yaniv I, Ben-Gal Y, Stein J, Ben-Zvi N, FreedmanLS, et al.A randomized, controlled clinical trial of the homeopathicmedication TRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem celltransplantation. American Cancer Society 2001;92(3):684–90.Oberbaum M, Yaniv I, Ben-Gal Y, Stein J, Ben-Zvi N, FreedmanLS, et al.A randomized, controlled clinical trial of thehomoeopathic medication Traumeel S in the treatment of chemotherapy-induced stomatitis in children undergoing stem celltransplantation. Biologische Medizin 2002;31(1):25–31.

Okuno 1999 {published data only}

Okuno SH, Woodhouse CO, Loprinzi CL, Sloan JA, LaVasseur BI,Clemens-Schutjer D, et al.Phase III controlled evaluation of

glutamine for decreasing stomatitis in patients receiving

fluorouracil (5-FU)-based chemotherapy. American Journal of Clinical Oncology 1999;22(3):258–61.

Papas 2003 {published data only}

Papas AS, Clark RE, Martuscelli G, O’Loughlin KT, Johansen E,Miller KB. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem celltransplantation. Bone Marrow Transplantation 2003;31(8):705–12.

Pfeiffer 1990 {published data only}

Pfeiffer P, Madsen EL, Hansen O, May O. Effect of prophylacticsucralfate suspension on stomatitis induced by cancerchemotherapy. Acta Oncologica 1990;29(2):171–3.

Pillsbury 1986 {published data only}

Pillsbury HC 3rd, Webster WP, Rosenman J. Prostaglandin

inhibitor and radiotherapy in advanced head and neck cancers. Archives of Otolaryngology - Head & Neck Surgery 1986;112(5):552–3.

Pitten 2003 {published data only}

Pitten FA, Kiefer T, Buth C, Doelken G, Kramer A. Do cancerpatients with chemotherapy-induced leukopenia benefit from anantiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study. Journal of Hospital Infection 2003;53

(4):283–91.

Prada 1987 {published data only}

Prada A, Chiesa F. Effects of benzydamine on the oral mucositisduring antineoplastic radiotherapy and/or intra-arterialchemotherapy. International Journal of Tissue Reaction 1987;9(2):115–9.

Rahn 1997 {published data only} Adamietz IA, Rahn R, Bottcher HD, Schafer V, Reimer K,Fleischer W. Prophylaxis of radiochemotherapy-induced mucositis.Efficacy of prophylactic oral rinsing with povidone iodine solution[Pophylaxe der radiochemotherapeutisch bedingten mukositis].Stranhlentherapie und Onkologie 1998;174(3):149–55. Adamietz IA, Rhan R, Bottcher HD, Schafer V, Reimer K,Fleischer W. Prophylaxis with povidone-iodine against induction of oral mucositis by radiochemotherapy. Supportive Care in Cancer

1998;6(4):373–7.∗ Rahn R, Adamietz IA, Boettcher HD, Schaefer V, Reimer K,Fleischer W. Povidone-iodine to prevent mucositis in patientsduring antineoplastic radiochemotherapy. Dermatology 1997;195

(Suppl 2):57–61.

Rahn R AI, Bottcher HD, Reimer K, Fleischer W. PVP-iodinesolution as a mucositis prophylaxis by radiotherapy. Deutsche

Zeitschrift fur Mund-, Kiefer- und Gesichtschirurgie 1996;20(3):137–9.

Rocke 1993 {published data only}

Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iverson RK, Finck G, et al.A randomized clinical trial of two different durations ororal cryotherapy for prevention of 5-fluorouracil-related stomatitis.Cancer 1993;72(7):2234–8.

Saarilahti 2002 {published data only}

Saarilahti K, Kajanti M, Joensuu T, Kouri M, Joensuu H.Comparison of granulocyte-macrophage colony-stimulating factorand sucralfate mouthwashes in the prevention of radiation-inducedmucositis: a double-blind prospective randomized phase III study.





International Journal of Radiation Oncology Biology and Physics

2002;54(2):479–85.Scarantino 2006 {published data only}

Scarantino C, LeVeque F, Swann RS, White R, Schulsinger A,Hodson DI, et al.Effect of pilocarpine during radiation therapy:results of RTOG 97-09, a phase III randomized study in head andneck cancer patients. The Journal of Supportive Oncology 2006;4(5):252–8.

Scherlacher 1990 {published data only}

Scherlacher A, Beaufort-Spontin F. [Radiotherapy of head-neck neoplasms: prevention of inflammation of the mucosa by sucralfatetreatment]. [German]. HNO 1990;38(1):24–8.

Schneider 1999 {published data only}

Schneider SB, Nishimura RD, Zimmerman RP, Tran L, Shiplacoff

J, Tormey M, et al.Filgrastim (r-metHuG-CSF) and its potentialuse in the reduction of radiation-induced oropharyngeal mucositis: An interim look at a randomized, double blind, placebo-controlledtrial. Cytokines, Cellular and Molecular Therapy 1999;5(3):175–80.

Shenep 1988 {published and unpublished data}

Shenep JL, Kalwinsky DK, Hutson PR, George SL, Dodge RK,Blankenship KR, et al.Efficacy of oral sucralfate suspension inprevention and treatment of chemotherapy-induced mucositis.

Journal of Pediatrics 1988;113(4):758–63.

Shieh 1997 {published data only}

Shieh SH, Wang ST, Tsai ST, Tseng CC. Mouth care fornasopharyngeal cancer patients undergoing radiotherapy. Oral

Oncology 1997;33(1):36–41.

Spencer 2005 {published data only}Spencer A, Horvath N, Gibson J, Prince HM, Herrmann R,Bashford J, et al.Prospective randomised trial of amifostinecytoprotection in myeloma patients undergoing high-dosemelphalan conditioned autologous stem cell transplantation. Bone

Marrow Transplantation2005;35(10):971–7.

Spielberger 2004 {published data only}

Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D,Kewalramani T, et al.Palifermin for oral mucositis after intensivetherapy for hematologic cancers. The New England Journal of

Medicine 2004;351(25):2590–8.

Spijkervet 1989 {published data only}

Spijkervet FKL, van Saene HK, Panders AK, Vermey A, van Saene

JJ, Mehta DM, et al.Effects of chlorhexidine rinsing on theoropharyngeal ecology in patients with head and neck cancer whohave irradiation mucositis. Oral Surgery, Oral Medicine, Oral Pathology 1989;67(2):154–61.

Stokman 2003 {published data only}

Stokman MA, Spijkervet FK, Burlage FR, Dijkstra PU, Manson WL, de Vries EG, et al.Oral mucositis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: adouble-blind randomised clinical trial. British Journal of Cancer

2003;88(7):1012–6.

Su 2003 {published data only}

Su C, Mehta V, Ravikumar L, Shah R, Pinto H, Halpern J, etal.Phase II double-blind randomized study comparing oral aloe vera(AV) versus placebo to prevent radiation (RT)-related mucositis in

patients with head and neck (HN) neoplasms. International Journal

of Radiation, Oncology, Biology and Physics 2004;60(1 Sept):171–7.Symonds 1996 {published data only}

Symonds RP, McIlroy P, Khorrami J, Pyper E, Alcock SR,McCallum I, et al.The reduction of radiation mucositis by selectivedecontamination antibiotic pastilles: a placebo-controlled double-blind trial. British Journal of Cancer 1996;74(2):312–7.

Trotti 2004 {published data only}∗ Trotti A, Garden A, Warde P, Symonds P, Langer C, Redman R, etal.A multinational, randomized phase III trial of iseganan HCl oralsolution for reducing the severity of oral mucositis in patientsreceiving radiotherapy for head-and-neck malignancy. International

Journal of Radiation Oncology, Biology and Physics 2004;58(3):674–81.Trotti A, Garden AS, Warde P, Symonds P, Langer C, Fleming T, et

al.Phase III trial of iseganan HCL oral solution (iseganan) forreducing oral mucositis severity in patients receiving radiotherapy for head and neck malignancies (PROMPT-RT). Proceedings of the Annual Meeting of the American Society of Clinical Oncology.2002:(Abs No 908).

van der Lelie 2001 {published data only}

van der Lelie H, Thomas BL, van Oers RH, Ek-Post M,Sjamsoedin SA, van Dijk-Overtoom ML, et al.Effect of locally applied GM-CSF on oral mucositis after stem cell transplantation:a prospective placebo-controlled double-blind study. Annals of

Hematology 2001;80(3):150–4.

Vokurka 2005 {published data only}

Vokurka S, Bystricka E, Koza V, Scudlova J, Pavlicova V, ValentovaD, et al.The comparative effects of povidone-iodine and normalsaline mouthwashes on oral mucositis in patients after high-dosechemotherapy and APBSCT--results of a randomized multicentrestudy. Supportive Care in Cancer 2005;13(7):554–8.

Wahlin 1989 {published and unpublished data}

Wahlin YB. Effects of chlorhexidine mouthrinse on the oral healthin patients with acute leukemia. Oral Surgery, Oral Medicine, Oral

Pathology 1989;68(3):279–87.

Wang 2002a {published data only}

Wang J. Effect on Chinese herbs decoction gargling to treat and toprevent chemotherapy caused stomatitis. Chinese Nursing Research

2002;16(10):578–9.

Wijers 2001 {published data only}

Wijers OB, Levendag PC, Harms ER, Gan-Teng AM, Schmitz PI,

Hendriks WD, et al.Mucositis reduction by selective elimination of oral flora in irradiated cancers of the head and neck: A placebo-controlled double-blind randomized study. International Journal of

Radiation Oncology, Biology and Physics 2001;50(2):343–52.

Yuen 2001 {published data only}

Yuen KY, Woo PCY, Tai JW, Lie AK, Luk J, Liang R. Effects of clarithromycin on oral mucositis in bone marrow transplantrecipients. Haematologica 2001;86(5):554–5.

References to studies excluded from this review

Adamietz 1997 {published data only}

Adamietz IA, Rahn R, Bottcher HD, Reimer K, Fleischer W.Prophylaxis of radiation induced oral mucositis with povidoneiodine. Supportive Care in Cancer 1997;5 Suppl:165 (Abs No 48).





Altmann 1999 {published data only}

Altmann S Hoffmanns H. [Cytoprotection with amifostine inradiotherapy or radio-chemotherapy of head and neck tumors].[German]. Strahlentherapie und Onkologie 1999;175(Suppl 4):30–3.

Andersen 1987 {published data only}

Andersen E, Pedersen H. Oral ftorafur versus intravenous 5-fluorouracil. A comparative study in patients with colorectal cancer.

Acta Oncologica 1987;26(6):433–6.

Anderson 1998b {published data only}

Anderson PM, Ramsay NKC, Shu XO, Rydholm N, Rogosheske J,Nicklow R, et al.Effect of low dose oral glutamine on painfulstomatitis during bone marrow transplantation. Bone Marrow


Antin 2002 {published data only} Antin JH, Lee SJ, Neuberg D, Alyea E, Soiffer RJ, Sonis S, et al.A phase I/II double-blind, placebo-controlled study of recombinanthuman interleukin-11 for mucositis and acute GVHD preventionin allogeneic stem cell transplantation. Bone Marrow


Antonadou 1998 {published data only}

Antonadou D, Athanassiou E, Synodinou M, Koliarakis N,Panoussaki K, Karageorgis P, et al.Evaluation of the efficacy of granulocyte macrophage colony stimulating factor (GM-CSF) inthe prevention of radiation induced mucositis [abstract].Radiotherapy Oncology 1998;48(S1):S39.

Apaydin 1996 {published data only}

Apaydin A, Karadeniz AN, Aysigi G, Blige N. The effect andtherapeutical use of benzydamine HCL on radiation-induced oralcavity and oropharyngeal mucositis. Medical Bulletin Istanbul

1996;29:1:59–63.

Aquino 2005 {published data only}

Aquino VM, Harvey AR, Garvin JH, Godder KT, Nieder ML, Adams RH, et al.A double-blind randomized placebo-controlledstudy of oral glutamine in the prevention of mucositis in childrenundergoing hematopoietic stem cell transplantation: a pediatricblood and marrow transplant consortium study. Bone Marrow


Ardizzoni 2002 {published data only}

Ardizzoni A, Tjan-Heijnen VC, Postmus PE, Buchholz E, BiesmaB, Karnicka-Mlodkowska H, et al.Standard versus intensified

chemotherapy with granulocyte colony-stimulating factor supportin small-cell lung cancer: a prospective European Organization forResearch and Treatment of Cancer-Lung Cancer Group Phase IIITrial-08923. Journal of Clinical Oncology 2002;20(19):3947–55.

Awada 2002 {published data only}

Awada A, Biganzoli L, Cufer T, Beex L, Lohrisch C, Batter V, etal.An EORTC-IDBBC phase I study of gemcitabine andcontinuous infusion 5-fluorouracil in patients with metastaticbreast cancer resistant to anthracyclines or pre-treated with bothanthracyclines and taxanes. European Journal of Cancer 2002;38(6):773–8.

Awada 2004 {published data only}

Awada A, Gil T, Sales F, Dubuisson M, Vereecken P, Klastersky J, etal.Prolonged schedule of temozolomide (Temodal) plus liposomal

doxorubicin (Caelyx) in advanced solid cancers. Anti-Cancer Drugs

2004;15(5):499–502. Awidi 2001 {published data only}

Awidi A, Homsi U, Kakail RI, Mubarak A, Hassan A, Kelta M,Martinez P, et al.Double-blind, placebo-controlled cross-over study of oral pilocarpine for the prevention of chemotherapy-induced oralmucositis in adult patients with cancer. European Journal of Cancer

2001;37(16):2010–4.

Awwad 2002 {published data only}

Awwad HK, Lotayef M, Shouman T, Begg AC, Wilson G, BentzenSM, et al.Accelerated hyperfractionation (AHF) compared toconventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cnacer: influence of proliferation. British Journal of Cancer 2002;86(4):517–23.

Barasch 1995 {published data only}Barasch A, Peterson DE, Tanzer JM, D’Ambrososio JA, Nuki K,Schubert MM, et al.Helium-Neon laser effects on conditioning-induced oral mucositis in bone marrow transplantation patients.Cancer 1995;76(12):2550–6.

Bensadoun 1995 {published data only}

Bensadoun R, Cowen D, Nguyen TD, Ciais G, Franquin JC,Dassonville O, et al.Low energy laser in the prevention of radiation-induced mucositis: A phase III randomized multicentric study inpatients with head and neck cancer. Fifth International Congresson Anti-Cancer Chemotherapy. 1995.


Bensadoun R, Franquin J, Benezery K, Ciais G, Tardieu C, Dejou J, et al.Low energy He/Ne laser in the prevention of radiationinduced mucositis: A multicenter phase III double blind study forpatients with head and neck cancer. Proceedings of ASCO. 1999.Bensadoun RJ, Ciais G, Darcourt V, Franquin JC, Cheynet C,Cowen D, et al.Low energy laser in the prevention of radiationinduced mucositis: a phase II randomized multicentre study forpatients with head and neck cancer. Supportive Care in Cancer 1999;7:SO–13.∗ Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM,Viot M, et al.Low-energy He/Ne laser in the prevention of radiation-induced mucositis. A multicentre phase III randomizedstudy in patients with head and neck cancer. Supportive Care in

Cancer 1999;7(4):244–52.


Bensadoun RJ, Benezery K, Dassonville O, Magne N, PoissonnetG, Ramaioli A, et al.French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngealcarcinoma: Results at 2 years (FNCLCC-GORTEC). International


Bentzen 2001 {published data only}

Bentzen SM, Saunders MI, Dische S, Bond SJ. Radiotherapy-related early morbidity in head and neck cancer: quantitativeclinical radiobiology as deduced from the CHART trial.Radiotherapy Oncology 2001;60(2):123–35.

Bergmann 1995 {published data only}

Bergmann OJ, Ellermann-Eriksen S, Mogensen SC, Ellegaard J. Acyclovir given as prophylaxis against oral ulcers in acute myeloid





leukaemia: randomised, double blind, placebo controlled trial.

BMJ 1995;6(310):116–72.Bleehen 1996 {published data only}

Bleehen NM, Girling DJ, Hopwood P, Lallemand G, Machin D,Stephens RJ, et al.Randomised trial of four-drug vs less intensivetwo-drug chemotherapy in the palliative treatment of patients withsmall-cell lung cancer (SCLC) and poor prognosis. British Journal of Cancer 1996;73:406–13.

Bolwell 2004 {published data only}

Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L,Kuczkowski E, et al.A prospective randomized trial comparingcyclosporine and short course methotrexate with cyclosporine andmycophenolate mofetil for GVHD prophylaxis in myeloablativeallogeneic bone marrow transplantation. Bone Marrow


Bourhis 2006 {published data only}

Bourhis J, Lapeyre M, Tortochaux J, Rives M, Aghili M, Bourdin S,et al.Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cellhead and neck cancer: a GORTEC trial. Journal of Clinical Oncology 2006;24(18):2873–8.

Braaksma 2002 {published data only}

Braaksma M, Levendag P. Tools for optimal tissue sparing inconcomitant chemoradiation of advanced head and neck cancer:subcutaneous amifostine and computed tomography-based targetdelineation. Seminars in Oncology 2002;29(6 Supp 19):63–70.

Buentzel 1999 {published data only}

Buentzel J, Glatzel M, Weinaug R, Schuth J, Kuettner K, Froehlich

D. Amifostine in combined radio- and chemomodalities for headand neck cancer. European Journal of Cancer 1999;35(Suppl 4):363(Abs No 1472).

Calais 1998 {published data only}

Calais GM, Alfonsi E, Bardet C, Sire H, Bourgeois C, Bergerot B,et al.Randomized study comparing radiation alone (RT) versus RT with concomitant chemotherapy (CT) in stages III andf IV oropharynx carcinoma (ARCORO). Preliminary results of the94.01 study from the French Group of radiation oncology for headand neck cancer (GORTEC). Proceedings of Annual Meeting of the American Society of Clinical Oncology. 1998:(Abs No 1484).


Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, etal.[Stage III and IV cancers of the oropharynx: results of a

randomized study of Gortec comparing radiotherapy alone withconcomitant chemotherapy]. Bulletin du Cancer 2000;87 Spec No:48–53.


Calais G, Bardet E, Sire C, Alfonsi M, Bourhis J, Rhein B, etal.Radiotherapy with concomitant weekly docetaxel for stagesIII/IV oropharynx carcinoma. Results of the 98-02 GORTECphase II trial. International Journal of Radiation, Oncology, Biology

and Physics 2004;58(1 Jan):161–6.

Cassidy 2002 {published data only}

Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Boyer M, etal.First-line oral capecitabine therapy in metastatic colorectalcancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Annals of Oncology 2002;13(4):566–75.

Cella 2003 {published data only}

Cella D, Pulliam J, Fuchs H, Miller C, Hurd D, Wingard JR, etal.Evaluation of pain associated with oral mucositis during the acuteperiod after administration of high-dose chemotherapy. Cancer 2003;98(2):406–12.

Cheng 2001 {published data only}

Cheng KK Molassiotis A, Chang AM, Wai WC, Cheung SS.Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients.European Journal of Cancer 2001;37(16):2056–63.


Cheng KKF, Malassiotis A, Chang AM. An oral care protocolintervention to prevent chemotherapy-induced oral mucositis inpaediatric cancer patients: a pilot study. European Journal of Oncology Nursing 2002;6(2):66–74.


Cheng KK, Chang AM. Palliation of oral mucositis symptoms inpediatric patients treated with cancer chemotherapy. Cancer

Nursing 2003;26(6):476–84.

Cheng 2004a {published data only}

Cheng KK. Children’s acceptance and tolerance of chlorhexidineand benzydamine oral rinses in the treatment of chemotherapy-induced oropharyngeal mucositis. European Journal of Oncology

Nursing 2004;8(4):341–9.

Cheng 2004b {published data only}

Cheng KK, Chang AM, Yuen MP. Prevention of oral mucositis inpaediatric patients treated with chemotherapy; a randomisedcrossover trial comparing two protocols of oral care. European

Journal of Cancer 2004;40(8):1208–16.

Chi 1995 {published data only}

Chi KH, Chen CH, Chan WK, Yen SH, Liang MJ, Chou KC, etal.Effect of granulocyte-macrophage colony-stimulating factor(GH-CFS) on oral mucositis in head and neck cancer patients aftercisplatin, 5-FU and leucovorin chemotherapy. Proceedings of Annual Meeting American Society of Clinical Oncology. 1994;Vol. 13:A1469.∗ Chi KH, Chen SY, Chan WK, Yen SH, Liang MJ, Chou KC, etal.Effect of granulocyte-macrophage colony-stimulating factor(GH-CFS) on oral mucositis in head and neck cancer patients aftercisplatin, 5-FU and leucovorin chemotherapy. Journal of Clinical

Oncology 1995;13(10):2620–8.

Collova 2004 {published data only}Collova E, Castagna L, Nozza A, Perfetti V, Patrone F, Danova M,et al.New approaches for reduction of oral mucositis in patientsundergoing high-dose chemotherapy with hematopoietic stem cellsupport. Bone Marrow Transplantation 2004;33(Suppl 1):S323–S4.

Colombat 1995 {published data only}

Colombat P, Colin B. Comparison of fluconazole and amphotericinB in the prevention of mucositis in patients with long term aplasia.Bone Marrow Transplantation 1995;15:178.

Costa 1999 {published data only}

Costa EMMB, Pinto LP, Fernandes MZ, Costa ALL. Preventingoral complications in leukemic children submitted tochemotherapy. Journal of Dental Research 1999;78:1021 (Abs NoB-220).





Costa 2003 {published data only}

Costa EM, Fernandes MZ, Quinder LB, de Souza LB, Pinto LP.Evaluation of an oral preventive protocol in children with acutelymphoblastic leukemia. Pesquisa Odontologica Brasileira 2003;17

(2):147–50.

Cowen 1997 {published data only}

Cowen D, Tardieu C, Resbeut M, Hannoun-Levi JM, Alzieu C,Schubert M, et al.Low energy helium-neon laser presents oralmucositis after high-dose chemo-radiotherapy: results of a double-blind randomized trial. International Journal of Radiation Oncology,

Biology and Physics 1996;36(1S):264 (A1041).∗ Cowen D, Tardieu C, Schubert M, Peterson D, Resbeut M,Faucher C, et al.Low energy Helium-neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant:Results of a double blind randomized trial. International Journal of

Radiation Oncology, Biology and Physics 1997;38(4):697–703.Crawford 1994 {published data only}

Crawford J, Glaspy J, Vincent M, Tomita D, Mazanet R. Effect of filgrastim (r-metHug-CSF) on oral mucositis in patients with smallcell lung cancer (SCLC) receiving chemotherapy (cyclophosphamide, doxorubicin and etoposide, CAE). Proceedingsof Annual Meeting of American Society Clinical Oncology. 1994;Vol. 13:(Abs No A1523).

Crispino 1997 {published data only}

Crispino SP, Olmi C, Fallai F, Rossi S, Marsoni A, Tinazzi M, etal.Conventional radiotherapy (RT) versus acceleratedhyperfractionated RT versus conventional RT and concomitantchemotherapy in locally advanced oropharyngeal carcinoma (ORO-93/01). Proceedings of the American Society of Clinical Oncology.1997.

Cruz 1997 {published data only}

Cruz J, Fonseca E, Rodriguez CA, Gomez-Bernal A, Martin G,Sanchez P, et al.Randomized trial of cisplatin (P) plus 5-fluorouracil(F) with or without folinic acid in locally advanced head and neck cancer (LAHNC). Proceedings of the European CancerConference. 1997:(Abs No 854).

Cunningham 1995 {published data only}

Cunningham D, Zalcberg JR, Rath U, Olver I, van Cutsem EV,Sevensson C, et al.’Tomudex’ (ZD1694): results of a randomisedtrial in advanced colorectal cancer demonstrate efficacy and reducedmucositis and leucopenia. European Journal of Cancer 1995;31A

(12):1945–54.

De Boer 2002 {published data only}De Boer RH, Eisen TG, Ellis PA, Johnston SR, Walsh G, Ashley S,et al.A randomised phase II study of conventional versus acceleratedinfusional chemotherapy with granulocyte colony-stimulatingfactor support in advanced breast cancer. Annals of Oncology 2002;13(6):889–94.

Decker-Baummann 1999 {published data only}

Decker-Baumann C, Buhl K, Frohmuller S, von Herbay A, Dueck M, Schlag PM. Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastaticcolorectal cancer. European Journal of Cancer 1999;35(2):202–7.

Denham 1999 {published data only}

Denham JW, Peters LJ, Johansen J, Poulsen M, Lamb DS, Hindley A, et al.Do acute mucosal reactions lead to consequential late

reactions in patients with head and neck cancer?. Radiotherapy

Oncology 1999;52(2):157–64.Djuric 2006 {published data only}

Djuric M, Hillier-Kolarov V, Belic A, Jankovic L. Mucositisprevention by improved dental care in acute leukemia patients.Supportive Care in Cancer 2006;14(2):137–46.

Dobrowsky 1998 {published data only}

Dobrowsky W, Naude J, Widder J, Dobrowsky E, Millesi W,Pavelka R, et al.Continuous hyperfractionated acceleratedradiotherapy with/without mitomycin C in head and neck cancer.International Journal of Radiation Oncology, Biology and Physics

1998;42(4):803–6.

Doroshow 1987 {published data only}

Doroshow JH, Berthtand M, Newman E, Multhauf P, Leong L,

Blayney D, et al.Preliminary analysis of a randomized comparisonof 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer. NCI

Monographs 1987;5:171–4.

Dudjak 1987 {published data only}

Dudjak LA. Mouth care for mucositis due to radiation therapy.Cancer Nursing 1987;10(3):131–40.

Edelman 1998 {published data only}

Edelman MJ, Gandara Dr, Perez EA, Lau D, Lauder I, Turrell C, etal.Phase I trial of edatrexate plus carboplatin in advanced solidtumors: amelioration of dose-limiting mucositis by ice chipcryotherapy. Investigational New Drugs 1998;16(1):69–75.

Eisen 2003 {published data only}

Eisen D, Essel J, Broun ER, Sigmund D, DeVoe M. Clinical utility of oral valacyclovir compared with oral acyclovir for the preventionof herpes simplex virus mucositis following autologous bonemarrow transplantation or stem cell rescue therapy. Bone Marrow Transplantation 2003;31(1):51–5.

El-Sayed 2000 {published data only}

El-Sayed S, Nabid A, MacKenzie R, Gelinas M, Hay J, Shelley, etal.Prophylaxis of radiation associated mucositis (RAM) in head andneck cancer, results of a double blind phase III trail evaluating theclinical efficacy of an antimicrobial lozenge utilizing a new validatedmucositis scoring system. Proceedings of the 42nd Annual Meetingof the American Society of Therapeutic Oncology. 2000; Vol. 321:(Abs No 2115).

El-Sayed 2002b {published data only}El-Sayed S, Epstein J, Minish E, Burns P, Hay J, Laukkanen E. A pilot study evaluating the safety and microbiologic efficacy of aneconomically viable antimicrobial lozenge in patients with head andneck cancer receiving radiation therapy. Head & Neck 2002;24(1):6–15.

Epstein 1986 {published data only}

Epstein JB, Stephenson-Moore P. Benzydamine hydrochloride inprevention and management of pain in oral mucositis associated with radiation therapy. Oral Surgery, Oral Medicine, Oral Pathology

1986;62(2):145–8.


Epstein JB, Stevenson-Moore P, Jackson S, Mohamed JH, Spinelli JJ. Prevention of oral mucositis in radiation therapy: A controlled





study with benzydamine hydrochloride rinse. International Journal

of Radiation Oncology, Biology and Physics 1989;16(6):1571–5.Epstein 1992 {published data only}

Epstein JB, Vickars L, Spinalli J, Reece D. Efficacy of chlorhexidineand nystatin rinses in prevention of oral complications in leukemiaand bone marrow transplantation. Oral Surgery, Oral Medicine,

Oral Pathology 1992;73(6):682–9.


Epstein JB, Wong FLW. The efficacy of sucralfate suspension in theprevention of oral mucositis due to radiation therapy. International

Journal of Radiation Oncology, Biology and Physics 1994;28(3):693–8.


Epstein J, Silverman S Jr, Pagerino D, Lockhart P, Schubert M,Crockett R. Benzydamine HCL for prophylaxis of irradiationinduced oral mucositis: a randomized double-blind, multicenterstudy. Supportive Care in Cancer 1999;7 Suppl:169 (Abs No O-18).


Epstein JB, Silverman S, Paggiarino DA, Crockett S, SchubertMM, Senzer NN, et al.Benzydamine HCI for prophylaxis of radiation-induced oral mucositis. Cancer 2001;92(4):875–85.

Erkisi 1996 {published data only}

Erkisi M, Erkurt E, Ozbarlas S, Burgut R, Doran F, Seyrek E. Theuse of recombinant human granulocyte colony-stimulating factor incombination with single or fractionated doses of ifosfamide anddoxorubicin in patients with advanced soft tissue sarcoma. Journal of Chemotherapy 1996;8(3):224–8.

Etiz 1998 {published data only}

Etiz M, Erkal HS, Serin M, Kucuk B, Hepari A, Tulunay O, etal.Clinicohistopathological evaluation of effectiveness of sucralfatein prevention of severe radiation-induced mucositis in patients withhead and neck malignancies. Radiotherapy Oncology 1998;48(S1):S68.

Etiz 2000 {published data only}

Etiz D, Erkal HS, Serin M, Kucuk B, Hepari A, Elhan AH, etal.Clinical and histopathological evaluation of sucralfate inprevention of oral mucositis induced by radiation therapy inpatients with head and neck malignancies. Oral Oncology 2000;36

(1):116–20.

Evans 1990 {published data only}

Evans G, Mahendra P, Brightwell M, Jestivfe K, Marcus R. A doubleblind randomised trial of oral GMCFS mouthwash versus placebo

in the treatment of mucositis following PBSC/bone marrow transplantation. Bone Marrow Transplantation 1998;21(S1):S88.∗ Evans WK, Wierzbicki R, Shepherd FA, Rusthoven J, Stewart DJ, Aitken SE, et al.5-Fluorouracil with folinic acid is not effectiveagainst metastatic adenocarcinoma of the lung. Cancer Investigation

1990;8(3-4):345–9.

Evensen 2001 {published data only}

Evensen JF, Bjordal K, Jacobsen AB, Lokkevik E, Tausjo JE. Effectsof Na-sucrose octasulfate on skin and mucosa reactions duringradiotherapy of head and neck cancers--a randomized prospectivestudy. Acta Oncologica 2001;40(6):751–5.

Ezzat 2005 {published data only}

Ezzat M, Shouman T, Zaza K, Safwat A, El-Khoudary A, El-SenosiM, et al.A randomized study of accelerated fractionation

radiotherapy with and without mitomycin C in the treatment of

locally advanced head and neck cancer. Journal of the EgyptianNational Cancer Institute 2005;17(2):85–92.

Fahlke 1999 {published data only}

Fahlke J, Ridwelski K, Lippert H. High-dose therapy withcombined 5-fluorouracil and folinic acid with and withoutamifostine in the treatment of patients with metastatic colorectalcarcinoma. International Journal of Colorectal Disease 1999;14(2):128–30.

Falcone 2001 {published data only}

Falcone A, Allergrini G, Masi G, Lencioni M, Panner E, Brunetti I.5-fluorouracil administered as a 48-hour chronomodulated infusionin combination with leucovorin and cisplatin: a randomized phaseII study in metastatic colorectal cancer. Oncology 2001;61(1):

28–35.Fay 1994 {published data only}

Fay JW, Lazarus H, Herzig R, Saez R, Stevens DA, Collins RH Jr,et al.Sequential administration of recombinant human interleukin-3 and granulocyte-macrophage colony-stimulating factor afterautologous bone marrow transplantation for malignant lymphoma:a phase I/II multicenter study. Blood 1994;84(7):2151–7.

Feber 1995 {published data only}

Feber T. Mouth care for patients receiving oral irradiation.Professional Nurse 1995;10(10):666–70.

Feber 1996 {published data only}

Feber T. Management of mucositis in oral irradiation. Clinical Oncology 1996;8(2):106–11.

Ferreira 2002 {published data only}

Ferreira PR, Fleck J, Filho AB, Barletta D, Barletta A, Diehl A, etal.Protective effect of vitamin E (VE) in head and neck cancerradiation induced mucositis: a double-blind randomized trial.Proceedings of American Society of Clinical Oncology Meeting.2002:(Abs No 909).

Ferreira 2004 {published data only}

Ferreira PR, Fleck JF, Diehl A, Barletta D, Braga-Filho A, Barletta A, et al.Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: a double-blind randomizedtrial. Head & Neck 2004;26(4):313–21.

Ferretti 1985 {published data only}

Ferretti G, Largent B, Brown A, Lillich T, Ash R. The effect of chlorhexidine mouthrinse on mucositis, plaque, gingivitis and stainin bone marrow transplant patients. Journal of Dental Research

1985;64(Special Issue):235 (Abs No 546).

Foncuberta 2001 {published data only}

Foncuberta MC, Cagnoni PJ, Brandts CH, Mandanas R, Fields K,Derigs HG, et al.Topical transforming growth factor-beta3 in theprevention or alleviation of chemotherapy-induced oral mucositisin patients with lymphomas or solid tumors. Journal of

Immunotherapy 2001;24(4):384–8.

Gabison 1995 {published data only}

Gabison R. Can zinc picolinate in patients receiving chemotherapy for metastatic colorectal carcinoma prevent stomatitis?. European

Journal of Cancer 1995;31A (Suppl 5):S258 (Abs No 1234).





Giles 2003b {published data only}

Giles FJ, Faderl S, Thomas DA, Cortes JE, Garcia-Manero G,Douer D, et al.Randomized phase I/II study of troxacitabinecombined with cytarabine, idarubicin, or topotecan in patients withrefractory myeloid leukemias. Journal of Clinical Oncology 2003;21

(6):1050–6.

Goldberg 2003 {published data only}

Goldberg S. Safety and tolerability of en3247 in the prevention of oral mucositis associated with chemotherapy with or without totalbody irradiation: results of a randomized, double-blind, placebo-controlled trial. Proceedings of the American Society of ClinicalOncology. 2003:770.

Grotz 2001 {published data only}∗ Grotz KA, Henneicke-Von Zepelin H-H, Kohnen R, Kutzner J.Belz GG. Prophylaxis of mucositis and dry mouth after head and

neck radiotherapy. A new treatment. Krankenhauspharmazie 2002;23(5):193–8.Grotz KA, Wustenberg P, Kohnen R, Al-Nawas B, Henneicke-vonZepelin H, Bockisch A, et al.Prophylaxis of radiogenic sialadenitisand mucositis by coumarin/troxerutine in patients with head andneck cancer- a prospective, randomized, placebo-controlled,double-blind study. British Journal of Oral and Maxillofacial Surgery 2001;39(1):34–9.

Gujral 1999 {published data only}

Gujral MS, Patnaik PM, Kaul R, Daftary GV, Parikh HK,Tamhankar CP, et al.Oral enzymes preventing side effects of radiation therapy in patients with head and neck cancers. European

Journal of Cancer 1999;35(Suppl 4):168 (Abs No 634).

Gutierrez 1996 {published data only}Gutierrez AR, Boizas EC, Carreras PS, Rodriguez CS, RodriguezOA, Chicote MJV, et al.Fluconazol as prophylaxis of radioinducedoral mucositis. Preliminary study [Fluconazol en la profilaxis de lamucositis oral radioinducida. Estudio preliminar]. Oncologia 1996;19(6):56–9.

Hanson 1995 {published data only}

Hanson WR, Marks JE, Reddy SP, Simon S, Mihalo WE, Tova Y.Protection from radiation-induced oral mucositis by misoprostol, aprostaglandin E(1) analog: a placebo-controlled, double-blindclinical trial. American Journal of Therapeutics 1995;2(11):850–7.

Hanson 1997 {published data only}

Hanson WR, Marks JE, Reddy SP, Simon S, Mihalo WE, Tova Y.Protection from radiation-induced oral mucositis by a mouth rinse

containing the prostaglandin E1 analog, misoprostol: A placebocontrolled double blind clinical trial. Advances in Experimental

Medicine and Biology 1997;400B:811–8.

Harris 1995 {published data only}

Harris JR, Russell NH, Hunter AE. Folinic acid mouthwashes donot reduce the degree of mucositis in patients undergoingallogeneic bone marrow transplantation. Bone Marrow

Transplantation 1995;15(S2):S164.

Hartmann 1999 {published data only}

Hartmann J, von Vangerow A, Knop S, Brugger W, Fels L, StolteH, et al.A randomized trial comparing the toxicity and thetreatment costs of HD-VIC plus PBSC transplantation with or without amifostine (AMI) in patients with solid tumors. European

Journal of Cancer 1999;35(Suppl 4):361 (Abs No 1464).

He 2004 {published data only}

He XY, Hu CS, Wu YR. Radioprotective effect of amifostine innasopharyngeal carcinoma. Acta Academiae Medicinae Shanghai2004; Vol. 31, issue 1.

Hickey 1982 {published data only}

Hickey AJ, Toth BB, Lindquist SB. Effect of intravenoushyperalimentation and oral care on the development of oralstomatitis during cancer chemotherapy. The Journal of Prosthetic

Dentistry 1982;47(2):188–93.

Howell 1983 {published data only}

Howell SB, Pfeifle CE, Wung WE. Effect of allopurinol on thetoxicity of high-dose 5-fluorouracil administered by intermittentbolus injection. Cancer 1983;51(2):220–5.

Hu 2003 {published data only}Hu K, Ship JA, Harrison LB. Rationale for integrating high-doserate intraoperative radiation (HDR-IORT) and postoperativeexternal beam radiation with subcutaneous amifostine for themanagement of stage III/IV head and neck cancer. Seminars inOncology 2003;30(6 Suppl 18):40–8.

Ito 2002 {published data only}

Ito A, Hanawa T, Fujii E. The preventive effect of allopurinol spray on stomatitis induced by anti-cancer drugs. Gan To Kagaku Ryoho

2002;29(4):563–7.

Jebb 1995 {published data only}

Jebb SA, Marcus R, Elia M. A pilot study of oral glutaminesupplementation in patients receiving bone marrow transplants.

Clinical Nutrition 1995;14:162–5. Johnson 2002 {published data only}

Johnson DJ, Scott CB, Marks JE, Seay TE, Atkins JN, Berk LB, etal.Assessment of quality of life and oral function of patientsparticipating in a phase II study of radioprotection of oral andpharyngeal mucosa by the prostaglandin E(1) analog misoprostol(RTOG 96-07). International Journal or Radiation Oncology Biology

and Physics 2002;54(5):1455–9.

Kante 1995 {published data only}

Kante V. Comparative study of two prophylactic regimes for theprevention of mucositis in autologous bone marrow transplants.Bone Marrow Transplantation 1995;15:253.

Karthaus 1998 {published data only}

Karthaus M, Rosenthal C, Huebner G, Paul H, Elser C,Hertenstein B, et al.Effect of topical oral G-CSF on oral mucositis:a randomised placebo-controlled trial. Bone Marrow


Kasten-Sportes 2003 {published data only}

Kasten-Sportes C. Randomized study of acupuncture for mucositis-related pain secondary to high-dose chemotherapy in patientsundergoing hematopoietic stem cell transplantation. PDQ (NCI-03-C-0125) 2003.

Kenny 1990 {published data only}

Kenny SA. Effect of two oral care protocols on the incidence of stomatitis in hematology patients. Cancer Nursing 1990;13(6):345–53.





Klocke 2006 {published data only}

Klocke J, Cannon M, Gissinger D, Bayer R, Devoe C, John V.Prevention of mucositis in auto BMT/stem cell transplant patients.Oncology Nursing Forum 2006;33(2):454.

Kokkonen 2002 {published data only}

Kokkonen J, Mottonen M, Karttunen TJ, Lanning M. Mucosalpathology of the upper gastrointestinal tract associated withintensive chemotherapy in children: Vitamin a supplements do notprevent lesions. Pediatric Hematology and Oncology 2002;19(3):181–92.

Labar 1990 {published data only}

Labar B, Pavletic Z, Bogdanic V, Nemet D, Aurer I, Jakie J.Prostaglandin E2 for prevention of oral mucositis in patients withleukaemia undergoing bone marrow transplantation: a radomizeddouble-blind clinical trial. Experimental Hematology 1990;18:700.

Labbate 2003 {published data only}

Labbate R, Lehn CN, Denardin OVP. Effects of chlorhexidinemouthwash on radiation induced mucosistis in head and neck cancer. Revista Brasileira de Otorrinolaringologia 2003;69(3):349–54.

Leong 1995 {published data only}

Leong L, Sakurai C, Sebastian W, Shaw N, Grant E, Grant M, etal.Phase III trial assessing the use of oral thymidine (THY) forprevention of fluorouracil (5-FU)-induced mucositis. Proceedingsof the Annual Meeting of the American Society of ClinicalOncology. 1995; Vol. 14:A334.

Levendag 1998 {published data only}

Lavendag PC, Wijers OB, Harms RE, Schmitz PIM, Wilms BE,

Visch LL. Mucositis prevention by selective elimination of oral florain irradiated cancers of the head and neck: a prospectiverandomized study. Radiotherapy Oncology 1998;48:S10.

Levi 1997 {published data only}

Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid inmetastatic colorectal cancer. Lancet 1997;350(9079):681–6.

Lievens 1998 {published data only}

Lievens Y, Haustermans K, van den Weyngaert D, van den Bogaert W, Scalliet P, Hutsebaut L, et al.Does sucralfate reduce the acuteside-effects in head and neck cancer treated with radiotherapy?A double-blind randomized trial. Radiotherapy Oncology 1998;47(2):149–53.

Lin 2006 {published data only}

Lin LC, Que J, Lin LK, Lin FC. Zinc supplementation to improvemucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. International


Lopez 1994 {published data only}

Lopez I, Goudou C, Ribrag V, Sauvage C, Hazebroucq G, DreyfusF. Traitement des mucites par la vitamine E lors de l’administrationd’anti-neoplasiques neutropeniants. Annuals Medicine Interne

1994;145(6):405–8.

Loprinzi 1997 {published data only}

Loprinzi CL, Ghosh C, Camoriano J, Sloan J, Steen PD, Michalak JC, et al.Phase III controlled evaluation of sucralfate to alleviatestomatitis in patients receiving fluorouracil-based chemotherapy.

Journal of Clinical Oncology 1997;15(3):1235–8.

Lorusso 2003 {published data only}

Lorusso D, Ferrandina G, Greggi S, Gadducci A, Pignata S, TateoS. Phase III multicenter randomized trial of amifostine ascytoprotectant in first-line chemotherapy in ovarian cancer patients.

Annals of Oncology 2003;14(7):1086–93.

Lozada 1998 {published data only}

Lozada-Nur F, Schoelch M, Fu K, Muscoplat C, Trivedi M, SmithC, et al.A pilot study to evaluate the effect of pilocarpine tablets onsalivary flow and mucositis in head and neck cancer patients duringradiotherapy. Proceedings of the Annual Meeting of the Society of Clinical Oncology. 1998:1541.

Madero 1999 {published data only}

Madero L, Diaz MA, Ortega JJ, Olive T, Martinez A, Badell I, etal.Recombinant human granulocyte-macrophage colony-

stimulating factor accelerates engraftment kinetics after allogeneicbone marrow transplantation for childhood acute lymphoblasticleukemia. Haematologica 1999;84(2):133–7.

Mahmoud 1996 {published data only}

Mahmoud HK SE, Kamel M, El HMA, Nassar A. Influence of folinic acid rescue on methotrexate-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation. Tumor Diagnostik Und Therapie 1996;17(1):18–21.

Malaker 1991 {published data only}

Malaker K, Anderson BJ, Beecroft WA, Hodson DI. Managementof oral mucosal dysplasia with beta-carotene retinoic acid: a pilotcross-over study. Cancer Detection and Prevention 1991;15(5):335–40.

Mantovani 2003 {published data only}

Mantovani G, Massa E, Astara G, Murgia V, Gramignano G, LussoMR, et al.Phase II clinical trial of local use of GM-CSF forprevention and treatment of chemotherapy- and concomitantchemoradiotherapy-induced severe oral mucositis in advanced headand neck cancer patients: an evaluation of effectiveness, safety andcosts. Oncology Reports 2003;10(1):197–206.

Marcial 1994 {published data only}

Marcial F, Schubert M, Niccoli-Filho WD, Lloid ME, Kelly J,Franquin JC, et al.A phase I/II nonblinded randomized trial todetermine the efficacy of low-energy laser to prevent oral mucositisresulting from conditioning regimens for bone marrow transplantation. Oral Surgery, Oral Medicine, Oral Pathology 1994;

78(6):738.

Masucci 2005 {published data only}

Masucci G, Broman P, Kelly C, Lindahl S, Malmberg L,Reizenstein J, et al.Therapeutic efficacy by recombinant humangranulocyte/monocyte-colony stimulating factor on mucositisoccurring in patients with oral and oropharynx tumors treated withcurative radiotherapy: a multicenter open randomized phase IIIstudy. Medical Oncology 2005;22(3):247–56.

Matejka 1990 {published data only}

Matejka M, Nell A, Kment G, Schein A, Leukauf M, Porteder H,et al.Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis. British Journal of Oral Maxillofacial Surgery

1990;28(2):89–91.





McGaw 1985 {published data only}

McGaw WT, Belch A. Oral complications of acute leukemia:prophylactic impact of a chlorhexidine mouthrinse regimen. Oral

Surgery, Oral Medicine, Oral Pathology 1985;60(3):275–80.

McIlroy 1996 {published data only}

McIlroy P. Radiation mucositis: a new approach to prevention andtreatment. European Journal of Cancer Care 1996;5(3):153–8.

Merte 1999 {published data only}

Merte H, Wied R, Engenhart-Cabillic R. Der effekt vonimmunglobulinen in der behandlung der radiogenen dermatitisund mukositis bei patienten mit hals-nasen und rachentumoren.Strahlentherapy und Onkologie 1999;175(1):135.

Mills 1995 {published data only}

Mills W, Strang J, Goldstone AH, Linch DC. Dose intensification

of etoposide in the BEAM ABMT protocol for malignantlymphoma. Leukemia & Lymphoma 1995;17(3-4):263–70.

Minn 1999 {published data only}

Minn HR, Makkonen TA, Jekunen A, Vilja P, Tuominen J, JoensuuH. Granulocyte macrophage-colony stimulating factor (GM-CSF)and sucralfate in prevention of radiation-induced mucositis: aprospective randomized study. International Journal of RadiationOncology Biology Physics 1999;45(3 Suppl):239.

Nicholl 1995 {published data only}

Nicholl TA, Nimmo CR, Shepherd JD, Phillips P, Jewweson PJ. Amphotericin B infusion-related toxicity: comparison of two- andfour-hour infusions. Annals of Pharmacotherapy 1995;29(11):1081–7.

Niibe 1985b {published data only}Niibe H, Takahashi I, Mitsuhashi N, Miyaishi K, Itoh J, Maehara Y, et al.An evaluation of the clinical usefulness of amifostine (YM-08310), radioprotective agent. A double-blind placebo-controlledstudy.2 Abdominal and pelvic tumours. Nippon Gan Chiryo Gakkai

Shi 1985;20(5):994–1001.

Nikoletti 2005 {published data only}

Nikoletti S, Hyde S, Shaw T, Myers H, Kristjanson LJ. Comparisonof plain ice and flavoured ice for preventing oral mucositisassociated with the use of 5 fluorouracil. Journal of Clinical Nursing

2005;14(6):750–3.

Ohnmacht 2001 {published data only}

Ohnmacht GA, Phan GQ, Mavroukakis SA, Steinberg SM, Shea YR, Witebsky FG, et al.A prospective, randomized, double-blind,

placebo-controlled trial evaluating the effect of nystatin on thedevelopment of oral irritation in patients receiving high-doseintravenous interleukin-2. Journal of Immunotherapy 2001;24(2):188–92.


Okuno SH, Foote RL, Loprinzi CL, Gulavita S, Sloan JA, Earle J, etal.A randomized trial of a nonabsorbable antibiotic lozenge given toalleviate radiation-induced mucositis. Cancer 1997;79(1):2193–9.


Okuno SH, Swan L, Ebbert C. Phase III placebo-controlled clinicaltrial evaluation of glutamine for decreasing mucositis in patientsreceiving 5 FU (Fluorouracil)-based chemotherapy. Proceedings of the Annual Meeting of the American Society of Clinical Oncology.1998:256.

Okutomi 2000 {published data only}

Okutomi T, Kato Y, Ichihara H, Hyodo I, Fujitsuka H, Yasuda S, etal.[Clinical effects of adjuvant therapy using Z-100 (Ancer 20injection) for oral cancer--prevention of stomatitis andhematopoietic impairment]. Gan To Kagaku Ryoho 2000;27(1):65–71.

Papas 1984 {published data only}

Papas A, Johansen E. Prevention of mucositis in oncology patientsundegoing radiation therapy. Journal of Dental Research 1984;63

(Special Issue March):311 (Abs No 1267).

Peters 1993 {published data only}

Peters E, Antczak-Bouckoms A, Burdick E. Meta-analysis of chlorhexidine in the prevention of mucositis from chemotherapy.

Journal of Dental Research 1993;Special Issue(259):1249.

Peterson 2003 {published data only}

Peterson DE, Petit RG. Phase III study: AES-14 in chemotherapy patients at risk for mucositis. Proceedings of the American Society of Clinical Oncology. 2003:725.

Pfeiffer 1989 {published data only}

Pfeiffer P, May O. Sucralfate prophylaxis of chemotherapy-inducedstomatitis. Proceedings of the Annual Meeting of the AmericanSociety of Clinical Oncology. 1989.

Phillips 2002 {published data only}

Phillips II, GL. The potential of amifostine in high-dosechemotherapy and autologous hematopoietic stem celltransplantation. Seminars in Oncology 2002;29(6 Supp 19):53–6.

Piccirillo 2003 {published data only}

Piccirillo N, De Matteis S, Laurenti L, Chiusolo P, Sora F, Pittiruti

M, et al.Glutamine-enriched parenteral nutrition after autologousperipheral blood stem cell transplantation: effects on immunereconstitution and mucositis. Haematologica 2003;88(2):192–200.

Porta 1994 {published data only}

Porta C, Moroni M, Nastasi G, Montecucco CM, Caporali R,Notario A. Allopurinol mouthwashes can reduce oral mucositis inchemotherapy-treated patients. Annals of Oncology 1994;5(Suppl8):208.

Pouli 1999 {published data only}

Pouli A, Nikiforakis E. A prospective randomized trial of GM-CFSmouthwash versus sodium bicarbonate mouthwash in thetreatment of stomatitis following allogeneic bone marrow transplantation. Bone Marrow Transplantation 1999;23:S166.

Prada 1985 {published data only}Prada A, Lozza L, Moglia D, Sala L, Chiesa F. Effects of benzydamine on radio-polychemotherapeutic mucositis of the oralcavity. International Journal of Tissue Reaction 1985;7(3):237–9.

Pyrhonen 1995 {published data only}

Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomisedcomparison of fluorouracil, epidoxorubicin and methotrexate(FEMTX) plus supportive care with supportive care alone inpatients with non-resectable gastric cancer. British Journal of Cancer

1995;71(3):587–91.

Pytlik 2002 {published data only}

Pytlik R, Benes P, Patorkova M, Chocenska E, Gregora E,Prochazka B, et al.Standardized parenteral alanyl-glutaminedipeptide supplementation is not beneficial in autologous





transplant patients: a randomized, double-blind, placebo controlled

study. Bone Marrow Transplantation 2002;30(12):953–61.

Rabinovitch 2006 {published data only}

Rabinovitch R, Grant B, Berkey BA, Raben D, Ang KK, Fu KK, etal.Impact of nutrition support on treatment outcome in patients with locally advanced head and neck squamous cell cancer treated with definitive radiotherapy: a secondary analysis of RTOG trial90-03. Head & Neck 2006;28(4):287–96.

Rades 2004 {published data only}

Rades D, Fehlauer F, Bajrovic A, Mahlmann B, Richter E, Alberti W. Serious adverse effects of amifostine during radiotherapy in headand neck cancer patients. Radiotherapy and Oncology 2004;70(3):261–4.

Radmard 2002 {published data only}

Radmard A, Niewohner-Desbordes U, Wagner W. [rhGM-CSF inthe treatment of radiogenic mucositis: prospective randomisedphase-II study on the effectivity and tolerance of rhGM-CSF in thetreatment of oral mucositis under radiotherapy of head and neck tumors]. Strahlentherapie und Onkologie 2002;178(Suppl 1):24.

Raether 1989 {published data only}

Raether D, Walker PO, Bostrum B, Weisdorf D. Effectiveness of oral chlorhexidine for reducing stomatitis in a pediatric bonemarrow transplant population. Pediatric Dentistry 1989;11(1):37–42.

Robustelli 1999 {published data only}

Robustelli della Cuna FS, Ucci G, Cuomo AM, Goglio AM.Galenic preparation for the prophylaxsis of oral mucositis induced

by 5-fluororacil continous infusion. Supportive Care in Cancer 1999;7 Suppl:132 (Abs No P-67).

Rocci 2005 {published data only}

Rocci L, Vincenzi B, Santini D, Tonini G. [Timing of 5-fluorouracile infusion: a randomized clinical trial]. International

Nursing Perspectives 2005;5(2):53–60.

Rojas 2001 {published data only}

Rojas de Morales T, Zambrano O, Rivera L, Navas R, Chaparro N,Bernardonni C, et al.Oral-disease prevention in children withcancer: testing preventive protocol effectiveness. Medicina Oral

2001;6(5):326–34.

Rutkauskas 1993 {published data only}

Rutkauskas JS, Davis JW. Effects of chlorhexidine duringimmunosuppressive chemotherapy: A preliminary report. Oral

Surgery, Oral Medicine, Oral Pathology 1993;76(4):441–8.

Samaranayake 1988 {published data only}

Samaranayake LP, Robertson AG, MacFarlane TW, Hunter IP,MacFarlane G, Soutar DS, et al.The effect of chlorhexidine andbenzydamine mouthwashes on mucositis induced by therapeuticirradiation. Clinical Radiology 1988;39(3):291–4.

Sato 1997 {published data only}

Sato A, Kumagai S, Sakaki K, Morikawa H, Song ST, Mori S.[Inhibition of 5-fluorouracil-cisplatin-induced stomatitis by oralcryotherapy: use of an ice-bar containing fibrinolysin anddeoxyribonuclease comiben (Elase)]. Gan to Kagaku Ryoho

[Japanese Journal of Cancer & Chemotherapy] 1997;24(9):1135–9.

Scarantino 2001a {published data only}

Scarantino CW, LeVeque FG, Scott CB, White RL, Rotman M,Hodson DI, et al.A phase III study of concomitant oral pilocarpineto reduce hypo-salivation and mucositis assocated with curativeradiation therapy (RT) in head and neck (H&N) cancer patients.RTOG 9709. Proceedings of the American Society of ClinicalOncology. 2001:(Abs No 897).

Scarantino 2001b {published data only}

Scarantino CW, Leveque F, Scott C, White RL, Rotman M,Hodson DI, et al.A Phase III study on the concurrent use of oralpilocarpine to reduce hyposalivation and mucositis associated withradiation therapy in head and neck cancer patients. Final results of RTOG 97-09. International Journal of Radiation Oncology, Biology,

Physics 2001;51(3 Suppl 1):85–6.

Schwerkkoske 1999 {published data only}Schwerkkoske J, Schwartzberg L, Weaver CH, Schwertschlag US,Goodfellow J, Berdosian CL. A phase I double-masked, placebo-controlled study to evaluate tolerability of Neumega (rhIL-11;Oprelvekin) to reduce mucositis in patients with solid tumors orlymphoma receiving high-dose chemotherapy (CT) withautologous peripheral blood stem cell reinfusion (PBSCT).Proceedings of the American Society of Clinical Oncology. 1999;Vol. 18:584a.

Spadaro 1991 {published data only}

Spadaro P, Buemi B, Ferraro G, Marabello G, Russi E, Pergolizzi S.Prophylaxis of chemotherapy-radiotherapy induced mucositis ororal fungal infection with vitamin E + vitamin A and Fluconazolo.European Journal of Cancer 1991;27(Suppl 2):S288.

Staar 2001 {published data only}Staar S. Benefits and toxicities of accelerated radiochemo- versusaccelerated radiotherapy in advanced head and neck cancer -Results of a German randomized study. European Journal of Cancer

2001;37(Suppl 6):38 (Abs No 126).

Stokman 2004 {published data only}

Stokman MA, Wachters FM, Koopmans P, Burgerhof JG, GroenHJ, Spijkervet FK, et al.Outcome of local application of amifostine(WR-1065) on epirubicin-induced oral mucositis. A phase II study.

Anticancer Research 2004;24(5B):3263–7.

Su 2004a {published data only}

Su C, Mehta V, Ravikumar L, Shah R, Pinto H, Halpern J, etal.Phase II double-blind randomized study comparing oral aloe vera

(AV) versus placebo to prevent radiation (RT)-related mucositis inpatients with head and neck (HN) neoplasms. Proceedings of the Amercian Society of Clinical Oncology. 2004.

Su 2004b {published data only}

Su YB. Double-blind, randomized trial of granulocyte-colony stimulating factor (GCSF) versus (v.) placebo during postoperativeradiation (RT) for advanced resectable squamous cell head and neck cancer (SCCHN): impact on mucositis. Journal of Clinical

Oncology 2004;22(Suppl):14S.

Suc 1999 {published data only}

Suc A, Gandemer V, Le Deley MC, Schmitt C, Pichard-Leandri E,French Group. Gum98: Preventing mucositis with chewing gumin children receiving chemotherapy, a multicentric trial. Supportive

Care in Cancer 1999;7S:180 (Abs No P-60).





Svanberg 2004 {published data only}

Svanberg A, Öhrn K. Cryotherapy during chemotherapy - could itdelay or alleviate the development of mucositis?. Bone Marrow

Transplantation 2004;33(Suppl 1):S292.

Sykes 2004 {published data only}

Sykes AJ, Slevin NJ, MacDougall RH, Ironside JAD, Mais KL.Results of a phase I study to determine the maximum tolerated doseof capecitabine when given concurrently with radical radiotherapy in the treatment of squamous cell carcinoma of the head and neck.Radiotherapy and Oncology 2004;71(1):81–4.

Symonds 1995 {published data only}

Symonds RP, Thomas M, Alcock SR, Khorrami J, McEllroy P,McMuuuray A. The reduction of radiation mucositis by antibioticpastilles: a placebo-controlled double-blind trial. European Journal

Surgery Oncology 1995;21:447.Teshima 1986 {published data only}

Teshima T. [Clinical evaluation of kenalog ointment for radiationmucositis of patients with head and neck cancer]. Yakuri to Chiryo

(Japanese Pharmacology and Therapeutics) 1986;14(11):7163–6.

Thieblemont 2002 {published data only}

Thieblemont C, Dumontet C, Saad H, Roch N, Bouafia F, ArnaudP, et al.Amifostine reduces mucosal damage after high-dosemelphalan conditioning and autologous peripheral bloodprogenitor cell transplantation for patients with multiple myeloma.Bone Marrow Transplantation 2002;30(11):769–75.

Throuvalas 1995 {published data only}

Throuvalas N, Antonadou D, Pulizzi M, Sarris G. Evaluation of the

efficacy and safety of GM-CSF in the prophylaxis of mucositis inpatients with head and neck cancer treated with RT. European

Journal of Cancer 1995;31(Suppl 5):S93 (Abs No 431).

Toubai 2003 {published data only}

Toubai T, Tanaka J, Fujisawa F, Kondo Y, Imamura M, Ota S, etal.Effect of prophylaxis against myocosis in patients withhematological malignancy disease: efficacy of dosage of itraconazole. Japanese Journal of Antibiotics 2003;56(1):61–5.

Uchiyama 2005 {published data only}

Uchiyama Y, Murakami S, Kakimoto N, Nakatani A, Furukawa S.Effectiveness of Cepharanthin in decreasing interruptions duringradiation therapy for oral cancer. Oral Radiology 2005;21(1):41–4.

Vacha 1999 {published data only}

Vacha P, Marx M, Engel A, Richter E, Feyerabend T. Side effects of postoperative radiochemotherapy with amisfostine versusradiotherapy alone in head and neck tumors. Preliminary results of a prospective randomized trial [Nebenwirkungen einerposoperativen radiochemotherapie mit amifostin versus alleinigerradiochemotherapie bei kopf–hals–tumoren. Vorlaufige ergebnisseeiner prospektiv randomisierten untersuchung]. Strahlentherapie und onkologie 1999;175(S4):18–22.

Vacha 2003 {published data only}

Vacha P, Fehlauer F, Mahlmann B, Marx M, Hinke A, Sommer K,et al.Randomized phase III trial of postoperativeradiochemotherapy amifostine in head and neck cancer: Is thereevidence for radioprotection?. Strahlentherapie und Onkologie 2003;179(6):385–9.

Valcarcel 2002a {published data only}

Valcarcel D, Sanz M, Sureda A, Sala M, Munoz L, Subira M, etal.Topically applied recombinant human granulocyte-macrophagecolony stimulating factor (rhGM-CSF) for oropharyngeal mucositis(OM) in stem cell transplantation recipients: a randomized double-blind placebo-controlled study. Bone Marrow Transplantation 2002;Suppl 2:S20.

Valcarcel 2002b {published data only}

Valcarcel D, Sanz MA Jr, Sureda A, Sala M, Munoz L, Subira M, etal.Mouth-washings with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) do notimprove grade III-IV oropharyngeal mucositis (OM) in patients with hematological malignancies undergoing stem celltransplantation. Results of a randomized double-blind placebo-controlled study. Bone Marrow Transplantation 2002;29(9):783–7.

Valcárcel 1997 {published data only}

Valcárcel F, De la Torre A, Aragón G, Lanzós E, Rodríguez R, VeirasC. Double-blind randomized and pilot study on the potential of thymostimulin to reduce the incidence of mucositis in head andneck cancer patients with radical radiotherapy. Oncología IX Congreso Nacional de la Asociación Española de Radioterapia y Oncología. 1997; Vol. 20:161.

van Zaanen 1994 {published data only}

van Zaanen HC, van der Lelie H, Timmer JG, Furst P, SauerweinHP. Parenteral g lutamine dipeptide supplementation does notameliorate chemotherapy-induced toxicity. Cancer 1994;74(10):2879–84.

Verdi 1995 {published data only}

Verdi CJ, Garewal HS, Koenig LM, Vaughn B, Burkhead T. A double-blind, randomized, placebo-controlled, crossover trial of pentoxiflline for the prevention of chemotherapy-induced oralmucositis. Osomopore 1995;80(1):36–42.

Vesole 1999 {published data only}

Vesole D, Fuchs HJ. IB-367 reduces the number of days of severeoral mucositis complicating myeloablative chemotherapy. Blood 1999;94(10 Suppl 1):154 (Abs No 675).

Vitello 2000 {published data only}

Vitello M, Cianio SG. A comparison of two mouthrinse agentsused during head/neck radiation. Journal of Dental Research 2000;79(Special Issue):215 (Abs No 576).

Wagner 2002 {published data only}

Wagner W, Radmard A, Niewohner-Desbordes U, Haus U, Matt J.

rhGM-CSF in the treatment of radiotherapy induced mucositis-prospective randomized, double-blind study to investigate thefeasibility and effectiveness of rhGM-CSF in patients with head andneck cancer. Proceedings of the American Society for TherapeuticRadiology and Oncology Meeting. 2002:311 (Abs No 2175).

Wang 2002b {published data only}

Wang HM, Wang CS, Chen JS, Chen IH, Liao CT, Chang TC.Cisplatin, tegafur, and leucovorin: a moderately effective andminimally toxic outpatient neoadjuvant chemotherapy for locally advanced squamous cell carcinoma of the head and neck. Cancer

2002;94(11):2989–95.

Warde 2002 {published data only}

Warde P, O’Sullivan B, Aslanidis J, Kroll B, Lockwood G, Waldron J, et al.A Phase III placebo-controlled trial of oral pilocarpine in





patients undergoing radiotherapy for head-and-neck cancer.

International Journal of Radiation Oncology Biology and Physics 2002;54(1):9–13.

Weisdorf 1989 {published data only}

Weisdorf DJ, Bostrom B, Raether D, Mattingly M, Walker P,Pihlstrom B, et al.Oropharyngeal mucositis complicating bonemarrow transplantation: prognostic factors and the effect of chlorhexidine mouthrinse. Bone Marrow Transplantation 1989;4(1):89–95.

Weiss 1990 {published data only}

Weiss GR, Green S, Hannigan EV, Boutselis JG, Surwit EA, Wallace DL, et al.A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of theuterine cervix: a Southwest Oncology Group trial. Gynecologic

Oncology 1990;37(3):354–8.

Whelan 2002 {published data only}

Whelan HT, Connelly JF, Hodgson BD, Barbeau L, Post AC,Bullard G, et al.NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients. Journal of Clinical Laser Medicine & Surgery 2002;20(6):319–24.

Whelan 2004 {published data only}

Whelan H. Phase II randomized study of NASA-developed light-emitting diode therapy for the prevention of oral mucositis inchildren receiving a myeloablative conditioning regimencomprising chemotherapy with or without radiotherapy followedby first allogeneic bone marrow transplantation. http:// www.clinicaltrials.gov (accessed 2003).

Wollina 2002 {published data only}

Wollina U, Christen N, Kostler E, Schorcht J. On prophylaxis andtreatment of radiation-induced dermatitis and mucositis. Zeitschrift

fur Hautkrankheiten 2002;77(9):418–23.

Wymenga 1999a {published data only}

Wymenga AN, van der Graaf WT, Hofstra LS, Timens W,Spijkervet FK, Hospers GAP, et al.TGF-b3 mouthwashes aimed atprevention of chemotherapy induced mucositis, a phase-I study.Supportive Care in Cancer 1999;7:168.

Wymenga 1999b {published data only}

Wymenga AN, van der Graaf WT, Hofstra LS, Spijkervet FK,Timens W, Timmer-Bosscha H, et al.Phase I study of transforminggrowth factor-beta3 mouthwashes for prevention of chemotherapy-induced mucositis. Clinical Cancer Research 1999;5(6):1363–8.

Yokomizo 2004 {published data only}

Yokomizo H, Yoshimatsu K, Hashimoto M, Ishibashi K, Umehara A, Yoshida K, et al.Prophylactic efficacy of allopurinol ice ball forleucovorin/5-fluorouracil therapy-induced stomatitis. Anticancer Research 2004;24(2C):1131–4.

Zalcberg 1995 {published data only}

Zalcberg J, Cunningham D, Rath U, Olver I, Kerr D, van CutsemE, et al.’Tomudex’ (ZD1694) has a higher response rate,significantly less leucopenia and mucositis and a simpler dosingregimen than 5-Fluorouracil (5-FU) and leucovorin (LV) foradvanced colorectal cancer (CRC): first results of a phase III study.European Journal of Cancer 1995;31f :S146 (Abs No 701).

References to ongoing studies

Haddad 2003 {published data only}

Haddad R, Wirth L, Costello R, Weeks L, Posner M. Phase IIrandomized study of concomitant chemoradiation using weekly carboplatin/paclitaxel with or without daily subcutaneousamifostine in patients with newly diagnosed locally advancedsquamous cell carcinoma of the head and neck. Seminars inOncology 2003;30(6 Suppl 18):84–8.

Additional references

Andreassen 2003

Andreassen CN, Grau C, Lindegaard JC. Chemicalradioprotection: a critical review of amifostine as a cytoprotector inradiotherapy. Seminars in Radiation Oncology 2003;13(1):62–72.

Barasch 2003

Barasch A, Peterson DE. Risk factors for ulcerative oral mucositis incancer patients: unanswered questions. Oral Oncology 2003;39(2):91–100.

Begg 1996

Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, etal.Improving the quality of reporting of randomized controlledtrials: the CONSORT statement. JAMA 1996;276(8):637–9.

Bellm 2002

Bellm LA, Cunningham G, Durnell L, Eilers J, Epstein JB, FlemingT, et al.Defining clinically meaningful outcomes in the evaluation of new treatments for oral mucositis: oral mucositis patient provideradvisory board. Cancer Investigation 2002;20(5-6):793–800.

Chang 2003

Chang VT, Ingham J. Symptom control. Cancer Investigation 2003;21(4):564–78.

Clarkson 2004

Clarkson JE, Worthington HV, Eden OB. Interventions fortreating oral candidiasis for patients with cancer receivingtreatment. Cochrane Database of Systematic Reviews 2004, Issue 1.[Art. No.: CD001972. DOI: 10.1002/14651858.CD1972.pub2]

Clarkson 2007a

Clarkson JE, Worthington HV, Eden OB. Interventions forpreventing oral candidiasis for patients with cancer receivingtreatment. Cochrane Database of Systematic Reviews 2007, Issue 1.[Art. No.: CD003807. DOI: 10.1002/14651858.CD003807.pub3]

Clarkson 2007b

Clarkson JE, Worthington HV, Eden OB. Interventions fortreating oral mucositis for patients with cancer receiving treatment.Cochrane Database of Systematic Reviews 2007, Issue 2. [Art. No.:CD001973. DOI: 10.1002/14651858.CD001973.pub3]

De Pauw 1997

De Pauw BE. Practical modalities for prevention of fungalinfections in cancer patients. European Journal of Clinical

Microbiological Infectious Diseases 1997;16(1):32–41.

Denning 1992

Denning DW, Donnelly JP, Hellreigel KP, Ito J, Martino P, van’t Wout JW. Antifungal prophylaxis during neutropenia or allogeneicbone marrow transplantation: what is the state of the art?.Chemotherapy 1992;38(S1):43–9.





Duncan 2003

Duncan M, Grant G. Oral and intestinal mucositis - causes andpossible treatments. Alimentary Pharmacology Therapeutics 2003;18:853–74.

Elbourne 2002

Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV,Vail A. Meta-analyses involving cross-over trials. International

Journal of Epidemiology 2002;31(1):140–9.

Gotzsche 2002

Gotzsche PC, Johansen HK. Routine versus selective antifungaladministration for control of fungal infections in patients withcancer. Cochrane Database of Systematic Reviews 2002, Issue 2.[DOI: 10.1002/14651858.CD000026]

J Briggs Inst 1998

Joanna Briggs Institute. Prevention and treatment of oralmucosistis in cancer patients. Best Practice: evidence based practiceinformation sheets for health professionals 1998; Vol. 2, issue 3:1–6.

Kowanko 1998

Kowanko I, Long L, Hodgkinson B, Evans D. The effectiveness of strategies for preventing and treating chemotherapy and radiationinduced oral mucositis in patients with cancer. Joanna BriggsInstitute for Evidence Based Nursing and Midwifery 1998:1–84.

Lortholary 1997

Lortholary O, Dupont B. Antifungal prophylaxis duringneutropenia and immunodeficiency. Clinical Microbiological Review

1997;10(3):477–504.

McGuire 2004

McGuire DB, Rubenstein EB, Peterson DE. Evidence-basedguidelines for managing mucositis. Seminars in Oncology Nursing

2004;20(1):59–66.

Meunier 1994

Meunier F, Paesmans M, Autier P. Values of antifungal prophylaxis with antifungal drugs against oropharyngeal candidiasis in cancerpatients. Oral Oncology, European Journal of Cancer 1994;30B(3):196–9.

Moher 2001

Moher D, Schulz KF, Altman DG. The CONSORT statement:revised recommendations for improving the quality of reports of parallel-group randomized trials. Annals of Internal Medicine 2001;134(8):657–62.

Rubenstein 2004

Rubestein EB, Peterson DE, Schubert M, Keefe D, McGuire D,Epstein J, et al.Clinical practice guidelines for the prevention andtreatment of cancer therapy-induced oral and gastrointestinalmucositis. Cancer Supplement 2004;100(9):2026–46.

Savarese 2003

Savarese DM, Savy G, Vahdat L, Wischmeyer PE, Corey B.Prevention of chemotherapy and radiation toxicity with glutamine.Cancer Treatment Reviews 2003;29(6):501–13.

Sonis 2004

Sonis ST, Elting LS, Keefe D, Peterson ED, Schubert M, Hauer- Jensen M, et al.Perspectives on cancer therapy-induced mucosalinjury. Cancer Supplement 2004;100(9):1995–2025.

Stevens 1995

Stevens DA. Therapy for opportunistic fungal infections: pastpresent and future. Indian Journal of Cancer 1995;32(1):1–9.

Stokman 2006

Stokman MA, Spijkervet FK, Boezen HM, Schouten JP,Roodenburg JL, de Vries EG. Preventive intervention possibilitiesin radiotherapy- and chemotherapy-induced oral mucositis: resultsof meta-analyses. Journal of Dental Research 2006;85(8):690–700.

Sunderland 2001

Sutherland SE, Browman GP. Prophylaxis of oral mucositis inirradiated head-and-neck cancer patients: a proposed classificationscheme of interventions and meta-analysis of randomizedcontrolled trials. International Journal of Radiation Oncology,

Biology and Physics 2001;49(4):917–30.

Symonds 1998Symonds RP. Treatment-induced mucositis: an old problem withnew remedies. British Journal of Cancer 1998;77(10):1689–95.

Verdi 1993

Verdi CJ. Cancer therapy and oral mucositis. Drug Safety 1993;9(3):185–95.

White 1993

White M. Antifungal prophylaxis. Current Opinion in Infectious

Diseases 1993;6:737–43.

Worthington 2004a

Worthington HV, Clarkson JE, Eden OB. Interventions fortreating oral mucositis for patients with cancer receiving treatment.Cochrane Database of Systematic Reviews 2004, Issue 2. [Art. No.:

CD001973. DOI: 10.1002/14651858.CD001973.pub2] Worthington 2004b

Worthington HV, Clarkson JE, Eden OB. Interventions forpreventing oral candidiasis for patients with cancer receivingtreatment. Cochrane Database of Systematic Reviews 2004, Issue 4.[Art. No.: CD003807. DOI: 10.1002/14651858.CD003807.pub2]

Worthington 2007

Worthington HV, Clarkson JE, Eden OB. Interventions for treatingoral candidiasis for patients with cancer receiving treatment.Cochrane Database of Systematic Reviews 2007, Issue 2. [Art. No.:CD001972. DOI: 10.1002/14651858.CD001972.pub3]

Wright 2003

Wright JR, McKenzie M, DeAngelis C, Foroudi F, Paul N,Rajaraman M, et al.Radiation induced mucositis: co-ordinating aresearch agenda. Clinical Oncology 2003;15(8):473–7.

References to other published versions of this review

Clarkson 2000

Clarkson JE, Worthington HV, Eden OB. Prevention of oralmucositis or oral candidiasis for patients with cancer receivingchemotherapy (excluding head and neck cancer). Cochrane

Database of Systematic Reviews 2000, Issue 2.

Clarkson 2003a

Clarkson JE, Worthington HV, Eden OB. Interventions forpreventing oral mucositis for patients with cancer receiving





treatment. Cochrane Database of Systematic Reviews 2003, Issue 3.

[Art. No.: CD000978. DOI: 10.1002/14651858.CD000978] Worthington 2006

Worthington HV, Clarkson JE, Eden OB. Interventions forpreventing oral mucositis for patients with cancer receivingtreatment. Cochrane Database of Systematic Reviews 2006, Issue 2.[Art. No.: CD000978. DOI: 10.1002/14651858.CD000978.pub2]

∗ Indicates the major publication for the study





C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Ahmed 1993

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Clear infor-mation on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: return of bloodcount or resolution of mucositis.

Participants Adults with haematological malignancies prior to BMT after conditioning with etoposide. 12 enrolledand completed.

Interventions 2 groups, placebo versus propantheline (30 mg every 6 hours during infusion and 12 hours after, for totalof 6 doses).

Outcomes Mucositis graded with reference to previous publication. Data presented as number of patients developingmucositis in both groups. Assessment used: day3. Other reported outcomes: blood counts febrile episodes,survival, tumour response.

Notes All patients received acyclovir, and nystatin or clotrimazole.Funding source: unclear.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Anderson 1998

Methods Randomised, cross-over study conducted in USA. Patients, providers and assessors blind. Clear informa-tion on withdrawals. Dentist not involved in study. Drop outs: 46%. Duration 14 days.

Participants Children and adults with solid cancer who have previously had chemotherapy and experienced mucositis.24 patients eligible and enrolled, 13 completed.

Interventions 2 groups, glycine control (described as placebo) versus glutamine (4 ml/M² twice daily swish and swallow).

Outcomes Mucositis (patient’s description on 0-4 scale). Grade >= 2 painful mucositis which altered food intake. Assessment used: day 14. Other reported outcomes: none.

Notes Funding source: private.

Risk of bias






Anderson 1998 (Continued)


Antonadou 2002

Methods Randomised, parallel group study conducted in Greece. Patients, providers and assessors not blind. Clearinformation on withdrawals: 3/26 control, 2/24 test. Dentist not involved in study. Drop outs: 10%.Duration 3 months.

Participants Adults with head and neck cancer. Radiotherapy total 60-74 Gy 2 Gy fractions 5 days weekly. Chemo-therapy carboplatin (90 mg/m2 once per week (no surgery before radiotherapy)). 50 patients enrolled, 45

completed.

Interventions 2 groups, no treatment control versus amifostine 300 mg/m2 15-30 min before radiotherapy for 6-7 weeks.

Outcomes Mucositisassessed weeklyEORTCcriteria.Assessmentused: day 28. Otherreportedoutcomes:dysphagia,xerostomia, treatment interruptions, haematological changes, side effects (nausea, transient hypotention).

Notes Funding source: unclear.

Risk of bias



Attal 1993

Methods Randomised, parallel group study conducted in France. Patient and providers not blind, unclear whetherassessor blind. Clear information on withdrawals: 6/70 control, 6/70 test. Dentist not involved in study.Drop outs: 0%. Duration: day -8 to day +100.

Participants Adults with mixed cancer admitted to BMT unit. 140 patients enrolled 6 died in each group, but all wereevaluated.

Interventions 2 groups, no treatment control versus pentoxifylline (oral PTX 1600 mg 1 per day in 4 doses).

Outcomes Number requiring MSO4 for grade II or higher mucositis (by published criteria). Assessment used: day 100. Other reported outcomes: duration of stay in hospital, renal insufficiency, days morphine, fever,septicaemia, 100 day survival.

Notes All patients received fluconazole, acyclovir and ranitidine.Funding source: unclear.

Risk of bias





Attal 1993 (Continued)


Allocation concealment? Yes A - Adequate

Biswal 2003

Methods Randomised, parallel group study conducted in Malaysia. Patient and provider not blinded. Unclear whether assessor blind. Clear information on withdrawals. Unclear whether dentist was involved in study.Drop outs: 0%. Duration: 49days.

Participants Adults with head and neck cancer. 40 patients recruited and evaluated.

Interventions 2 groups, rinse then swallow 20 ml natural honey before radiotherapy, 20 ml after and 20 ml 6 hours afterthat versus no treatment control.

Outcomes Mucositis RTOG grading. Other reported outcomes: weight gain.

Notes Funding source: university.

Risk of bias



Borowski 1994

Methods Randomised, parallel group study conducted in France. Patient, providers and assessors not blind. Clearinformation on withdrawals: 7/82 control, 9/84 test. Dentist involved in study. Drop outs: 7%. Duration:30 days.

Participants Childrenandadultswithmixedcancer and candidates for BMT. 166 eligibleandenrolled,150completing.

Interventions 2 groups, limited oralhygiene versusintenseoralhygiene(brushing 3 times per day after meals asinstructed

by dentist).

Outcomes Moderate or severe mucositis with detailed description of each category. Assessment used: day 30. Otheroutcomes: plaque, fever, septicaemia.

Notes Chlorhexidine mouthrinse used at least 5 times daily by both groups.Funding source: unclear.

Risk of bias






Borowski 1994 (Continued)


Bourhis 2000

Methods Randomised, parallel group study conducted in France. Patients and providers not blind, unclear whetherassessors blind. Unclear information on withdrawals: 1 died and 1 refused, unclear which group. Dentistnot involved in study. Drop outs: 8%. Duration: unclear.

Participants Adults with head and neck cancer, stage IV not amenable to conventional radiosurgical treatment. Karnof-sky performance > 60. Radiotherapy 64 Gy in 22-23 days. 26 patients enrolled, 24 were evaluated.

Interventions 2 groups, no treatment control versus amifostine (subcutaneous infusion 150 mg/m² amifostine admin-istered IV twice daily 15-30 mins prior to each radiotherapy session).

Outcomes Max WHO grade (I to IV). Assessment used: day 23. Other reported outcomes: duration of feeding tube,vomiting, liver function, erythaema (tolerance of amifostine). Duration of feeding tube.

Notes RTOG index also given with mean duration of at least grade 3 mucositis.Funding source: pharmaceutical.

Risk of bias



Brizel 2000

Methods Randomised, parallelgroupstudyconductedas multicentreUSA, Germany and France.Patients, providersand assessors not blind (c). Clear information about withdrawals: none. Dentist not involved in study.Drop outs: 0%.Duration: 1 year.

Participants Adults with head and neck cancer. Newly diagnosed squamous cell radiation more than or equal to 70%

both parotid glands more than or equal to 40 Gy - daily 2 Gy. 315 enrolled and randomised. 12 patientsnever received any treatment or follow up. The results are presented for the remaining 303.

Interventions 2 groups, no treatment control versus amifostine 200 mg/m2 daily 15-20 minutes prior to radiation.

Outcomes Mucositis assessed weekly by physician. Radiation Therapy Oncology Group Scoring systems. Assessmentused: day 90. Other reported outcomes: nausea, vomiting, xerostomia, saliva production, survival, localdisease control.

Notes Funding source: pharmaceutical.

Risk of bias





Brizel 2000 (Continued)



Bubley 1989

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Unclearinformation on withdrawals. Dentist not involved in study. Drop outs: unclear. Duration: unclear.

Participants Adults with head and neck cancer. Prior positive titre to Herpes Simplex. Results presented for 57 patients.

Interventions 2 groups, placebo versus acyclovir 200 mg tablets 12 hourly.

Outcomes Mucositis assessed by nurse. Assessment used: unclear. Other reported outcomes: herpes simplex virus.

Notes Data presented separately for patients receiving chemo and radiotherapy.Funding source: pharmaceutical.

Risk of bias



Buentzel 2006

Methods Randomised, parallel group, multicentre study conducted in USA/Europe. Patients, providers (c) andassessors blind. Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%.Duration: up to 90 days.

Participants Adults with head and neck cancer. 132 randomised 102 completed but ITT analysis presented.

Interventions 2 groups, placebo versus intravenous amifostine (300 mg/m2 before carboplatin 70 mg/m2 and radiother-apy on days 1 to 5 and 21 to 25, and intravenous amifostine 200 mg/m2 or placebo before radiotherapy

on 6 to 20 and 26 to 30/35 days).

Outcomes Mucositis graded with reference to RTOG criteria on a 0-4 scale. Assessment used up to 90 days. Otherreported outcomes: xerostomia, 1 yr locoregional failure, progression-free survival, overall survival, treat-ment related adverse events: vomiting, nausea, asthenia, allergic reaction, anaemia, phlebitis, leukopenia,hypotension, allergic reaction.

Notes Funding source: industry.Pharmacological company provided drug and organised randomisation.

Risk of bias





Buentzel 2006 (Continued)



Buntzel 1998

Methods Randomised, parallel group study conducted in Germany. Patient and providers not blind, unclear if assessors blind. Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%.Duration: 6 weeks.

Participants Adults with head and neckcancer, hospitalised with stage III-IV tumour, no evidence ofsystemicinfection,liver or renal impairment, tumour resected or excised before adjuvant radiotherapy. 28 patients enrolled,28 were evaluated.

Interventions 2 groups, radiotherapy with or without amifostine (15 min infusion 500 mg preceded by antiemeticregimen of 12 mg dexamethasone and 8 mg ondansetron).

Outcomes WHO mucositis grades 3/4. Assessment used: day 42. Other reported outcomes: xerostomia, dysphagia,loss of taste, dermatitis, haematological side effects.

Notes More data presented but included extra 11 patients in amifostine group who were not entered into study.Funding source: pharmaceutical.

Risk of bias



Cartee 1995

Methods Randomised, parallel group study conducted in USA. Patient, provider and assessor blind. Unclear infor-mation on withdrawals: 5 withdrew, unclear from which groups. Dentist involved in study. Drop outs:10%. Duration: 21 days.

Participants Adults with breast cancer stage IV, with combination of chemotherapy including 5-FU, adriamycin &methotrexate. First cycle of chemotherapy. 50 patients were enrolled and 45 were evaluated.

Interventions 5 groups, 0.1% albumin (described as placebo, dose 0), GM-CSF (molgramostim, range of doses, 0.01,0.10, 1.00, 10.00 mcg/ml. Mouthwash solutions administered 4 times daily starting 24 hours afterchemotherapy initiation). Continuing until end of cycle.

Outcomes Mucositis (CALGB GRADE >= 3). Assessment used: day 15. Other reported outcomes: WBC, plasmaGM-CSF.

Notes Doses 0.01, 0.10, 1.00, 10.00 were combined and compared with dose 0 (control).Funding source: government.





Cartee 1995 (Continued)

Risk of bias



Carter 1999

Methods Randomised, parallel group study conducted in USA. Patient, provider and assessor blind. Clear infor-mation on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: up to 4 monthspostradiotherapy.

Participants Adults with head and neck cancer receiving curative intent radiotherapy, Karnofsky performance > 60.102 patients enrolled and 102 completed.

Interventions 2 groups, placebo versus sucralfate (added as suspension of 1 gm sucralfate/15 ml solution) swish 2 minsand swallow 4 times per day.

Outcomes RTOG graded mucositis. Assessment used: maximum during treatment at 60 Gy. Other reported out-comes: pain, need for placement of feeding tube, use of narcotics, need for intravenuous fluids, diet, needfor treatment break. All assessed weekly.


Risk of bias



Cascinu 1994

Methods Randomised, parallel group study conducted in Italy. Patient, provider and assessor not blind (c). Clearinformation on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: unclear.

Participants Adults with solid cancer (GI & prostate). Chemotherapy: 5-FU. First course of chemotherapy. 84 patientseligible, enrolled and completed.

Interventions 2 groups, control (no treatment)versus ice chips (cryotherapy, 5 mins before 5-FU for 30 mins after).Checked every week and judgement on mucositis performed on day of next chemotherapy course.

Outcomes Mucositis(globalassessment ofphysician’s and patient’s description on0-4scale).Assessment used: unclear.

Notes Statistical handling of data incorrect as all cycles included but used data from first cycle.Funding source: unclear.





Cascinu 1994 (Continued)

Risk of bias



Castagna 2001

Methods Randomised, parallel group multicentre study conducted in France, Italy and Switzerland. Patient and

assessor blind. Unclear whether provider blind. Clear information about withdrawals: 2/53 sucralfate,1/52 placebo. Dentist not involved in study. Drop outs: 2.8%.

Participants Adults with mixed cancer (hospitalised for allogenic or autologous BMT). 105 enrolled, 102 completed.

Interventions 2 groups, placebo versus 2 g sucralfate every 3 hours daily for a maximum of 7 mouthwashes.

Outcomes Mucositis grade 3-4. Other reported outcomes: duration, diarrhoea, caloric intake by oral nutrition.

Notes Funding source: pharmaceutical (c).

Risk of bias



Cengiz 1999

Methods Randomised, parallel group study conducted in Turkey. Patient and provider blind unclear if assessorblind. Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Durationfrom beginning to end of radiotherapy.

Participants Adults with head and neck cancer. 28 patients enrolled and completed.

Interventions 2 groups, placebo versus sucralfate (6 g sucralfate suspension mouthwash 4 doses orally before meals andbedtime).

Outcomes RTOG mucositis (0-IV). Topical and systemic analgestic use, weight loss, dry mouth. Assessment used:day 42. Other reported outcomes: pain, difficulty eating, constipation, analgesics, dry mouth.


Risk of bias






Cengiz 1999 (Continued)


Cerchietti 2006

Methods Randomised, parallel group study conducted in Argentina. Patients, providers (c) and assessors blind.Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: 60days.

Participants Adults with head and neck cancer. Radiotherapy plus cisplantin and 5-FU. 32 enrolled 29 randomisedand completed.

Interventions 2 groups, placebo versus glutamine (patients received chemoradiotherapy (radiotherapy daily up to 70 Gy plus cisplatin/5-FU once a week) and intravenous L-alanyl-L-glutamine 0.4 g/kg weight/day).

Outcomes Mucositis assessed by mean of 3 highest scores by Objective Mucositis Score (OMS) and the WHOgrading system on a 0-4 scale. Mucositis graded once/week during chemo and every other day duringCRT. Assessment used up to 60 days. Other reported outcomes: pain, feeding tubes, mucositis relatedhospitalisation, adverse drug effects, body weight change, incidence of local infections, tumour response.

Notes Funding source: industry and foundation. Pharmacological company provided drug and organised ran-domisation.

Risk of bias



Crawford 1999

Methods Randomised, parallel group study conducted in USA. Patient blind, unclear whetherassessor and provider was. Unclear information on withdrawals (previously described): 6/110 placebo, 6/101 test. Dentist notinvolved in study. Drop outs: 9%. Duration: from day 4 to day 17 of cycle.

Participants Adults with small cell lung cancer. 211 patients enrolled, 199 evaluated, 195 evaluated on first cycle.

Interventions 2 groups: placebo (not described)versus filgrastim (230 ug/m²).

Outcomes WHO mucositis grades 0-4. Assessment used: day 21. Other reported outcomes: neutropenia, infectionscomplications.

Notes Used first cycle data.Funding source: unclear.

Risk of bias





Crawford 1999 (Continued)



Damon 2004

Methods Randomised, parallel group study conducted in USA. Unclear whether patients, providers and assessorsblind. Unclear information on withdrawals. Dentist not involved in study. Drop outs: 0%. Duration: upto 100 months.

Participants Adults with haematological malignancies. High dose etoposide combined with high dose cytarabine andidarubicin (IDEA). 138 enrolled, 119 completed.

Interventions 2 groups, etoposide as a continuous infusion days 1-6 or as a bolus infusion over 10 hours on day 7.

Outcomes Mucositis graded daily by the attending physician according to the University of California, San Francisco(UCSF) Bone Marrow Transplant toxicity grading scale (0-4), which is a modification of the Bearmanscale. Assessment used upto 1 month. We used maximum scores obtained from trialist. Other reportedoutcomes: total parenteral nutrition, length of hospital stay, complete remission, death, treatment relatedcomplications.

Notes Funding source: industry (c). Pharmacological company provided drug and organised randomisation. 7patients relapsed after IDEA and were re-randomised.

Risk of bias



Dazzi 2003

Methods Randomised, parallel group study conducted in Italy. Patient and assessor blinded, unclear if providerblinded. Clear information about withdrawals: 0. Dentist not involved in study. Drop outs: 0%.

Participants Adults with solid cancer. 90 enrolled, 90 completed.

Interventions 2 groups, placebo versus GM-CSF mouthwash (150 ug/day) in 100 cl 4 times per day. Rinse 1 minute. All patients 0.2% chlorhexidine and amphotericin B.

Outcomes Mucositis severity evaluated daily using NCI CTC. Other reported outcomes: oral pain evaluated daily using visual scale and pain requiring opioids.

Notes Funding source: none (c).

Risk of bias





Dazzi 2003 (Continued)



Dickson 2000

Methods Randomised, parallel group study conducted in USA. Patient not blind (c), assessor blind and unclear whether provider was. Clear information on withdrawals: none. Dentist not involved in study. Drop outs:0%. Duration: first day of treatment until discharge or max 28 days after transplant.

Participants Adults receiving bone marrow transplant (BMT). 58 enrolled and evaluated with haematological andsolid cancer.

Interventions 2 groups, sugar water (placebo) versus glutamine (30 g in 10 g doses mixed with food or liquid chosen by patient).

Outcomes Stamford University Hospital BMT toxicity scale for mucositis scale 0-4. Reported as grade 2+. Parenteralnutrition with TPN. Assessment used: day 28. Other reported outcomes: length of hospital stay. Days intotal, parenteral nutrition, diarrohea, toxicity.

Notes Funding source: pharmaceutical supply product.

Risk of bias



Dodd 1996

Methods Randomised, parallel group study conducted in USA. Patient not blind (c), providers and assessors wereblinded. Clear information on withdrawals: none. Dentist involved in study. Drop outs: 0%. Duration:up to 3 months.

Participants Adults with solid cancer receiving chemotherapy. Followed for 3 cycles of chemotherapy. 303 eligible, 227enrolled and evaluated.

Interventions 2 groups: water control (described as placebo) versus chlorhexidine mouthrinse (0.12%, 20 ml, 2 timesper day).

Outcomes Oral Assessment Guide (OAG) 0-24, scores over 10 were considered to be oral mucositis. Maximum of 3 months. Assessment used: day 90. Other reported outcomes: cost.

Notes Severity of mucositis at onset measured. Intent to treat analysis.Funding source: government.





Dodd 1996 (Continued)

Risk of bias



Dozono 1989

Methods Randomised, cross-over study conducted in Japan. Patients and providers were not blind, it is unclear if assessor was. Clear information on withdrawals: none. Unclear if dentist was involved. Drop outs: 0%.Duration: unclear.

Participants Adults with solid cancer receiving chemotherapy. 15 patients enrolled and completed both periods.

Interventions 2 groups: no treatment control versus allopurinol mouthwash (carboxymethylcellulose (CMC-Na) 5 gand allopurinol 500 mg, water to 500 ml solution).

Outcomes Japan Society for Cancer Therapy criteria for stomatitis 0-4 scale.


Risk of bias



Duenas 1996

Methods Randomised, parallel group study conducted inMexico. Patients, providers and assessors wereblind. Clearinformation on withdrawals: none. No dentist was involved in study (c).Drop outs: 0%. Duration: -4 to day 16.

Participants Adults with mixed cancer undergoing peripheral stem cell transplant, receiving high dose (ifosfamide,

carbiplatin, etoposide). 15 patients enrolled (16 course of chemotherapy)and completed.

Interventions 2 groups, placebo versus misoprostol (racemic prostaglandin E1 analogue) 250 ug 3 times per day.

Outcomes WHO mucositis grades 0-4, candidiasis, days in hospital with range. Assessment used: day 16.Other reported outcomes:diarrohea, fever, days in hospital, duration of antibiotics.

Notes All patients received fluconazole prophylaxis. Also received ranitidine, ketoconazole & ciprofloxacin.Severity of mucositis also given but no SD. Study stopped prematurely due to a significant finding at aninterim analysis, favouring the placebo.Funding source: government, pharmaceutical.





Duenas 1996 (Continued)

Risk of bias



El Sayed 2002a

Methods Randomised, parallel group, multicentre study conducted in Canada. Patients, providers (c) and assessors

blind. Clear information on withdrawals. Dentist not involved in study. Drop outs: 0%. Duration: overradiotherapy.

Participants Adults with head and neck cancer treated with radiotherapy to the oral cavity, pharynx or larynx. 137enrolled randomised and completed.

Interventions 2 groups, placebo versusantimicrobial lozenge (bacitracin, clotrimazole and gentamicin (BCoG) 1 lozengeqid, day 1 to end of radiotherapy).

Outcomes Mucositis graded according to the Oral Mucosa Assessment Scale (OMAS) extent of severe mucositisscore, worst-ever grade of ulceration/pseudomembrane. Assessment used: time to development of severemucositis. Other reported outcomes: number of treatment days lost, changes in body weight, worst-evergrade of oral toxicity measured in patient diary, general non-mucosal toxicity assessed by the investigator.

Mucositis measured twice weekly using the National Cancer Institute Common Toxicity Criteria (NCICTC v2) scoring scale and the OMAS scale. Assessment used up to 28 days. Other reported outcomes:oral pain and ability to swallow using 10 cm VAS, salivary flow rate, adverse events nausea and vomiting.

Notes Funding source: National Cancer Institute.

Risk of bias



Elad 2006

Methods Randomised, parallel group study conducted in Israel. Patients, providers and assessors blind. Clearinformation on withdrawals (c). Dentist involved in study. Drop outs: 13%. Duration: 28 days.

Participants Adults with mixed cancer. BMT. 45 enrolled and randomised 39 completed.

Interventions 2 groups, placebo versustopical histamine gel (a semiviscous solution containing 0.12% w/w HDC (histamine dihydrochloride)in a carbomer-based vehicle). Patients instructed to use 5 ml (1 teaspoon) 4 times a day.





Elad 2006 (Continued)

Outcomes Mucositis measured twice weekly using the National Cancer Institute Common Toxicity Criteria (NCICTC v2) scoring scale and the OMAS scale. Assessment used up to 28 days. Other reported outcomes:oral pain and ability to swallow using 10 cm VAS, salivary flow rate, adverse events nausea and vomiting.

Notes Funding source: industry. All received standard oral care: chlorhexidine mouthrinse 2/day amphotericinB lozenges 4/day. Pharmacological company provided drug and organised randomisation.

Risk of bias



Erlichman 1988

Methods Randomised, parallelgroup study conducted inCanada. Patients and providers not blind,unclearwhetherassessor blind. Unclear information on withdrawals. Dentist not involved in study. Drop outs: 4%.Duration: unclear.

Participants Adults with solid cancer - recurrent colorectal metastatic. Chemotherapy 5 FU. 130 patients were ran-domized, 5 were evaluable and 125 were evaluated.

Interventions 2 groups, notreatment control versusfolic acid200 mg/m2/d 5 consecutivedaysbefore5-FU. 206eligible,130 enrolled, 165 completed.

Outcomes Mucositis (clinical 0-3 scale). Assessment used: day 28. Other reported outcomes: GI toxicity grades.


Risk of bias



Ertekin 2004

Methods Randomised, parallel group study conducted in Turkey. Patient and assessor blinded (c), unclear whetherprovider blind. Clear information about withdrawals, 3 in placebo. Dentist not involved in study. Dropouts: 10%.

Participants Adults with hand and neck cancer. 30 enrolled, 27 completed.

Interventions 2 groups, zinc sulphate 5 mg zinc capsules 3 times per day starting first day of radiotherapy until 6 weeksafter versus placebo. All patients access to local anaesthetic solutions and analgesic agents.

Outcomes Mucositis RTOG grading. Other reported outcomes: non-steroidal analgesics.





Ertekin 2004 (Continued)


Risk of bias



Ferretti 1988

Methods Randomised, parallel group study conducted in USA. Patient, providers and assessors were blind. Unclearinformation on withdrawals: 1/28 control, 4/28 test.Dentist involvedin study. Drop outs:10%. Duration:up to 90 days.

Participants Children and adults (1-51 years) with mixed blood haematological and solid cancers receiving BMT. 56patients enrolled and 51 completed, but data from 41 patients were used.

Interventions 2 groups, placebo versus chlorhexidine gluconate mouthrinse (15 cc 0.12%, 3 times per day for 30s).

Outcomes Mucositis (clinical scale 0-3, but then dichotomised and measured at 7, 14, 25, 33, 60 & 90 days). Assessment used: day 33. Other reported outcomes: gross candida (clinical appearance + swab culture orKOH preparation), oral streptococus, yeast, gram -ve bacilli, death, morphine use.

Notes Candidemia (persistant candidiasis)also recorded, with 3 deaths due to candida in the control group.Mean mucositis scores given graphically with bars for SE. Given oral nystatin suspension 15 ml 4 timesdaily or clotrimazole troches. Supplemental nystatin soaks or popsicles were used liberally.Funding source: pharmaceutical.

Risk of bias



Ferretti 1990

Methods Randomised, parallel group study conducted in USA. Patient, providers and assessors were blind. Unclearinformation on withdrawals: 18/46 control, 15/46 test. Dentist involved in study.Drop outs: 36%. Duration: 28 days.

Participants Children and adults (1-70 years) with mixed blood and solid cancer. High dose chemotherapy or headand neck radiation (data separate). 92 enrolled, 59 completed.

Interventions 2 groups, placebo versus chlorhexidine 0.12% ml 3 times/day.





Ferretti 1990 (Continued)

Outcomes Mucositis (scale where 0 = no ulceration). Assessment used: day 28+. Other reported outcomes: oral micr-strep, yeast, gram-ve bacilli. Systematicinfection measured at day 7, 14, 21, 28.

Notes Mucositis severity given with no s.d. Both groups had some mucositis at baseline.Funding source: pharmaceutical.

Risk of bias



Fidler 1996

Methods Randomised, parallel group study conducted in USA. Patient, providers and assessors were blind. Unclearinformation on withdrawals: 1/165 total. Dentist not involved in study. Drop outs: 1%. Duration: 14days.

Participants Adults, cancer type not given. Chemotherapy: first course 5-FU based. 165 enrolled, 164 clinical evalua-tion, 135 patient evaluation.

Interventions 2 groups, placebo versus camomile (30 drops in 100 ml water, 3 times per day).

Outcomes Mucositis (physician and patient scales 0-4). Score judged historically 4-5 weeks after chemotherapy cycleinitiation. Additionally patient form filled outon dailybasisfor first 3 weeks after first dayof chemotherapy.

Assessment used: day 21. Other reported outcomes: toxicity.

Notes Mean daily mucositis scores shown graphically but no s.d. All patients used ice chips 5 mins beforechemotherapy and for 30 minutes in total.Patient’s mucositis scores used.Funding source: government.

Risk of bias



Foote 1994

Methods Randomised, parallel group, multicentre study conducted in USA and Canada. Patient, providers andassessors were blind. Clear information on withdrawals: none. Unclear if dentist involved in study. Dropouts: 0%. Duration: 14 days.

Participants Adults with head and neck cancer. 52 patients were eligible, enrolled and evaluated.





Foote 1994 (Continued)

Interventions 2 groups, placebo versus chlorhexidine (15 ml 4 times per day for 130s).

Outcomes Mucositis scale 0-4 by patient and clinician at weekly intervals. Assessment used: day unclear.

Notes Funding source: pharmaceutical and government.

Risk of bias



Franzen 1995

Methods Randomised, parallel group study conducted in Sweden. Patient, providers and assessors were blind.Statistician blind. Unclear information on withdrawals: 2/50 total. Unclear if dentist involved in study.Drop outs: 10%. Duration: -2 to 14 weeks.

Participants Adults with head and neck cancer. 50 patients were enrolled and 48 evaluated.

Interventions 2 groups, placebo versus sucralfate (granules of sucralfate an alkaline aluminimum hydroxide of suphatedsucrose, swish with 1 dose package 1 g dissolved in water 6 times/day).

Outcomes Patient based assessment of mucositis on 0-3 scale, number with grades 2 or 3 reported. Assessement used:day 28. Other reported outcomes: mucosal reaction, pain, functional impairment.

Notes Funding source: charity.

Risk of bias



Freytes 2004

Methods Randomised, parallel group, multicentre study conducted in USA. Patients, providers and assessors blind.Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: 28days after last dose of intervention.

Participants Adults with mixed cancer. BMT. 42 enrolled, randomised and evaluated.

Interventions 3 groups, placebo versus repifermin 25 mug/kg and repifermin 50 mug/kg (patients received intravenousrepifermin or placebo for 3 days before their autologous hematopoietic stem cell transplantation (auto-HSCT)conditioning regimen and for up to 10 days after auto-HSCT).





Freytes 2004 (Continued)

Outcomes Mucositis measured 3/week until mucositis resolved using the NCI CTC mucositis toxicity scale for bonemarrow transplant studies (on a scale of 0-4). Mucositis was also assessed by the OMAS scale. Assessmentused: up to day 28. Other reported outcomes: severity and duration of ambient oral and orophanyngealpain and pain on swallowing, an ability to eat score, narcotic pain medication use, adverse events incudedthe frequency, severity and duration of diarrhea.


Risk of bias



Giles 2003a

Methods Randomised, parallelgroup, multicentre study conducted inUSA/Europe.Patients, providers and assessorsblind. Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration:up to 42 days.

Participants Adults with mixed cancer. BMT. 323 randomised and completed. Protocol violation outcome only onparticipants given correct drug (n = 221).

Interventions 2 groups, placebo versus iseganan (patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days).

Outcomes Mucositis gradedwith reference totheNCICTC stomatitis5-point scale (0-5).Assessment usedup today 21. Otherreported outcomes: mouthand throatpain, difficulty swallowing, days with febrile neutropenia,the duration of UOM and systemic absorption of iseganan.

Notes Funding source: industry. Protocol violation some patients received wrong drug used only data in patientsgiven correct drug. Pharmacological company provided drug and organised randomisation.Correspondence with Dr D Peterson: Clinical trials with iseganan were discontinued approximately 6years ago. Approval of the drug for oral mucositis was not obtained in the United States.

Risk of bias







Giles 2004

Methods Randomised, parallel group, multicentre study conducted in USA. Patients, providers and assessors blind.Clear information on withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: 21days.

Participants Adults and children with mixed cancer. BMT. 502 randomised and completed.

Interventions 2 groups, placebo versus iseganan (patients received an oral rinse, consisting of iseganan 9 mg or placebo,to be swished/swallowed 6 times daily, for up to 21 days).

Outcomes Mucositisassessed 3/weeklyby the proportionof patientswhodidnot develop a peakNCI CTC stomatitisgrade 2 or above. Assessment used up to 21 days. Other reported outcomes: mouth pain, difficulty

swallowing, incidence of ulcerative oral mucositis (UOM), opioid use, adverse events included fatigue,anxiety, sore throat, dermatitis, insomnia and erythema.

Notes Funding source: unclear. Pharmacological company provided drug and organised randomisation.Correspondence with Dr D Peterson: Clinical trials with iseganan were discontinued approximately 6years ago. Approval of the drug for oral mucositis was not obtained in the United States.

Risk of bias



Gujral 2001

Methods Randomised, parallel group study conducted in India. Patients, providers and assessors not blinded.Unclear information aboutwithdrawals.Dentistno involvedin study. Dropouts: 1%.Duration:6 months.

Participants Adults with head and neck cancer. T3 and T4 squamous cell cancer, 100 enrolled, 99 evaluated.

Interventions 2 groups, no treatment versus hydrolytic enzymes, papain 100 mg, trypsin 40 mg and chymotrypsin 40mg. 3 tablets 3 times a day - 3 until + 5.

Outcomes RTOG/EORTC scoring. Assessment used: day 54. Other reported outcomes: dysphagia, dermatitis.

Notes No oral care except toothbrushing. Funding source: pharmaceutical.

Risk of bias







Hartmann 2001

Methods Randomised, parallel group study conducted in Germany. Unclear whether patient, provider or assessorblind. Clear information about withdrawals, 0. Dentist not involved in study. Drop outs: 0%.

Participants Adults with solid cancer. 40 enrolled, 40 completed.

Interventions 2 groups, amifostine 910 mg/m2 ,15 minute IV infusion before carboplatin and ifosfamide for 3 consec-utive days versus control.

Outcomes Mucositis WHO percentage patients grade 3-4. Other reported outcomes nausea/vomiting, costs of totalcare, diarrhoea.

Notes Funding source: pharmaceutical (c).

Risk of bias


Allocation concealment? No C - Inadequate

Huang 2000

Methods Randomised, parallel group study conducted in Taiwan. Unclear whether patient, providers and assessors were blind. Clear information about withdrawals (c): none. Dentist not involved in study. Drop outs:

0%. Duration: beginning of radiation treatment until 25 factions (5 weeks).

Participants Adults with head and neck cancer. 17 patients were enrolled and evaluated.

Interventions 2 groups, placebo (30 ml saline) versus glutamine (2 g in 30 ml saline, swish 30 ml 3 mins exporate).

Outcomes Clinicians assessed subjective mucositis on 0-4 scale and objective RTOG/EORTC 0-4 scale. WHO stepof analgesic drugs. Assessment used: day unclear.

Notes Subjective mucositis scale used. Funding source: none.

Risk of bias







Huang 2003

Methods Randomised, parallel group study conducted in China. Patients and providers not blind. Unclear whetherassessors blind. Clear information on withdrawals. Unclear whether dentist involved in study. Drop outs:0%. Duration: average radiotherapy 50 days.

Participants Adultswithhead and neckcancertreatedwith chemotherapy cisplatin (DDP30 mg/m²) withconcomitantradiotherapy.

Interventions 2 groups, Dobell’s solution versus Chinese medicine 6 times from first to sixth week of radiotherapy.Patients received either Chinese medicine or Dobell’s solution 5-8 times daily.The decoction is made as solution by cooking the 11 herbs together with water. Doses of the herbs for 1day are: Coastal Glehnia 30 gram, Dwarf Lilyturf Tuber Root 30 gram, Rehmannia Dried Root 30 gram,

Figwort Rood 15 gram, Spreading Hedyotis Herb 30 gram, Belamcauda Rhizome 15 gram, PlatycodonRoot 15 gram, Shinyleaf Pricklyoash Root 15 gram, Honeysuckle Flower 15 gram, Licorice Root 3 gram,Lalanggrass Rhizome 20 gram.The authors follow theoretical principles of Chinese medicine: treatment should be modified in adaptingthe changes of the diagnosis. So, if the patients with symptoms of rhinorrhagia or blood clot in thesputum, adding Hairy Vein Agrimony Herb 20 gram, Hyacinth Bletilla Tuber 15 gram; with nausea andvomiting adding Red Ochre 15 gram, Magnolis Bark of Sichuan 15 gram, Bamboo Shaving 15 gram;

with obstruction of the nose, adding Sibirian Cocklebur Fruit 15 gram, Magnolia Flower 15 gram; withmalaise and poor appetite, adding Pseudostellaria Root 30 gram, Bighead Atractylodes Rhizome 15 gram,Malt 30 gram, Millet Sprout 30 gram; with the tongue in dark pink color, adding Root of Red RootedSalvia 15 gram, powder of Notoginsen 3 gram.

Outcomes Mucositis assessed according to acute oropharyngeal mucositis grade on a 0-4 scale.

Notes Pharmacological company provided drug and organised randomisation.

Risk of bias



Hwang 2004

Methods Randomised, parallel group study conducted in Singapore. Patients, providers and assessors not blind.Clear information on withdrawals: 1 died in amifostine group. Dentist not involved in study. Drop outs:2%. Duration: up to 49 days.

Participants Adults and children with mixed cancer. BMT. 60 enrolled and randomised 59 evaluated.

Interventions 2 groups, notreatmentcontrolversus amifostine(patientsreceiving myeloablativeconditioningtherapy forallogeneicbone marrow transplantation weregivenamifostine 1000 mg/day of conditioning radiotherapy).

Outcomes Mucositis was graded daily using the WHO grading system on a scale of 0-4. Other reported outcomes:the 1979 WHO Handbook for Reporting Results for Cancer Treatment was initially used when the trialstarted in 1998, but as the 1998 and 1999 Common Toxicity Criteria in the Cancer Therapy Evaluation





Hwang 2004 (Continued)

Programme (CTEP) became available, toxicology grading was, wherever possible, retrospectively definedaccording to the new criteria. Other outcomes were fever, nausea, vomiting, diarrhea and amifostine-associated toxicities (hypocalcemia, hypotension and nausea (grade 1) or vomiting).

Notes Funding source: industry. All participantswere given subcutaneous G-CSF until ANC exceeded500/cm3. All were randomly assigned to either itraconazole oral solution 200 mg/day or low dose iv amphotericinB 0.2 mg/Kg/day. Pharmacological company provided drug and organised randomisation.

Risk of bias



Ifrah 1999

Methods Randomised, parallel group study conducted in France. Patient and assessor blind. Unclear whetherprovider blind. Unclear information about drop outs. No dentist involved in study.

Participants Adults with blood cancer. 67 enrolled, results given on 64.

Interventions 2 groups, rGM-CSF 5 ug/kg as a 6 hour IV nfusion versus placebo.

Outcomes WHO mucositis score (>3).


Risk of bias



Jebb 1994

Methods Randomised, cross-over study conducted in UK. Patient, providers and assessors were blind. Unclearinformation about withdrawals: 11/28 in total. Dentist not involved in study.Drop outs: 39%. Duration: (1st part) 8 days.

Participants Adults with gastrointestinal cancer undergoing 5-FU & folic acid daily for 5 days and repeated 4 weeksfrom start. 28 patients enrolled and 17 completed 2 cycles.

Interventions 2 groups, glucose polymer (Polycal) (described as placebo) versus glutamine (16 gm daily divided into 4equal doses and dissolved in 150 ml water before consumption).

Outcomes WHO mucositis score, mouth comfort, ease of eating. Assessment used: day 8.





Jebb 1994 (Continued)

Notes Funding source: none.

Risk of bias



Karacetin 2004

Methods Randomised, parallel group study conducted in Turkey. Unclear whether patients, providers and assessorsblind. Clear information on withdrawals: none. Dentist involved in study. Drop outs: 0%. Duration:unclear.

Participants Adults with head and neck cancer treated with radiotherapy (RT). 53 enrolled and completed.

Interventions 2 groups, no treatment control versus amifostine (patients were randomly assigned to undergo RT or RTplus short intravenous infusion of amifostine 210 mg/m² before each RT fraction).

Outcomes Mucositis graded according to the RTOG toxicity criteria on a 0-4 scale. Assessment used time unclear.Other reported outcomes: xerostomia, loss of taste and dysphagia, salivary flow, decrease of salivary pH,nausea (grade 1), hypotension, body rash, arrhythmia, serum calcium levels.


Risk of bias



Katano 1995

Methods Randomised, parallel group study conducted in Japan. Patients, providers and assessors were not blind

(c). Clear information about withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration:administration ceased when leukocyte exceeded 8,000/mm³.

Participants Adults with solid (breast cancer). 14 patients enrolled and evaluated.

Interventions 2 groups, no treatment versus G-CSF (granulocyte colony-stimulating factor, by injection 125 ug).

Outcomes WHO mucositis score (0-4) by clinician. Other reported outcomes: alopecia, fever. Assessment used: day 8.

Notes Funding source: pharmaceutical supply product.





Katano 1995 (Continued)

Risk of bias



Kaul 1999

Methods Randomised, parallel group study conducted in India. Patient, provider and assessor not blind. Unclearinformation about withdrawals. Dentist not involved in study. Drop outs unclear. Duration unclear.

Participants Adults with head and neck cancer radiotherapy 50-60 Gy/5-6 weeks. 50 patients enrolled.

Interventions 2 groups, no treatment control versus wobe-mugos enzyme preparation 3 tablets/day 3 days prior to RTuntil 1 week after.

Outcomes Mucositis. Assessment used: day 28. Other reported outcomes: xerostomia, skin changes, dysphagia,hospitalisation.


Risk of bias



Koukourakis 2000

Methods Randomised, parallel group study conducted in Greece. Patient, provider and assessor not blind. Unclearinformation on withdrawals 0/20 control, 1/20 test. Dentist not involved in study. Drop outs: 3%.Duration 6-7 weeks.

Participants Adults with head and neck cancer RT postoperative or inperable dose 64-70 Gy. 40 patients enrolled, 39completed.

Interventions 2 groups, no treatment control versus amifostine 500 mg daily before RT.

Outcomes Mucositis 0-4 scale combined categories. Assessment used: unclear. Other reported outcomes RT delay,side effects.

Notes Patients selectedfromother types of cancer because mucositis data available. Funding source: government& pharmaceutical.

Risk of bias






Koukourakis 2000 (Continued)


Labar 1993

Methods Randomised, parallel group study conducted in Croatia. Patients and assessors blind but unclear if providers were. Clear information about withdrawals: none. Dentist not involved in study. Drop outs:0%. Duration: +7 to day +21.

Participants Children and adults (5-43 years) with blood cancers, undergoing BMT. 60 patients eligible, enrolled andevaluated.

Interventions 2 groups, placebo versus prostaglandin E2 (0.5 mg 3 times per day).

Outcomes Clinical and culture fungal measurement. Mucositis (WHO scale for 0-II vs III+, and 0 vs 1+). Severity over -7 to +35 days. Severity of mucositis also measured but no s.d. given. Assessment used: day 35. Otherreported outcomes: HSV infection, microbiology, vomiting, diarrhoea, fever, death, GVHD (c).


Risk of bias



Leborgne 1997

Methods Randomised, parallel group study conducted in Uruguay (c). Patient, provider and assessor blind. Unclearinformation about withdrawals. Dentist not involved in study. Drop outs: 4%. Duration 90 days.

Participants Adults with head and neck cancer radical RT. 69 enrolled, 66 completed.

Interventions 2 groups, placebo versus prednisone 40 mg once daily through day 28 reduced dose to day 43.

Outcomes Mucositis WHO. Assessment used: unclear. Other reported outcomes: treatment interruptions.


Risk of bias







Lee 1989

Methods Randomised, parallel group study conducted in USA. Patient and provider not blind. Unclear whetherassessor blind. Unclear information about withdrawals. Dentist not involved in study.

Participants Adults with head and neck cancer. Enrolled 42, results given on 40.

Interventions 2 groups, no treatment control versus misonidazole (1.5 gm/m2 3 times a week for 7 doses).

Outcomes Mucositis on scale 0-5. Otherreportedoutcomes: numbness, parasthesia, nausea and vomiting, dysphagia.

Notes Funding source: government.

Risk of bias



Lilleby 2006

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors not blind. Clearinformation on withdrawals: 1 in saline group withdrew consent because wanted ice-chips. Dentist notinvolved in study. Drop outs: 2%. Duration: -2 to 28 days post transplant.

Participants Adults with blood cancer - multiple myeloma scheduled to receive melphalan 200 mg/m² followed by BMT- autologous stem cell transplantation (ASCT). 41 enrolled and randomised, 40 completed.

Interventions 2 groups, room temperature normal saline rinse versus ice chips (oral cryotherapy)30 min before and 6 hafter high-dose therapy.

Outcomes Mucositis was assessed as part of routine care using the NCI CTC grades 0-4. Assessment used: -2 to 28days. Other reported outcomes: days of total parenteral nutrition (TNP), narcotic use, hospitalisation,

weight loss and resumption of oral caloric intake for 28 days after transplant.

Notes Funding source: charity.

Risk of bias







Lockhart 2005

Methods Randomised, parallel group study conducted in USA. Patients and assessors blind. Unclear whetherproviders blind. Clear information on withdrawals: none. Unclear whetherdentist involved in study. Dropouts: 0%. Duration: unclear.

Participants Adultswith mixed cancer. BMT - autologousbloodstem cell transplant(ABSCT).36enrolled, randomisedand completed.

Interventions 2 groups, placebo versus pilocarpine (patients were randomised to receive a 5 mg tablet of pilocarpine, ora placebo, during and following chemotherapy).

Outcomes Mucositis assessed every other day using the WHO mucositis score and the authors’ own developed data

entry forms to capture subjective and objective data, including toxicity criteria. This new tool is a highly modified version of the Southwest Oncology Group (SWOG) toxicity scale. We used the highest scoremucositis score recorded, supplied by author. Assessment used: up to day 10. Other reported outcomes:problems with nutrition, oral infection, use of narcotics for mucosal pain, problems with oral hygiene,gingival bleeding, eating, speaking and sleeping (ordinal variables), pain at rest or with swallowing, mouthdryness (VAS scale).

Notes Funding source: charity/foundation.

Risk of bias



Loprinzi 1990

Methods Randomised cross-over trial conducted in USA. Patients, providers and assessors were blind. Clear infor-mation on withdrawals: none. Dentist was not involved. Drop outs: 0%. Duration: 5 days.

Participants Adults with colorectal cancer receiving first 5 day course of 5-FU. 77 patients enrolled, and completed1st period, only 20 completed 2nd period.

Interventions 2 groups, placebo versus allupurinol mouthrinse 1 mg/ml made from 450 mg + 150 ml cologel (450 mg/5mg methylcellulose with 5% alcohol) +450 ml flavouring agent. 20 ml used for 30s immediately aftertreatment then at 1, 2, 3 hours).

Outcomes Mucositis (physician and patient scales 0-4). Assessed used: day 30.

Notes Data cross-tabulated in a form suitable for meta-analysis provided by authors.Funding source: none.

Risk of bias






Loprinzi 1990 (Continued)


Mahood 1991

Methods Randomised, cross-over study conducted in USA. Patients, providers and assessors not blind. Unclearinformation on withdrawals: 2/45 control, 0/50 treatment in first cycle. Dentists not involved in study.Drop outs 2%. Duration from 5 mins before 5-FU and for 30 mins after.

Participants Adults mostly over 40 years with cancer of the colon (solid cancer). Chemotherapy first 5 day course of 5-FU. 95 patients eligible and enrolled and 93 completed first cycle, however, only 82 patients assessedmucositis.

Interventions 2 groups, no treatment control versus ice chips (cryotherapy)placed in the mouth 5 mins before each doseof 5 FU and replenished over 30 mins.

Outcomes Mucositis (physician & patients scales 0-4) and historical 1 month after treatment. Assessment used: day 28.

Notes Data cross-tabulated in a form suitable for meta-analysis provided by authors.Funding source: government.

Risk of bias



Makkonen 1994

Methods Randomised, parallel group study conducted in Finland. Patients blind but unclear if providers andassessors were. Clear information about withdrawals: none mentioned. Dentist involved in study. Dropouts: 0%. Duration: during therapy (9 weeks).

Participants Adults with head and neck cancer. 40 patients eligible, enrolled and evaluated.

Interventions 2 groups, placebo versus sucralfate (suspension 1 g 6 times per day orally, patients mix granules with 100ml water rinse for 1 min then swallow). Rinsed throughout radiotherapy, dose 45-73 Gy.

Outcomes Mucositis on scale 0-2 (0 = no mucositis, 1 = moderate, 2 = severe), at 9 weekly evaluation visits. Assess-ment used: day 28. Other reported outcomes: salivary lactoferrin, salivary albumin, amount of anestheticmouthwash, radiotherapy interrupted, toxicity.

Notes Visit at week 4 taken. Antifungal agents given to 29 patients during study.Funding source: government.

Risk of bias





Makkonen 1994 (Continued)



Makkonen 2000

Methods Randomised, parallel group study conducted in Finland. Patients, providers and assessors not blind. Clearinformation about withdrawals: none.Dentist involved in study. Drop outs:0%. Duration:during therapy (9 weeks).


Interventions 2 groups, no treatment control versus GM-CSF (150 to 300 ug given subcutaneously daily until last day of irradiation. Dose depends on body weight).

Outcomes Mucositis on scale 0-2 (0 = no mucositis, 1 = moderate, 2 = severe). Assessment used: day 28. Otherreported outcomes: oral pain on scale 1-4, and patient VAS scale for pain. Evaluated weekly duringtreatment then 1 and 6 months after therapy, use of analgesic, weight loss, toxicity, survival.

Notes All patients used sucralfate suspension 1 g 6 times daily.Funding source: pharmaceutical.

Risk of bias



Meropol 2003

Methods Randomised, parallel group, multicentre study conducted in USA. Patient and assessor blind. Unclear whether provider blind. Clear information about withdrawals: 0. Dentist not involved in study. Dropouts: 0% Duration: 28 days.

Participants Adults with solid cancer treated with 5-FU. Patients enrolled, 81 completed.

Interventions 2 groups, keratinocyte growth factor IV injection patient cohorts treated with escalating doses of KGF1,10, 20, 40, 60 and 80 micrograms/kg per day versus placebo control.

Outcomes Mucositis WHO grading evaluated by examination on day 1,4, 8, 15 and 28. Other reported outcomes:nausea, vomiting, blood changes.


Risk of bias





Meropol 2003 (Continued)



Mills 1988

Methods Randomised, parallel group study conducted in South Africa. Patient and provider not blind. Unclear whether assessor blind. Clear information about withdrawals: 0. Dentist not involved in study. Drop outs:0%Duration: unclear.

Participants Adults with head and neck cancer. 10 enrolled, 10 completed.

Interventions 2 groups, beta carotene (250 mg/day for 21 days, 75 mg daily after this) versus no treatment control.

Outcomes Mucositis.


Risk of bias



Nemunaitis 1995

Methods Randomised, parallel group, multicentre study conducted in USA and Canada. Patient, provider andassessor blind. Clear information about withdrawals: none.Dentist not involved in study. Drop outs: 0%. Duration: 1 year.

Participants Adults with mixed cancer receiving BMT, chemotherapy cyclosporine & prednisolone. 109 patientsenrolled, 109 completed.

Interventions 2 groups, placebo versus RhGM-CSF (human granulocyte macrophage colony stimulating factor) 250ug/m2/day IV day 0-20.

Outcomes Mucosistis scored by nurse 3 grades. (Categorised according to WHO criteria for analysis). Assessmentused: day 28. Other reported outcomes: infection, anorexia, diarrohea, hypertension, stomatitis.


Risk of bias






Nemunaitis 1995 (Continued)


Niibe 1985

Methods Randomised, parallel group study conducted in Japan. Patients, providers and assessors blind. Clearinformation about withdrawals: 4/24 control, 6/23 treatment. Dentist not involved in study. Drop outs:21%. Duration: day 1 to end of radiation.

Participants Adults with head and neck cancer. 47 patients enrolled and 37 completed.

Interventions 2 groups, placebo versus amifostine (200 mg per day).

Outcomes Mucositis measured at >= 2 on scale similar to WHO scale. Assessment used: day unclear.


Risk of bias



Nottage 2003

Methods Randomised, parallel group study conducted in Canada. Patient, provider and assessor blind. Clear in-formation about withdrawals, 1 placebo. Dentists not involved in study. Drop outs: 1.2%.

Participants Adults with solid cancer treated with 5-FU. 81 enrolled 80 completed.

Interventions 2 groups, placebo versus sucralfate mouthwash (10 ml mouthwash for 2 minutes then swallow 4 timesper day).

Outcomes Mucositis severity (patient daily diary scores). Other reported outcomes: pain eating/drinking difficulty,quality of life score, weight loss, nausea and vomiting.


Risk of bias







Oberbaum 2001

Methods Randomised, parallel group study conducted in Israel. Patients, providers and assessors blind. Clearinformation about withdrawals: 1/16 control, 1/16 test. No dentist involved in study. Drop outs: 6%.Duration: unclear.

Participants Children and adults with mixed cancer receiving a BMT. 32 consecutive patients enrolled, 30 completed.

Interventions 2 groups, placebo versus traumeel (homeopathic)rinse vigorously 30 sec before swallowing 5/day for aminimum 14 days.

Outcomes Mucositis WHO scale evaluated every 2 days. Assessment used: day 7.

Notes All patients 2 daily chlorhexidine oral amphotericin B.Funding source: pharmaceutical and possibly charity.

Risk of bias



Okuno 1999

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Clear infor-

mation about withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: up to 5 weeksafter initial chemotherapy.

Participants Adults with cancer (type unclear). 134 eligible, enrolled and evaluated, but patient assessment only completed by 124 patients.

Interventions 2 groups, placebo versus glutamine (4 g twice a day, swish for 10 s then swallow).

Outcomes Maximum severity of mucositis over 14 days using 0-4 scale, both physician and patient assessment. Otherreported outcomes: toxicity (no detail). Assessment used: day 14.

Notes All patients used ice chips 5 minutes before 5-FU for 30 minutes.Funding source: government.

Risk of bias







Papas 2003

Methods Randomised, parallel goup study conducted in USA. Patients, provider and assessor blind. Clear infor-mation about withdrawals, 1/46 placebo, 1/51 test (c). Dentist involved in study. Drop outs: 2%.Duration: up to 24 days.

Participants Adults with mixed cancer (HSCT). 97 enrolled, 94 completed.

Interventions 2 groups, placebo versus calcium phosphate rinse (3 ml 4 times per day, Ca2+ 4.74 mm PO43, 2.96 mm,Na+ 97.67 mm, Cl- 116.6 mm, pH 7.1).

Outcomes Absence/presence days of mucositis. Other reported outcomes: pain, use of morphine.

Notes Funding source:pharmaceutical (c).

Risk of bias



Pfeiffer 1990

Methods Randomised, cross-over study conducted in Denmark. Patients, providers and assessors blind. Unclear

information about withdrawals. Dentist not involved in study. Drop outs: 43%. Duration: 14 days.

Participants Adults with head and neck cancer. 40 patients enrolled, 23 evaluable.

Interventions 2 groups, placebo versus sulcralfate (1 g 15 ml suspension, swish for 2 min then spit out or swallow).

Outcomes Ulceration or not. Assessment used: day 14. Other reported outcomes: pain, problems eating.

Notes Funding source: pharmaceutical support for product.

Risk of bias







Pillsbury 1986

Methods Randomised, parallel study conducted in USA. Patients and assessor blind. Unclear whether providerblind. Clear information about withdrawals, 2/10 control, 0/10 test. Dentist involved in study. Dropouts: 10%.Duration: until treatment was completed.


Interventions 2 groups, placebo versus prostaglandin inhibitor (25 mg of indomethacin 4 times per day).

Outcomes Mucositis grade at day 1, 2 and 3.


Risk of bias



Pitten 2003

Methods Randomised, parallel group study conducted in Germany. Patients, provider and assessor blind. Clearinformation about withdrawals: 0. Dentist involved in study. Drop outs:0%.

Participants Adults with mixed cancer. 47 enrolled, 47 completed.

Interventions 2 groups, placebo versus chlorhexidine 100 ml 0.3% chlorhexidine, 10.4 g ethanol, 1.67 g hydrogenperoxide versus stannous fluoride.

Outcomes Mucositis WHO grading.

Notes Funding source: external.

Risk of bias



Prada 1987

Methods Randomised, parallel group study conducted in Italy. Patients, providers and assessors blind. Unclearinformation about withdrawals. Dentist not involved in study. Drop outs 10%. Duration: 10 days.

Participants Adults with head and neck cancer. 40 patients eligible and enrolled, 36 evaluated.





Prada 1987 (Continued)

Interventions 2 groups, placebo versus benzydamine (120 ml solution of 0.15% benzydamine, 15 ml mouthwash for 5mins every 3 hours up to max of 6 times daily).

Outcomes Physician evaluation of mucositis on 0 (absent) to 3 (intense or remarkable)scale every day for 10 days. Assessment used: day 10. Other reported outcomes: global clinical symptomatology, burning, chewingpain, dysphasia and odynophasia assessed.


Risk of bias



Rahn 1997

Methods Randomised, parallel group study conducted in Germany. Patients and providers not blind, assessors were blind (c). Clear information about withdrawals: none. Dentist involved in study. Drop outs: 0%.Duration: until one week after end of radiotherapy.

Participants Adults with head and neck cancer. 40 patients eligible, enrolled. 2 died but all 40 were evaluated.

Interventions 2 groups, control (sterile water) versus providone iodine rinse (rinsing for 3 mins with 100 ml solution 4times daily).

Outcomes WHO assessment of mucositis on 0-4 scale. During therapy and at 2, 6 weeks after therapy. Assessmentused: day 28.

Notes All patients received nystatin, dexpanthenol, ratoside and immunoglobin.Funding source: unclear.

Risk of bias



Rocke 1993

Methods Randomsiedparallelgroupstudyconducted inUSA.Patientsandprovidersnot blinded,unclearif assessors were blinded. Clear explanation of withdrawals: one in 30 min arm. Drop outs: <1%. Duration: 5 days.

Participants Adults receiving first course of 5-FU, cancer type unclear. 179 eligible, and randomised, 178 evaluated.





Rocke 1993 (Continued)

Interventions 2 groups, 30versus 60minute cryotherapy. Ice chips placedin mouth 5 min before5-FU and thenswishedround during treatment and replenished as ice melted.

Outcomes Physician and patient assessment of mucositis on 0-4 scale.

Notes Some cross-over data were included in paper. We have not included this as only patients with mildmucositis crossed-over.

Risk of bias



Saarilahti 2002

Methods Randomised, parallel group study conducted in Finland. Patients and assessors blinded, but unclear whether providers not blind (c). Clear information about withdrawals: none (c). Dentist not involved instudy. Drop outs: 0%. Duration: 10 weeks.


Interventions 2 groups, GM-CSF mouthwash made by dissolving 150 mg of dried powder in 100 ml sterile water versusmouthwash of 4 g sucralfate with 100 ml sterile water. 4 doses x 25 ml per day after meals.

Outcomes RTOG rating for mucositis on 0-4 scale. Author provided data in right form for the review.

Notes Maximum value of mucositis taken.

Risk of bias



Scarantino 2006

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Clear infor-mation on withdrawals: 1 in pilocarpine and 2 in placebo group refused protocol treatment. Dentist notinvolved in study. Drop outs: 1%. Duration: 13 weeks.

Participants Adults with head and neck cancer. Planned radiotherapy to include have 50% of the volume of the majorsalivary glands receive 50 Gy. 249 enrolled, 4 ineligible 245 randomised, 242 completed.

Interventions 2 groups, placebo versus pilocarpine 5 mg 4 times per day.





Scarantino 2006 (Continued)

Outcomes Mucositis graded 3 times per week according to the RTOG Acute Mucositis Toxicity Scale (0-4). Assess-ment used: unclear. We used the highest RTOG score recoded. Other reported outcomes: sialometry of unstimulated and stimulated whole saliva, eating, taste swallowing, pain, adverse events included nauseaand vomiting.

Notes Funding source: government. Pharmacological company provided drug and organised randomisation.

Risk of bias



Scherlacher 1990

Methods Randomised, parallel group study conducted in Germany. It was unclear whether patients, providers orassessors were blind. Clear description of withdrawals: none. Unclear if dentist involved in study. Dropouts: 0%. Duration 6-7 weeks.

Participants Adults with head and neck cancer. 45 eligible.

Interventions 2 groups: control versus sucralfate suspension (1 g orally 4 times per day for 5 mins).

Outcomes Mucositis scored on 1-5 scale and number with mucositis 3-5 given.

Notes Bothgroupsreceivedstandardoralhygiene,frequenttooth cleaninganddisinfectionof oraland pharyngealmucosa.Funding source: unclear.

Risk of bias



Schneider 1999

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Clear infor-mation about withdrawals: none. Dentist involved in study. Drop outs: 0%.

Participants Adults with head and neck cancer. 14 patients enrolled and evaluated.

Interventions 2 groups, placebo versus filgrastim (subcutaneous injections daily throughout treatment titrated to keepneutrophil count between 10x 10² and 30x 10³/l).





Schneider 1999 (Continued)

Outcomes WHO mucositis 0-4 scale, and Hickey mucositis scores. Proportion of patients greater than WHOmucositis grade 3 presented. Assessment used: week 10.

Notes All patients had oral hygiene instruction. Funding source: pharmaceutical.

Risk of bias



Shenep 1988

Methods Randomised, parallel group study conducted in USA. Patients, providers and assessors blind. Clear infor-mation about withdrawals: none. Dentist not involved in study. Drop outs: 0%. Duration: 50 days.

Participants Children with leukaemia. Chemotherapy- remission induction multiagent ANLL-83. 48 patients enrolledand evaluated.

Interventions 2 groups, placebo versus sucralfate (0.75 mg/kg daily, suspension swished every 6 hours).

Outcomes Mucositis (clinical and patients scales given, 0-4), gram-ve, gram+ve, fungal, all organisms. Assessment

used: day 50. Other reported outcomes: gastroenteritis, gingival bleeding, nutrition, fever, infection, rash.

Notes Clinician’s mucositis score used.Funding source: government.

Risk of bias



Shieh 1997

Methods Randomised, parallel group study conducted in China. Patients not blind, and assessors blind (c). Clearinformation about withdrawals: none. Dentist involved in study.Drop outs: 0%. Duration: 5 weeks.

Participants Adults with head and neck cancer. 30 patients enrolled and evaluated.

Interventions 3 groups (oral care protocols), control given no instructions, E1 given protocol to follow 1 day beforeradiotherapy, E2 given protocol to follow 1 week before radiotherapy. Oral care protocol included instruc-tions on how to brush teeth.





Shieh 1997 (Continued)

Outcomes Stomatitis freesurvival (graph).Also means and standarddeviations oforal assessmentguide (OAG) index, which includes multiple factors including voice and teeth. Assessment used: day 28.

Notes Funding source: government.

Risk of bias



Spencer 2005

Methods Randomised, parallel group, multicentre study conducted in Australia. Patients and providers not blind.Unclear whether assessors blind. Clear information on withdrawals: none. Dentist not involved in study.Drop outs: 0%. Duration: up to 46 months.

Participants Adults blood cancer - multiple myloma undergoing BMT high dose melphalan conditioned autologousstem cell transplantation (ASCT).

Interventions 2 groups, no treatment control versus amifostine (patients undergoing ASCT were randomised to receiveor not receive amifostine 910 mg/m² prior to melphalan 200 mg/m²).

Outcomes Mucositis graded according to the adapted WHO toxicity scale. Assessment used: time unclear. Otherreported outcomes: parenteral nutrition, analgesic use, complete remission, adverse events included: tox-icity, nausea (grade 1), vomiting and hypotention.

Notes Funding source: industry and charity. All participants received antibacterial prophylaxis and fluconazole.Pharmacological company provided drug and organised randomisation.

Risk of bias



Spielberger 2004

Methods Randomised, parallel group, multicentre study conducted in USA. Patients and assessors blind. Unclear whether providers blind. Clear information on withdrawals: none. Dentist involved in study. Drop outs:0%. Duration: 28 days.

Participants Adults with mixed cancer. BMT. Treated with fractionated total-body irradiation plus high-dose chemo-therapy and auto-HSCT. 212 enrolled, randomised and completed.





Spielberger 2004 (Continued)

Interventions 2 groups, placebo versus palifermin (recombinant human keratinocyte growth factor) 60 micrograms perkilogram of body weightper dayiv for3 consecutive days immediately beforethe initiation of conditioningtherapy.

Outcomes Mucositis assessed daily using 3 scales: the WHO oral-toxicity scale (0-4) (primary scale), RTOG (0-4)acute radiation morbidity scoring criteria for mucous membranes, and the 4-grade Western Consortiumfor Cancer Nursing Research (WCCNR) revised staging system for oral mucositis. Assessment used: -8 upto day 28. Other reported outcomes: soreness of the mouth and throat, swallowing limitations, opioid use,incidence of febrile neutropenia, incidence of infections, incidence of the use of total parenteral nutrition.

Adverse events: included rash, purities, erthema, taste alteration.

Notes Funding source: industry. Pharmacological company provided drug and organised randomisation.

Risk of bias



Spijkervet 1989

Methods Randomised, parallel group study conducted in the Netherlands. Patients, providers and assessors blind.

Clear information about withdrawals: none. Dentist involved in study. Drop outs: 0%. Duration: 5 weeks.


Interventions 2 groups, placebo versus chlorhexidine spray/rinse (0.1% chlorhexidine 100 ml per day (spray 50 ml)rinsing 3 times with 15 ml).

Outcomes Semiquantitativescoringof mucositis in’describedelsewhere’. Assessedthriceweeklyuntilendof treatment(at least 50 Gy). Assessment used: day 35. Other reported outcomes: microflora.

Notes Used data from text: 24 patients showed the most severe stage of pseudomembrane formation (12 inplacebo and 12 in test). During radiotherapy daily cleaning of teeth by hygienist.Funding source: government.

Risk of bias







Stokman 2003

Methods Randomised, parallel group study conducted in the Netherlands. Patient, provider and assessor blind.Clear information on withdrawals: 2/32 placebo, 5/33 test. Unclear whether dentist involved in study.Drop outs: 10.7%


Interventions 2 groups, placebo versus active lozenges (containing polymyxin E 2 mg, tobramycin 1.8 mg and ampho-tericin B 10 mg (PTA)).

Outcomes Percentage develop of mucositis (WHO 3-4). Other reported outcomes: weight loss.


Risk of bias



Su 2003

Methods Radomised, parallel group study conducted in USA. Patient and assessor blind. Unclear whether providerblind. Clear information about withdrawals: 0. Dentist not involved in study. Drop outs: 0%


Interventions 2 groups, placebo versus aloe vera (AV). 20 cc aloe vera a day during radiotherapy.

Outcomes Mucositis RTOG grade 3-4. Other reported outcomes: mean overall health, mean soreness score.


Risk of bias



Symonds 1996

Methods Randomised, parallel group study conducted in Scotland. Patients, providers and assessors blind. Clearinformation about withdrawals: 30/139 control, 24/136 test. Dentist not involved in study. Drop outs:20%. Duration: until radiation reaction settled, 8 weeks.

Participants Adults with head and neck cancer. 275 patients enrolled and 221 evaluated.





Symonds 1996 (Continued)

Interventions 2 groups, placebo versus antibiotic pastille (polymyxin E 2 mg, tobramycin 1.8 mg and amphotericin B10 mg, 4 times daily from start of radiotherapy).

Outcomes Physician assessment of mucositis (none, patchy confluent). Assessment used: day 56. Other reportedoutcomes: patients asked about pain on swallowing and dysphagia, weight loss and compliance.


Risk of bias



Trotti 2004

Methods Randomised, parallel group, multicentre study conducted in USA, Canada, Germany, France and UK.Patient and assessor blind. Unclear whether provider blind. Clear information about withdrawals: 0.Dentist not involved in study. Drop outs: 0%.

Participants Adults with head and neck cancer. 545 enrolled, 511 results reported

Interventions 3 groups, placebo plus standard oral care (SOC), iseganan (9 mg as 0.3% aqueous solution) plus SOC,SOC alone.

Outcomes Percentage mucositis NCI CTC grade 2-4. Other reported outcomes: completion of radiotherapy andchemotherapy.

Notes Funding source: pharmaceutical.Correspondence with Dr D Peterson: Clinical trials with iseganan were discontinued approximately 6years ago. Approval of the drug for oral mucositis was not obtained in the United States

Risk of bias



van der Lelie 2001

Methods Randomised, parallel group study conducted in the Netherlands. Patients, providers and assessors blind.Clear information about withdrawals: none. Dentist involved in study. Drop outs: 0%. Duration: untilneutrophil recovery.

Participants Adults with mixed cancer receving BMT or cell stem. 39 patients eligible, 36 enrolled and evaluated.





van der Lelie 2001 (Continued)

Interventions 2 groups, placebo versus GM-CSF (300 ug of GM-CSF daily dose in 2% methylocellulose gel, 5 ml geltwice daily, keep in oral cavity as long as possible then swallow).

Outcomes WHO mucositis scale 0-4. Assessment used: day 14. Other reported outcomes: VAS mucositis pain, OASmucositis, required morphine or not, fever, infection treated with antibiotics, duration of netropenia, daysin hospital.

Notes All rinsed with 0.9% saline and in case of inflamation 0.12% chlorhexidine 6 times daily. Funding source:university, pharmaceutical for intervention.

Risk of bias



Vokurka 2005

Methods Randomised, parallel group, multicentre study conducted in EU. Patients blind. Providers not blind.Unclear whether assessors blind. Unclear information on withdrawals: 3 refused after start, 2 lost. Dentistnot involved in study. Drop outs: 4%. Duration: 28 days.

Participants Adults. Disease unclear. BMT. High dose chemotherapy followed by autologous peripheral stem celltransplantation. 137 enrolled and randomised, 132 completed.

Interventions 2 groups, placebo (saline) versus povidone iodine (Betadine 1 ml and 100 ml water freshly made every morning) (1:100 mouthwashes after high-dose chemotherapy comprising BEAM or HD-L-PAM).

Outcomes Mucositis assessed once daily using the WHO grading on a scale of 0-4. Assessment used: up to 28 days.Other reported outcomes: oral pain, tolerability of mouthwashes, occurrence of infections, fever and oralmicrobiology in patients with clinical suspicion of local infection.


Risk of bias







Wahlin 1989

Methods Randomised, parallel group study conducted in Sweden. Patients and providers not blind, assessors blind.Clear information about withdrawals: 4/14 control, 3/14 test. Dentist involved in study. Drop outs: 0%.Duration: 21 days.

Participants Children and adults with acute leukaemia at start of chemotherapy. 28 patients enrolled, 14 patientscompleted (although mucositis data presented on 28).

Interventions Control: no treatment versus chlorhexidine (0.2% 10 ml twice daily).

Outcomes Mucositis scored at the level of ulceration. Assessment used: day 28. Other reported outcomes: candidiasisverified by detecting pseudohypae in smears, days fever, plaque, gingival bleeding, burning sensation.

Notes Data from the first course of chemotherapy used as unable to extract data for second course due to lack of information about drop outs.Funding source: government.

Risk of bias



Wang 2002a

Methods Randomised, parallel group study conducted in China. Patients and providers not blind, unclear of assessor blinded. Unclear information about withdrawals, although there appeared to be none. Dentistnot involved in study. Drop outs: 0%. Duration: 1 week after course of chemotherapy.

Participants Adults with solid cancer (breast, lung and lymphoma). CHOP for malignanat lymphoma, CMF for breastcancer and CAP for lung cancer. 147 eligible and enrolled, and with data.

Interventions 2 groups, Dobell’s solution as control (30 ml for 3 min, gargling 5 times per day). Concoction of Chinesemedicine including 5 herbs (corktree bark, European vebena herb, catechu, forsythia fruit) and borneol(sucked and gargled 5 times per day).

Outcomes Mucositis scored on 4-point scale. Time of healing ulcers.


Risk of bias







Wijers 2001

Methods Randomised, parallel group study conducted in the Netherlands. Patients providers and assessors wereblinded. Unclear information about withdrawals. Dentist involved in study. Drop outs: 32%. Duration:3 weeks after radiation.

Participants Adults with head and neck cancer. 114 patients enrolled, 37 refused to continue, 77 completed.

Interventions 2 groups, placebo versus PTA paste containing antibiotics, polymyxin E, tobramycin, amphotericin.

Outcomes Mucositis scored weekly, 5 point scale, Van der Schneren system. Assessment used: day 28 min. Otherreported outcomes: pain, microflora.


Risk of bias



Yuen 2001

Methods Randomised, parallel group study conducted in Hong Kong. Patients, providers and assessors not blind.Clear information on withdrawals: none. Dentist no involved in study. Drop outs: 0%. Duration: 60 days

after BMT.

Participants Adults with mixed cancer receiving BMT, 70 enrolled, 70 evaluated.

Interventions 2 groups no treatment versus Clarithromycin oral 500 mg twice daily or IV 500 mg 12 hourly. Start day -7.

Outcomes Mucositisscoringsystem not clear. Grade2 dataused.Assessment used: unclear. Other reportedoutcomes:toxicity (rash, diarrhoea, liver function), infection, duration of fever, neutropenic fever, use of antibiotics,parenteral nutrition, growth factors.


Risk of bias



ASTC = autologous stem cell transplantationBMT = bone marrow transplantEORTC = European Organization for Research and Treatment of Oral CancerGI = glycaemic indexGM-CSF = granulocyte/macrophage colony-stimulating factor





GVHD = graft-versus-host disease

HSCT = hematopoietic stem cell transplantHSV = herpes simplex virusKGF = keratinocyte growth factorNCI CTC = National Cancer Institute Common Toxicity CriteriaOAG = oral assessment guideOMAS = oral mucosa assessment scaleOMS = objective mucositis scoreRT = radiotherapy RTOG = Radiation Therapy Oncology Groups.d. = standard deviationSOC = standard oral careTPN = total parenteral nutritionUOM = ulcerative oral mucositis

VAS = visual analogue scale WBC - white blood count WHO = World Health Organization5-FU = 5-fluorouracil(c) indicates from correspondence with authors

Characteristics of excluded studies [ordered by study ID]

Adamietz 1997 Abstract - insufficient information (povidone iodine).

Altmann 1999 Not RCT (amifostine).

Andersen 1987 Cancer treatments comparing toxic effects.

Anderson 1998b Data not in suitable form, need number per group for self reported mouth sores for Fig 3 otherwisecannot use data (glutamine versus placebo).

Antin 2002 Study stopped when lower boundary of 90% confidence interval exceeded 17%, the historical death rateof a similar cohort of patients. Mucositis was a secondary outcome (rhIL-11 versus placebo).

Antonadou 1998 Abstract, insufficient information (radiotherapy with or without GM-CSF).

Apaydin 1996 Data not in suitable form. Unclear how mucositis assessed and means (SD) given (benzydamine versusno treatment).

Aquino 2005 No appropriate outcomes (oral glutamine).

Ardizzoni 2002 Cancer treatments comparing toxic effects and confounded by cancer (GCSF).

Awada 2002 Cancer treatment comparing toxic effects.

Awada 2004 Not RCT (temozolomide plus liposomal doxorubicin).





(Continued)

Awidi 2001 Episodes not patients. Type of cross-over study but some patients were included in more than 2 ’courses’(pilocarpine versus placebo).

Awwad 2002 Cancer treatments comparing toxic effects (conventional fractionation versus accelerated hyperfraction-ation).

Barasch 1995 Data not in suitable form. Mucositis presented as mean area (SD) (He-Ne laser versus no treatment).

Bensadoun 1995 Abstract - insufficient information (low energy laser).

Bensadoun 1999 Data not in suitable form. Mean (SD) of mucositis grade intensity per week (He-Ne laser versus notreatment).

Bensadoun 2006 Comparison of different cancer treatment regimens, not primary outcome.

Bentzen 2001 Comparing different chemotherapy regimens.

Bergmann 1995 Herpes simplex virus (acyclovir).

Bleehen 1996 Different chemotherapy regimens.

Bolwell 2004 Intervention to prevent GVHD not specifically mucositis.

Bourhis 2006 Comparing 2 radiotherapy regimens but looking at toxicity.

Braaksma 2002 Data in inappropriate form for review (amifostine). Means.

Buentzel 1999 Abstract - insufficient information (amifostine).

Calais 1998 Abstract - insufficient information (radiotherapy plus/chemotherapy).

Calais 2000 Survival was primary outcome not mucositis.

Calais 2004 Not RCT (chemotherapy).

Cassidy 2002 Cancer treatments comparing toxic effects.

Cella 2003 Author unable to supply additional data for review (iseganan versus placebo). Data in inappropriate formfor review.

Cheng 2001 Not RCT (oral care protocol).

Cheng 2002 Not RCT (oral care protocol).

Cheng 2003 Inappropriate study design. Cross-over study but only included patients who were clear of mucositis forsecond period.





(Continued)

Cheng 2004a Subjects assessment of ’helpful in reducing mucositis’, no clinical assessment.

Cheng 2004b Inappropriate study design. Cross-over study but only included patients who were clear of mucositis forsecond period (oral care).

Chi 1995 Data not in suitable form. Written to authors requesting cross-tabulated data (GM-CSF versus notreatment).

Collova 2004 Abstract - insufficient information.

Colombat 1995 Abstract - insufficient information (fluconazole versus amphotericin B).

Costa 1999 Abstract, not RCT (chlorhexidine versus no treatment).

Costa 2003 Not RCT (chlorhexidine versus control).

Cowen 1997 Data in inappropriate form. Daily mucositis index ranging from 0-48 used, with means (SD) presented(He-Ne laser versus no treatment).

Crawford 1994 Abstract - insufficient information (filigrastim (r-metHug-CSF).

Crispino 1997 Abstract - insufficient information (different radiotherapy regimens).

Cruz 1997 Abstract - insufficient information (folinic acid).

Cunningham 1995 Investigating new cancer treatment, tomudex, with oral mucositis as one of the minor side effects.

De Boer 2002 Cancer treatments comparing toxic effects (conventional versus accelerated infusional chemotherapy).

Decker-Baummann 1999 Unsuitable treatment outcome for review (parenteral glutamine versus no treatment).

Denham 1999 Cancer treatments comparing toxic effects (conventional versus accelerated fractionation).

Djuric 2006 Some mucositis present at baseline.

Dobrowsky 1998 Added to speed up radiotherapy, not radio-protection-toxic (mitomycin).

Doroshow 1987 Cancer treatments comparing toxic effects.

Dudjak 1987 Data not in suitable form. Mean (SD) of mouth and comfort scores (2 oral care protocols).

Edelman 1998 Not RCT (cryotherapy).

Eisen 2003 Not RCT (valacyclovir versus acyclovir).

El-Sayed 2000 Abstract, not RCT (antimicrobial lozenge).





(Continued)

El-Sayed 2002b Not RCT (antimicrobial lozenge).

Epstein 1986 Mucositis not presented in a useable form, however VAS pain scores presented (benzydamine versusplacebo).

Epstein 1989 Data not in suitable form. Mean (SD) for size and area of ulceration presented (benzydamine versusplacebo).

Epstein 1992 Data not in suitable form. Mean (SD) for size and area of ulceration presented (3 groups: chlorhexidinerinse, nystatin suspension and saline solution).

Epstein 1994 Data not in suitable form. Mean (SD) mucositis scores presented (sucralfate versus placebo).

Epstein 1999 Abstract, insufficient information (benzydamine versus placebo).

Epstein 2001 Excluded due to mucositis data presented as area under the curve (benzydamine versus placebo).

Erkisi 1996 Design fault - intervention confounded by radiotherapy (G-CSF versus no treatment).

Etiz 1998 Abstract, insufficient information (sucralfate versus placebo).

Etiz 2000 Data not in suitable form. Median oral mucositis scores and pain scores presented (sucralfate versus

placebo).

Evans 1990 Abstract, insufficient information (GM-CFS versus placebo).

Evensen 2001 Data in inappropriate form for review.

Ezzat 2005 Comparing 3 different radiotherapy regimens, survival not mucositis is primary outcome.

Fahlke 1999 Not RCT (amifostine).

Falcone 2001 Comparing different radiotherapy regimens.

Fay 1994 Not RCT (GM-CSF).

Feber 1995 No mucositis outcome reported in RCT (hydrogen peroxide versus sodium chloride rinses).

Feber 1996 Data not in suitable form. Oral assessment guide means presented (2 oral care protocols).

Ferreira 2002 Abstract. Data in wrong form for review, severe mucositis events per patient week presented (vitamin E).

Ferreira 2004 Data in wrong form for review, severe mucositis events per patient week presented (vitamin E).

Ferretti 1985 Abstract - insufficient information (chlorhexidine).

Foncuberta 2001 Patients assigned sequentially not RCT (GF-B3).





(Continued)

Gabison 1995 Abstract - insufficient information (zinc picolinate).

Giles 2003b Cancer treatment toxicity (troxacitabine).

Goldberg 2003 Abstract - insufficient information (en3247).

Grotz 2001 Datanotin suitableform. TotalRTOGscores mean(SD) presented(comarin/troxerutineversus placebo).

Gujral 1999 Abstract (oral enzymes).

Gutierrez 1996 Not RCT (fluconazole).

Hanson 1995 No response to query regarding drop outs and no suitable mucositis data (prostaglandin E1 versusplacebo).

Hanson 1997 Data not in suitable form. Mucositis mean (SD) graphically presented (prostaglandin versus placebo).

Harris 1995 Abstract, insufficient information (folinic acid mouthwash versus placebo).

Hartmann 1999 Abstract - insufficient information.

He 2004 Abstract - insufficient information (amifostine).

Hickey 1982 Problems with data. 21 patients in total, unclear how many patients per group, but data presented as 67courses of chemotherapy (oral hygiene protocols).

Howell 1983 Unclear if randomised. Cross-over study provided 59 paired course of treatment in 23 patients (allop-urinol).

Hu 2003 Not RCT (amifostine).

Ito 2002 Not RCT (allopurinol spray).

Jebb 1995 Data not in suitable form. Mean (SD) mucositis scores presented (glutamine versus placebo).

Johnson 2002 Not RCT (prostaglandin e1).

Kante 1995 Abstract - insufficient information (oral care regimens).

Karthaus 1998 Problems with the data. 8 patients, 32 chemo cycles and results presented assuming independent (G-CSF versus placebo).

Kasten-Sportes 2003 From authors: unfortunately, this protocol never accrued subjects as our patient population changed.

Kenny 1990 Data not in suitable form. Oral assessment guide mean (SD) presented (2 oral care protocols).

Klocke 2006 Abstract - insufficient information.





(Continued)

Kokkonen 2002 No useful outcomes.

Labar 1990 Abstract, insufficient infomation (prostaglandin E).

Labbate 2003 Not RCT.

Leong 1995 Abstract, insufficient information (thymidine versus no treatment).

Levendag 1998 Abstract, insufficient information (polyenes versus placebo).

Levi 1997 Comparison of 2 cancer treatments where the primary outcome was maximum tumour response totherapy.

Lievens 1998 Data not in suitable form. Mean (SD) mucositis scores presented graphically (sucralfate versus placebo).

Lin 2006 Data not in suitable form.

Lopez 1994 Data not in suitable form. Number of days with mucositis presented (vitamin E versus placebo).

Loprinzi 1997 Unable to use data.

Lorusso 2003 Episodes not patients considered in analysis (amifostine).

Lozada 1998 Abstract with insufficent information given (pilocarpine).

Madero 1999 No response to query whether patients were randomised to groups (rhGM-CFS).

Mahmoud 1996 Comparison of 2 cancer treatments where the primary outcome was survival (folinic acid).

Malaker 1991 Not RCT (B-Carotene retinoic acid).

Mantovani 2003 No useable mucositis outcome.

Marcial 1994 Abstract, insufficient information. It states it is an RCT but mentions historical control group (low energy laser versus no treatment).

Masucci 2005 Treatment of mucositis not prevention.

Matejka 1990 Not RCT (prostaglandin E2).

McGaw 1985 Data not in suitable form. Did not give the numbers in the 2 study groups and data presented as mean(SD) mucositis index (chlorhexidine versus placebo).

McIlroy 1996 Data not in suitable form. Qualitative assessment with no data given (polyenes versus placebo).

Merte 1999 Abstract (German).





(Continued)

Mills 1995 Not RCT.

Minn 1999 Abstract - insufficient information (GM-CSF).

Nicholl 1995 No suitable outcomes for review (amphotericin B - 2 doses).

Niibe 1985b No clear mucositis index presented (amifostine versus placebo).

Nikoletti 2005 Design flaw. Change in mucositis mentioned as increased from pre to post, onset or worsening of symptoms. Cross-over design not appropriate if they already had mucositis.

Ohnmacht 2001 Oral irritation not mucositis measured (nystatin).

Okuno 1997 Major change to protocol half way through study (antibiotic lozenge versus placebo). Chlorhexidinefor first part included as study by Foote 1994. Data from first part comparing antibiotic lozenge withplacebo mouthrinse has not been included as we feel this is an inappropriate control.

Okuno 1998 Abstract, insufficient information (glutamine versus placebo).

Okutomi 2000 Not RCT (Z-100 injections).

Papas 1984 Abstract (patient management system).

Peters 1993 CCT. Paper states “Randomisation procedure was done according to day of birth.”

Peterson 2003 Abstract - insufficient information (AES-13).

Pfeiffer 1989 Abstract, insufficient information (sucralfate versus placebo).

Phillips 2002 Not RCT (amifostine).

Piccirillo 2003 Data in wrong form for review and all patients had mucositis (response from authors).

Porta 1994 Abstract - insufficient information (allopurinol mouthwash).

Pouli 1999 Abstract, insufficient information (GM-CSF versus sodium bicarbonate mouthwash).

Prada 1985 Data not in suitable form. Mean (SD) mucositis scores presented (unsure if RCT) (benzydamine versusplacebo mouthwash).

Pyrhonen 1995 Mucositis not primary outcome.

Pytlik 2002 Data in wrong form and no response from authors to request for extra data (glutamine versus placebo).

Rabinovitch 2006 Mucositis not primary outcome.

Rades 2004 No oral mucositis outcomes- study halted due to adverse side effects of amifostine.





(Continued)

Radmard 2002 Abstract - insufficient information (rhGM-CSF).

Raether 1989 Data not in suitable form. Mean (SD) of ulceration over 7 sites per patient presented (chlorhexidineversus placebo).

Robustelli 1999 Abstract - insufficient information (galenic preparation).

Rocci 2005 Not eligible since it is not dealing with prevention or treatment of mucositis, but uses mucositis tomeasure side effect of 2 differentways to deliver an antitumoural drug forthe treatmentof gastrointestinaltumours.

Rojas 2001 Episodes not patients.

Rutkauskas 1993 Data not in suitable form. Mucositis mean (not SD) presented (chlorhexidine versus placebo).

Samaranayake 1988 Data not in suitable form. Mean (not SD) presented (benzydamine versus chlorhexidine).

Sato 1997 Unsure if RCT and author has not responded to letter requesting further information.

Scarantino 2001a Abstract insufficient information (pilocarpine versus placebo).

Scarantino 2001b Abstract - insufficient information.

Schwerkkoske 1999 Abstract - insufficient information (neumega rhIL-11; oprelvekin).

Spadaro 1991 Abstract, insufficient information (vitamin E + vitamin A + fluconazole versus no treatment).

Staar 2001 Abstract - insufficient information (different radiotherapy regimens).

Stokman 2004 Not RCT. This was a cross-over study but not randomised. All patients had control cycle first.

Su 2004a Abstract - insufficient information (aloe vera).

Su 2004b Abstract - insufficient information (GCSF).

Suc 1999 Abstract, insufficient information (chewing gum versus no treatment).

Svanberg 2004 Abstract - insufficient information (cryotherapy).

Sykes 2004 Not an RCT.

Symonds 1995 Abstract - could write for more info active lozenge (polymix tobramycin, amphotericin B versus placebolozenge).

Teshima 1986 Japanese paper. Unclear information on withdrawals. Written to authors but no reply.

Thieblemont 2002 Not RCT.





(Continued)

Throuvalas 1995 Abstract, probably not RCT described as comparative study (GM-CSF).

Toubai 2003 Probably not RCT, only 12 patients in total? (itraconazole).

Uchiyama 2005 Not RCT.

Vacha 1999 Mucositis scores presented, data not in suitable form for the review (amifostine versus no treatment).

Vacha 2003 Data not in appropriate form for review.

Valcarcel 2002a Abstract - insufficient information (rhGM-CSF).

Valcarcel 2002b Abstract - insufficient information.

Valcárcel 1997 Abstract - insufficient information (thymostimulin).

van Zaanen 1994 Patients randomised per treatment cycle and mucositis not primary outcome (glutamine).

Verdi 1995 Data not in suitable form. Oral assessment scores (0-24 scale) presented for each patient (pentoxifyllineversus placebo).

Vesole 1999 Abstract insufficient information (IB-367).

Vitello 2000 Abstract, insufficient information (lidocaine versus dyclone mouthrinses).

Wagner 2002 Abstract for treatment of mucositis review (CM-CSF).

Wang 2002b Not RCT.

Warde 2002 Xerostomia main outcome.

Weisdorf 1989 Data not in suitable form. Mean (SD) maximal area of ulceration presented (chlorhexidine versusplacebo).

Weiss 1990 Cross-over trial and data in wrong form for review (allopurinol).

Whelan 2002 Not RCT.

Whelan 2004 Not RCT (from author).

Wollina 2002 Not RCT (dexpanthenol).

Wymenga 1999a Abstract, insufficient information (TGF-B3 mouthrinse versus no treatment).

Wymenga 1999b Not RCT (TGF-B3 mouthrinse versus no treatment).

Yokomizo 2004 Not RCT.





(Continued)

Zalcberg 1995 Abstract insufficient information (cancer treatments).

CCT = controlled clinical trial; RCT = randomised controlled trial; SD = standard deviation

Characteristics of ongoing studies [ordered by study ID]

Haddad 2003

Trial name or title PhaseII randomized studyof concomitant chemoradiationusing weeklycarboplatin/paclitaxelwith or withoutdaily subcutaneous amifostine in patients with newly diagnosed locally advanced squamous cell carcinoma of the head and neck

Methods

Participants

Interventions

Outcomes

Starting date

Contact information Haddad R

Notes





D A T A A N D A N A L Y S E S

Comparison 1. Active treatment versus placebo/no treatment

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mucositis (absent versus present) 48 risk ratio (Random, 95% CI) Subtotals only 1.1 Aclyclovir versus placebo 1 57 risk ratio (Random, 95% CI) 1.33 [0.85, 2.08]

1.2 Allopurinol versusplacebo/no treatment

2 68 risk ratio (Random, 95% CI) 0.62 [0.15, 2.47]

1.3 Amifostine versus notreatment 5 632 risk ratio (Random, 95% CI) 0.95 [0.92, 0.98]

1.4 Antibiotic (pastille orpaste) versus placebo


1.5 Benzydamine versusplacebo


1.6 Chinese medicine versuscontrol (Dobell’s solution)


1.7 Calcium phosphate versusplacebo


1.8 Camomile versus placebo 1 135 risk ratio (Random, 95% CI) 0.79 [0.58, 1.07]

1.9 Chlorhexidine versusplacebo or no treatment


1.10 Folinic acid versus notreatment


1.11 Glutamine versusplacebo


1.12 GM-CSF versus notreatment


1.13 Histamine gel versusplacebo


1.14 Honey versus control 1 40 risk ratio (Random, 95% CI) 0.85 [0.66, 1.08]

1.15 Hydrolytic enzymesversus no treatment


1.16 Ice chips versus no

treatment


1.17 Iseganan versus placebo 1 221 risk ratio (Random, 95% CI) 0.59 [0.43, 0.80]

1.18 Misonidazole versuscontrol


1.19 Oral care protocol versusnone


1.20 Pilocarpine versusplacebo


1.21 Povidone versus water 2 172 risk ratio (Random, 95% CI) 0.84 [0.60, 1.18]

1.22 Prednisone versusplacebo


1.23 Propantheline versusplacebo






1.24 Prostaglandin versus

placebo


1.25 Sucralfate versus placebo 2 182 risk ratio (Random, 95% CI) 0.96 [0.85, 1.10]1.26 Traumeel versus placebo 1 30 risk ratio (Random, 95% CI) 0.71 [0.48, 1.04]

1.27 Zinc sulphate versusplacebo


2 Mucositis (0-1 versus 2+) 48 risk ratio (Random, 95% CI) Subtotals only 2.1 Aloe vera versus placebo 1 58 risk ratio (Random, 95% CI) 0.92 [0.64, 1.32]

2.2 Amifostine versus placeboor no treatment


2.3 Antibiotic pastille or pasteversus placebo or no treatment




2.5 Camomile versus placebo 1 164 risk ratio (Random, 95% CI) 0.63 [0.33, 1.21]2.6 Chinese medicine versus

control (Dobell’s solution)2 248 risk ratio (Random, 95% CI) 0.44 [0.33, 0.59]





2.9 Glutamine versus placebo 4 243 risk ratio (Random, 95% CI) 0.92 [0.75, 1.12]

2.10 GM-CSF versus notreatment


2.11 Hydrolic enzymes versusno treatment


2.12 Ice chips versus notreatment


2.13 Indomethacin versusplacebo

1 18 risk ratio (Random, 95% CI) Not estimable


2.15 Keratinocyte GF versusplacebo






2.18 Pentoxifylline versus notreatment







2.22 Sucralfate versus placebo 3 116 risk ratio (Random, 95% CI) 0.68 [0.41, 1.12]

2.23 Systemic antibioticclarithromycin versus notreatment


2.24 Zinc sulphate versusplacebo


3 Mucositis (0-2 versus 3+) 59 risk ratio (Random, 95% CI) Subtotals only





3.1 Amifostine versus no

treatment


3.2 Antibiotic pastille or pasteversus placebo


3.3 Beta carotene versuscontrol




3.5 Camomile versus placebo 1 164 risk ratio (Random, 95% CI) 1.14 [0.43, 3.00]

3.6 Chinese medicine versuscontrol (Dobell’s solution)






3.9 Glutamine versus placebo 5 240 risk ratio (Random, 95% CI) 0.57 [0.23, 1.38]3.10 GM-CSF versus placebo 6 358 risk ratio (Random, 95% CI) 0.69 [0.36, 1.32]

3.11 Histamine gel versusplacebo


3.12 Honey versus control 1 40 risk ratio (Random, 95% CI) 0.27 [0.11, 0.66]

3.13 Hydrolytic enzymesversus no treatment


3.14 Ice chips versus notreatment



3.16 Keratinocyte GF versus

placebo











3.22 Prostaglandin versusplacebo


3.23 Sucralfate versus placebo 6 423 risk ratio (Random, 95% CI) 0.78 [0.61, 1.00]3.24 Zinc sulphate 1 27 risk ratio (Random, 95% CI) 0.05 [0.00, 0.78]





Comparison 2. Comparisons between active interventions


studies

No. of


1 Mucositis (absent versus present) 2 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

1.1 Cryotherapy: 30 minversus 60 min

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

1.2 Etoposide: bolus versuscontinuous

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

2 Mucositis (0-1 versus 2+) 4 Risk Ratio (M-H, Random, 95% CI) Totals not selected


1 Risk Ratio (M-H, Random, 95% CI) Not estimable



2.3 GM-CFS versus sucralfate 1 Risk Ratio (M-H, Random, 95% CI) Not estimable

2.4 Keratinocyte: 50 mgversus 25 mg


3 Mucositis (0-2 versus 3+) 4 Risk Ratio (M-H, Random, 95% CI) Totals not selected





3.3 GM-CSF versus sucralfate 1 Risk Ratio (M-H, Random, 95% CI) Not estimable

3.4 Keratinocyte: 50 mg

versus 25 mg


Comparison 3. Side effects


studies

No. of


1 Amifostine 6 risk ratio (Random, 95% CI) Subtotals only 1.1 Survival at 24 months 1 66 risk ratio (Random, 95% CI) 1.14 [0.88, 1.48]

1.2 Recurrence at 18 monthsafter cancer treatment


1.3 Incomplete response toradiotherapy


1.4 Delay to radiotherapy 1 39 risk ratio (Random, 95% CI) 0.44 [0.19, 1.01]1.5 Hypotension 4 536 risk ratio (Random, 95% CI) 2.32 [1.40, 3.84]1.6 Nausea 4 500 risk ratio (Random, 95% CI) 1.69 [0.61, 4.67]1.7 Vomiting 3 370 risk ratio (Random, 95% CI) 5.95 [1.03, 34.29]





Analysis 1.1. Comparison 1 Active treatment versus placebo/no treatment, Outcome 1 Mucositis (absent

versus present).

Review: Interventions for preventing oral mucositis for patients with cancer receiving treatment

Comparison: 1 Active treatment versus placebo/no treatment

Outcome: 1 Mucositis (absent versus present)

Study or subgroup Treatment Control log [risk ratio] risk ratio Weight risk ratio

N N (SE) IV,Random,95% CI IV,Random,95% CI

1 Aclyclovir versus placebo

Bubley 1989 27 30 0.2852 (0.228) 100.0 % 1.33 [ 0.85, 2.08 ]

Subtotal (95% CI) 100.0 % 1.33 [ 0.85, 2.08 ]

Heterogeneity: not applicable

Test for overall effect: Z = 1.25 (P = 0.21)

2 Allopurinol versus placebo/no treatment

Dozono 1989 15 15 -1.2518 (0.463) 20.1 % 0.29 [ 0.12, 0.71 ]

Loprinzi 1990 19 19 0.167 (0.205) 79.9 % 1.18 [ 0.79, 1.77 ]

Subtotal (95% CI) 100.0 % 0.62 [ 0.15, 2.47 ]

Heterogeneity: Tau2 = 0.88; Chi2 = 7.85, df = 1 (P = 0.01); I 2 =87%


3 Amifostine versus no treatment

Brizel 2000 148 153 -0.0513 (0.021) 25.0 % 0.95 [ 0.91, 0.99 ]

Buentzel 2006 65 64 -0.0725 (0.039) 23.4 % 0.93 [ 0.86, 1.00 ]

Hwang 2004 29 30 -0.0346 (0.05) 22.2 % 0.97 [ 0.88, 1.07 ]

Karacetin 2004 33 20 0.1275 (0.125) 12.9 % 1.14 [ 0.89, 1.45 ]

Spencer 2005 43 47 -0.1222 (0.093) 16.6 % 0.88 [ 0.74, 1.06 ]

Subtotal (95% CI) 100.0 % 0.95 [ 0.92, 0.98 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 3.03, df = 4 (P = 0.55); I 2 =0.0%


4 Antibiotic (pastille or paste) versus placebo

El Sayed 2002a 69 68 0.0178 (0.06) 36.0 % 1.02 [ 0.91, 1.14 ]

Symonds 1996 112 109 -0.1625 (0.063) 35.4 % 0.85 [ 0.75, 0.96 ]

Wijers 2001 39 38 -0.0834 (0.093) 28.6 % 0.92 [ 0.77, 1.10 ]

Subtotal (95% CI) 100.0 % 0.93 [ 0.83, 1.04 ]



5 Benzydamine versus placebo

Prada 1987 19 17 -0.4005 (0.185) 100.0 % 0.67 [ 0.47, 0.96 ]

Subtotal (95% CI) 100.0 % 0.67 [ 0.47, 0.96 ]

0.2 0.5 1 2 5

Favours treatment Favours control

(Continued . . . )





(. . . Continued

)Study or subgroup Treatment Control log [risk ratio] risk ratio Weight risk ratio




6 Chinese medicine versus control (Dobell’s solution)

Wang 2002a 76 71 -0.821 (0.396) 100.0 % 0.44 [ 0.20, 0.96 ]

Subtotal (95% CI) 100.0 % 0.44 [ 0.20, 0.96 ]



7 Calcium phosphate versus placebo

Papas 2003 50 44 -0.282 (0.138) 100.0 % 0.75 [ 0.58, 0.99 ]

Subtotal (95% CI) 100.0 % 0.75 [ 0.58, 0.99 ]Heterogeneity: not applicable


8 Camomile versus placebo

Fidler 1996 70 65 -0.2357 (0.157) 100.0 % 0.79 [ 0.58, 1.07 ]

Subtotal (95% CI) 100.0 % 0.79 [ 0.58, 1.07 ]



9 Chlorhexidine versus placebo or no treatment

Dodd 1996 112 110 -0.0943 (0.237) 16.6 % 0.91 [ 0.57, 1.45 ]

Ferretti 1988 20 21 -1.3471 (0.726) 2.2 % 0.26 [ 0.06, 1.08 ]

Ferretti 1990 31 28 -0.5978 (0.28) 12.7 % 0.55 [ 0.32, 0.95 ]

Foote 1994 25 27 0.0392 (0.04) 68.5 % 1.04 [ 0.96, 1.12 ]

Subtotal (95% CI) 100.0 % 0.79 [ 0.53, 1.17 ]



10 Folinic acid versus no treatment

Erlichman 1988 46 61 1.2947 (0.217) 100.0 % 3.65 [ 2.39, 5.58 ]

Subtotal (95% CI) 100.0 % 3.65 [ 2.39, 5.58 ]


Test for overall effect: Z = 5.97 (P < 0.00001)

11 Glutamine versus placebo

Anderson 1998 13 13 -0.478 (0.22) 28.4 % 0.62 [ 0.40, 0.95 ]

Jebb 1994 17 17 -0.201 (0.38) 11.4 % 0.82 [ 0.39, 1.72 ]

Okuno 1999 66 68 0.077 (0.12) 60.3 % 1.08 [ 0.85, 1.37 ]

Subtotal (95% CI) 100.0 % 0.85 [ 0.57, 1.26 ]



12 GM-CSF versus no treatment

Crawford 1999 93 102 -0.5276 (0.197) 26.0 % 0.59 [ 0.40, 0.87 ]

0.2 0.5 1 2 5


(Continued . . . )





(. . . Continued



Dazzi 2003 46 44 -0.0932 (0.066) 70.3 % 0.91 [ 0.80, 1.04 ]

Katano 1995 7 7 -1.2379 (0.6) 3.8 % 0.29 [ 0.09, 0.94 ]

Subtotal (95% CI) 100.0 % 0.67 [ 0.42, 1.07 ]



13 Histamine gel versus placebo

Elad 2006 20 19 0.297 (0.199) 100.0 % 1.35 [ 0.91, 1.99 ]

Subtotal (95% CI) 100.0 % 1.35 [ 0.91, 1.99 ]



14 Honey versus control

Biswal 2003 20 20 -0.1684 (0.123) 100.0 % 0.85 [ 0.66, 1.08 ]

Subtotal (95% CI) 100.0 % 0.85 [ 0.66, 1.08 ]



15 Hydrolytic enzymes versus no treatment

Gujral 2001 53 46 -0.0408 (0.03) 79.3 % 0.96 [ 0.91, 1.02 ]

Kaul 1999 25 25 -0.821 (0.22) 20.7 % 0.44 [ 0.29, 0.68 ]

Subtotal (95% CI) 100.0 % 0.67 [ 0.31, 1.44 ]

Heterogeneity: Tau2

= 0.28; Chi2

= 12.35, df = 1 (P = 0.00044); I2

=92%Test for overall effect: Z = 1.03 (P = 0.30)

16 Ice chips versus no treatment

Cascinu 1994 44 40 -0.4526 (0.271) 25.0 % 0.64 [ 0.37, 1.08 ]

Lilleby 2006 21 19 -0.4479 (0.174) 48.3 % 0.64 [ 0.45, 0.90 ]

Mahood 1991 27 27 -0.462 (0.26) 26.7 % 0.63 [ 0.38, 1.05 ]

Subtotal (95% CI) 100.0 % 0.64 [ 0.50, 0.82 ]



17 Iseganan versus placebo

Giles 2003a 114 107 -0.536 (0.157) 100.0 % 0.59 [ 0.43, 0.80 ]

Subtotal (95% CI) 100.0 % 0.59 [ 0.43, 0.80 ]



18 Misonidazole versus control

Lee 1989 21 19 0.1739 (0.1) 100.0 % 1.19 [ 0.98, 1.45 ]

Subtotal (95% CI) 100.0 % 1.19 [ 0.98, 1.45 ]


0.2 0.5 1 2 5


(Continued . . . )





(. . . Continued




19 Oral care protocol versus none

Shieh 1997 20 10 -0.5108 (0.18) 100.0 % 0.60 [ 0.42, 0.85 ]

Subtotal (95% CI) 100.0 % 0.60 [ 0.42, 0.85 ]



20 Pilocarpine versus placebo

Lockhart 2005 18 16 -0.3481 (0.143) 31.2 % 0.71 [ 0.53, 0.93 ]

Scarantino 2006 120 122 0.0592 (0.025) 68.8 % 1.06 [ 1.01, 1.11 ]

Subtotal (95% CI) 100.0 % 0.89 [ 0.60, 1.32 ]



21 Povidone versus water

Rahn 1997 20 20 -0.3567 (0.14) 44.7 % 0.70 [ 0.53, 0.92 ]

Vokurka 2005 67 65 -0.009 (0.113) 55.3 % 0.99 [ 0.79, 1.24 ]

Subtotal (95% CI) 100.0 % 0.84 [ 0.60, 1.18 ]



22 Prednisone versus placebo

Leborgne 1997 32 34 0.0296 (0.098) 100.0 % 1.03 [ 0.85, 1.25 ]

Subtotal (95% CI) 100.0 % 1.03 [ 0.85, 1.25 ]



23 Propantheline versus placebo

Ahmed 1993 6 6 -0.9163 (0.606) 100.0 % 0.40 [ 0.12, 1.31 ]

Subtotal (95% CI) 100.0 % 0.40 [ 0.12, 1.31 ]



24 Prostaglandin versus placebo

Duenas 1996 9 7 1.1346 (0.609) 4.5 % 3.11 [ 0.94, 10.26 ]

Labar 1993 31 29 -0.0619 (0.05) 95.5 % 0.94 [ 0.85, 1.04 ]

Subtotal (95% CI) 100.0 % 1.47 [ 0.47, 4.55 ]



25 Sucralfate versus placebo

Castagna 2001 51 51 -0.045 (0.079) 57.0 % 0.96 [ 0.82, 1.12 ]

Nottage 2003 41 39 -0.0182 (0.116) 43.0 % 0.98 [ 0.78, 1.23 ]

0.2 0.5 1 2 5


(Continued . . . )





(. . . Continued



Subtotal (95% CI) 100.0 % 0.96 [ 0.85, 1.10 ]



26 Traumeel versus placebo

Oberbaum 2001 15 15 -0.3425 (0.195) 100.0 % 0.71 [ 0.48, 1.04 ]

Subtotal (95% CI) 100.0 % 0.71 [ 0.48, 1.04 ]



27 Zinc sulphate versus placebo

Ertekin 2004 15 12 -0.1393 (0.1) 100.0 % 0.87 [ 0.72, 1.06 ]

Subtotal (95% CI) 100.0 % 0.87 [ 0.72, 1.06 ]



0.2 0.5 1 2 5


Analysis 1.2. Comparison 1 Active treatment versus placebo/no treatment, Outcome 2 Mucositis (0-1

versus 2+).



Outcome: 2 Mucositis (0-1 versus 2+)

Study or subgroup Treatment Control log [risk ratio] risk ratio risk ratio


1 Aloe vera versus placebo

Su 2003 28 30 -0.0856 (0.185) 0.92 [ 0.64, 1.32 ]

Subtotal (95% CI) 0.92 [ 0.64, 1.32 ]



2 Amifostine versus placebo or no treatment

Antonadou 2002 22 23 -0.15 (0.085) 0.86 [ 0.73, 1.02 ]

Brizel 2000 148 153 -0.15 (0.06) 0.86 [ 0.77, 0.97 ]

Buentzel 2006 65 64 0.028 (0.112) 1.03 [ 0.83, 1.28 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued

)Study or subgroup Treatment Control log [risk ratio] risk ratio risk ratio


Hwang 2004 29 30 -0.0429 (0.096) 0.96 [ 0.79, 1.16 ]

Karacetin 2004 33 20 0.0257 (0.205) 1.03 [ 0.69, 1.53 ]

Koukourakis 2000 19 20 -0.821 (0.425) 0.44 [ 0.19, 1.01 ]

Niibe 1985 20 17 -0.713 (0.533) 0.49 [ 0.17, 1.39 ]

Spencer 2005 43 47 -0.4005 (0.201) 0.67 [ 0.45, 0.99 ]

Subtotal (95% CI) 0.88 [ 0.80, 0.98 ]



3 Antibiotic pastille or paste versus placebo or no treatment

El Sayed 2002a 59 68 0.087 (0.085) 1.09 [ 0.92, 1.29 ]

Wijers 2001 39 38 -0.105 (0.149) 0.90 [ 0.67, 1.21 ]

Subtotal (95% CI) 1.03 [ 0.87, 1.22 ]




Papas 2003 50 44 -0.464 (0.207) 0.63 [ 0.42, 0.94 ]

Subtotal (95% CI) 0.63 [ 0.42, 0.94 ]




Fidler 1996 82 82 -0.462 (0.334) 0.63 [ 0.33, 1.21 ]

Subtotal (95% CI) 0.63 [ 0.33, 1.21 ]




Huang 2003 52 49 -0.774 (0.158) 0.46 [ 0.34, 0.63 ]

Wang 2002a 76 71 -1.321 (0.542) 0.27 [ 0.09, 0.77 ]

Subtotal (95% CI) 0.44 [ 0.33, 0.59 ]




Foote 1994 25 27 0.122 (0.127) 1.13 [ 0.88, 1.45 ]

Pitten 2003 24 23 1.4616 (0.725) 4.31 [ 1.04, 17.86 ]

Subtotal (95% CI) 1.83 [ 0.52, 6.43 ]




Erlichman 1988 64 61 0.867 (0.291) 2.38 [ 1.35, 4.21 ]

Subtotal (95% CI) 2.38 [ 1.35, 4.21 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued






Dickson 2000 29 29 0.058 (0.2) 1.06 [ 0.72, 1.57 ]

Huang 2000 8 9 -0.02 (0.18) 0.98 [ 0.69, 1.39 ]

Jebb 1994 17 17 -0.3567 (0.2) 0.70 [ 0.47, 1.04 ]

Okuno 1999 66 68 -0.0202 (0.27) 0.98 [ 0.58, 1.66 ]

Subtotal (95% CI) 0.92 [ 0.75, 1.12 ]



10 GM-CSF versus no treatment

Makkonen 2000 20 20 0 (0) 0.0 [ 0.0, 0.0 ]

Meropol 2003 54 27 -0.4479 (0.209) 0.64 [ 0.42, 0.96 ]

Nemunaitis 1995 53 56 -0.062 (0.091) 0.94 [ 0.79, 1.12 ]

Subtotal (95% CI) 0.81 [ 0.56, 1.17 ]



11 Hydrolic enzymes versus no treatment

Gujral 2001 53 46 -0.616 (0.147) 0.54 [ 0.40, 0.72 ]

Kaul 1999 25 25 -1.386 (0.738) 0.25 [ 0.06, 1.06 ]

Subtotal (95% CI) 0.52 [ 0.36, 0.74 ]




Cascinu 1994 44 40 -0.673 (0.38) 0.51 [ 0.24, 1.07 ]

Lilleby 2006 21 19 -1.197 (0.408) 0.30 [ 0.14, 0.67 ]

Mahood 1991 27 27 -1.2 (0.57) 0.30 [ 0.10, 0.92 ]

Subtotal (95% CI) 0.38 [ 0.23, 0.62 ]



13 Indomethacin versus placebo

Pillsbury 1986 10 8 0 (0) 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 0.0 [ 0.0, 0.0 ]




Giles 2004 251 251 -0.0998 (0.073) 0.91 [ 0.78, 1.04 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued



Trotti 2004 253 171 0.001 (0.033) 1.00 [ 0.94, 1.07 ]

Subtotal (95% CI) 0.97 [ 0.89, 1.06 ]



15 Keratinocyte GF versus placebo

Freytes 2004 28 14 -0.562 (0.171) 0.57 [ 0.41, 0.80 ]

Meropol 2003 54 27 -0.2917 (0.253) 0.75 [ 0.45, 1.23 ]

Spielberger 2004 106 106 -0.078 (0.03) 0.92 [ 0.87, 0.98 ]

Subtotal (95% CI) 0.75 [ 0.54, 1.06 ]Heterogeneity: Tau2 = 0.07; Chi2 = 8.38, df = 2 (P = 0.02); I 2 =76%



Lee 1989 21 19 -0.0315 (0.195) 0.97 [ 0.66, 1.42 ]

Subtotal (95% CI) 0.97 [ 0.66, 1.42 ]




Borowski 1994 75 75 -0.094 (0.057) 0.91 [ 0.81, 1.02 ]

Trotti 2004 87 171 0.0816 (0.03) 1.09 [ 1.02, 1.15 ]

Subtotal (95% CI) 1.00 [ 0.84, 1.19 ]Heterogeneity: Tau2 = 0.01; Chi2 = 7.43, df = 1 (P = 0.01); I 2 =87%


18 Pentoxifylline versus no treatment

Attal 1993 70 70 0 (0.195) 1.00 [ 0.68, 1.47 ]

Subtotal (95% CI) 1.00 [ 0.68, 1.47 ]




Lockhart 2005 18 16 -0.1924 (0.174) 0.82 [ 0.59, 1.16 ]

Scarantino 2006 120 122 0.0751 (0.056) 1.08 [ 0.97, 1.20 ]

Subtotal (95% CI) 0.99 [ 0.78, 1.26 ]




Rahn 1997 20 20 -0.799 (0.25) 0.45 [ 0.28, 0.73 ]

Vokurka 2005 67 65 0.1579 (0.181) 1.17 [ 0.82, 1.67 ]

Subtotal (95% CI) 0.74 [ 0.29, 1.88 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued



Heterogeneity: Tau2 = 0.41; Chi2 = 9.61, df = 1 (P = 0.002); I2 =90%



Leborgne 1997 32 34 -0.342 (0.209) 0.71 [ 0.47, 1.07 ]

Subtotal (95% CI) 0.71 [ 0.47, 1.07 ]




Cengiz 1999 18 10 -0.587 (0.258) 0.56 [ 0.34, 0.92 ]

Franzen 1995 24 24 -0.755 (0.36) 0.47 [ 0.23, 0.95 ]

Makkonen 1994 20 20 0.0862 (0.27) 1.09 [ 0.64, 1.85 ]

Subtotal (95% CI) 0.68 [ 0.41, 1.12 ]



23 Systemic antibiotic clarithromycin versus no treatment

Yuen 2001 35 35 -0.371 (0.192) 0.69 [ 0.47, 1.01 ]

Subtotal (95% CI) 0.69 [ 0.47, 1.01 ]



24 Zinc sulphate versus placeboErtekin 2004 15 15 -0.875 (0.387) 0.42 [ 0.20, 0.89 ]

Subtotal (95% CI) 0.42 [ 0.20, 0.89 ]



0.1 0.2 0.5 1 2 5 10






Analysis 1.3. Comparison 1 Active treatment versus placebo/no treatment, Outcome 3 Mucositis (0-2

versus 3+).




Study or subgroup Treatment Control log [risk ratio] risk ratio risk ratio


1 Amifostine versus no treatment

Antonadou 2002 22 23 -1.2379 (0.408) 0.29 [ 0.13, 0.65 ]

Bourhis 2000 12 12 0 (0.123) 1.00 [ 0.79, 1.27 ]

Brizel 2000 148 153 -0.1054 (0.15) 0.90 [ 0.67, 1.21 ]

Buentzel 2006 65 64 0.564 (0.284) 1.76 [ 1.01, 3.07 ]

Buntzel 1998 14 14 -3.2189 (1.4) 0.04 [ 0.00, 0.62 ]

Hartmann 2001 20 20 -0.693 (0.447) 0.50 [ 0.21, 1.20 ]

Hwang 2004 29 30 -0.426 (0.261) 0.65 [ 0.39, 1.09 ]

Karacetin 2004 33 20 0.0383 (0.382) 1.04 [ 0.49, 2.20 ]

Koukourakis 2000 19 20 -2.5257 (1.44) 0.08 [ 0.00, 1.35 ]

Spencer 2005 43 47 -1.073 (0.467) 0.34 [ 0.14, 0.85 ]

Subtotal (95% CI) 0.70 [ 0.49, 1.00 ]



2 Antibiotic pastille or paste versus placebo

El Sayed 2002a 69 68 -0.106 (0.18) 0.90 [ 0.63, 1.28 ]

Stokman 2003 28 30 -0.1358 (0.116) 0.87 [ 0.70, 1.10 ]

Wijers 2001 39 38 -0.2107 (0.265) 0.81 [ 0.48, 1.36 ]

Subtotal (95% CI) 0.87 [ 0.73, 1.04 ]



3 Beta carotene versus control

Mills 1988 10 10 -0.9808 (0.508) 0.38 [ 0.14, 1.01 ]

Subtotal (95% CI) 0.38 [ 0.14, 1.01 ]




Papas 2003 50 44 -0.8651 (0.303) 0.42 [ 0.23, 0.76 ]

Subtotal (95% CI) 0.42 [ 0.23, 0.76 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued






Fidler 1996 82 82 0.131 (0.493) 1.14 [ 0.43, 3.00 ]

Subtotal (95% CI) 1.14 [ 0.43, 3.00 ]




Huang 2003 52 49 -1.852 (0.44) 0.16 [ 0.07, 0.37 ]

Wang 2002a 76 71 -1.871 (1.068) 0.15 [ 0.02, 1.25 ]

Subtotal (95% CI) 0.16 [ 0.07, 0.35 ]




Foote 1994 25 27 0.01 (0.247) 1.01 [ 0.62, 1.64 ]

Spijkervet 1989 15 15 0 (0.183) 1.00 [ 0.70, 1.43 ]

Wahlin 1989 14 14 -0.1165 (0.305) 0.89 [ 0.49, 1.62 ]

Subtotal (95% CI) 0.98 [ 0.76, 1.27 ]




Erlichman 1988 64 61 2.149 (1.48) 8.58 [ 0.47, 155.98 ]

Subtotal (95% CI) 8.58 [ 0.47, 155.98 ]




Anderson 1998 13 13 -1.109 (0.46) 0.33 [ 0.13, 0.81 ]

Cerchietti 2006 14 15 -1.542 (0.68) 0.21 [ 0.06, 0.81 ]

Huang 2000 8 9 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1994 17 17 0.2231 (0.23) 1.25 [ 0.80, 1.96 ]

Okuno 1999 66 68 -0.198 (0.65) 0.82 [ 0.23, 2.93 ]

Subtotal (95% CI) 0.57 [ 0.23, 1.38 ]Heterogeneity: Tau2 = 0.57; Chi2 = 11.16, df = 3 (P = 0.01); I2 =73%


10 GM-CSF versus placebo

Cartee 1995 36 9 0.6313 (0.654) 1.88 [ 0.52, 6.77 ]

Dazzi 2003 46 44 -0.1696 (0.295) 0.84 [ 0.47, 1.50 ]

Ifrah 1999 35 29 -1.2874 (0.777) 0.28 [ 0.06, 1.27 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued



Nemunaitis 1995 53 56 -1.3471 (0.525) 0.26 [ 0.09, 0.73 ]

Schneider 1999 8 6 -1.3863 (1.021) 0.25 [ 0.03, 1.85 ]

van der Lelie 2001 18 18 0.3221 (0.324) 1.38 [ 0.73, 2.60 ]

Subtotal (95% CI) 0.69 [ 0.36, 1.32 ]



11 Histamine gel versus placebo

Elad 2006 20 19 0.0516 (0.947) 1.05 [ 0.16, 6.74 ]

Subtotal (95% CI) 1.05 [ 0.16, 6.74 ]Heterogeneity: not applicable


12 Honey versus control

Biswal 2003 20 20 -1.3205 (0.465) 0.27 [ 0.11, 0.66 ]

Subtotal (95% CI) 0.27 [ 0.11, 0.66 ]



13 Hydrolytic enzymes versus no treatment

Gujral 2001 53 46 -1.772 (0.599) 0.17 [ 0.05, 0.55 ]

Kaul 1999 25 25 -1.6094 (1.52) 0.20 [ 0.01, 3.93 ]

Subtotal (95% CI) 0.17 [ 0.06, 0.52 ]Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I 2 =0.0%



Cascinu 1994 44 40 -1.022 (0.55) 0.36 [ 0.12, 1.06 ]

Lilleby 2006 21 19 -1.6399 (0.552) 0.19 [ 0.07, 0.57 ]

Mahood 1991 27 27 -2.04 (0.9) 0.13 [ 0.02, 0.76 ]

Subtotal (95% CI) 0.24 [ 0.12, 0.48 ]




Giles 2004 251 251 -0.0834 (0.076) 0.92 [ 0.79, 1.07 ]

Trotti 2004 253 171 0.0917 (0.077) 1.10 [ 0.94, 1.27 ]

Subtotal (95% CI) 1.00 [ 0.85, 1.19 ]



16 Keratinocyte GF versus placebo

Freytes 2004 28 14 0.6931 (1.069) 2.00 [ 0.25, 16.25 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued



Spielberger 2004 106 106 -0.4401 (0.075) 0.64 [ 0.56, 0.75 ]

Subtotal (95% CI) 0.69 [ 0.41, 1.15 ]




Lee 1989 21 19 -0.387 (0.695) 0.68 [ 0.17, 2.65 ]

Subtotal (95% CI) 0.68 [ 0.17, 2.65 ]




Borowski 1994 75 75 -0.1744 (0.105) 0.84 [ 0.68, 1.03 ]

Trotti 2004 87 171 0.2754 (0.083) 1.32 [ 1.12, 1.55 ]

Subtotal (95% CI) 1.06 [ 0.68, 1.64 ]




Lockhart 2005 18 16 -0.1065 (0.22) 0.90 [ 0.58, 1.38 ]

Subtotal (95% CI) 0.90 [ 0.58, 1.38 ]




Rahn 1997 20 20 -1.1712 (0.476) 0.31 [ 0.12, 0.79 ]

Vokurka 2005 67 65 -0.091 (0.302) 0.91 [ 0.51, 1.65 ]

Subtotal (95% CI) 0.57 [ 0.20, 1.62 ]




Leborgne 1997 32 34 -0.4463 (0.688) 0.64 [ 0.17, 2.46 ]

Subtotal (95% CI) 0.64 [ 0.17, 2.46 ]



22 Prostaglandin versus placebo

Labar 1993 31 29 0.0583 (0.242) 1.06 [ 0.66, 1.70 ]

Pillsbury 1986 10 8 1 (0) 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1.06 [ 0.66, 1.70 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued




Carter 1999 52 50 -0.1625 (0.22) 0.85 [ 0.55, 1.31 ]

Castagna 2001 51 51 -0.47 (0.263) 0.63 [ 0.37, 1.05 ]

Nottage 2003 41 39 -0.1555 (0.401) 0.86 [ 0.39, 1.88 ]

Pfeiffer 1990 23 23 -0.1748 (0.2) 0.84 [ 0.57, 1.24 ]

Scherlacher 1990 24 21 -1.5187 (0.572) 0.22 [ 0.07, 0.67 ]

Shenep 1988 24 24 -0.0619 (0.18) 0.94 [ 0.66, 1.34 ]

Subtotal (95% CI) 0.78 [ 0.61, 1.00 ]



24 Zinc sulphate

Ertekin 2004 15 12 -2.996 (1.4) 0.05 [ 0.00, 0.78 ]

Subtotal (95% CI) 0.05 [ 0.00, 0.78 ]



0.1 0.2 0.5 1 2 5 10


Analysis 2.1. Comparison 2 Comparisons between active interventions, Outcome 1 Mucositis (absent

versus present).


Comparison: 2 Comparisons between active interventions

Outcome: 1 Mucositis (absent versus present)

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Cryotherapy: 30 min versus 60 min

Rocke 1993 33/89 37/89 0.89 [ 0.62, 1.29 ]

2 Etoposide: bolus versus continuous

Damon 2004 18/44 50/53 0.43 [ 0.30, 0.62 ]

0.1 0.2 0.5 1 2 5 10






Analysis 2.2. Comparison 2 Comparisons between active interventions, Outcome 2 Mucositis (0-1 versus

2+).





n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Cryotherapy: 30 min versus 60 min

Rocke 1993 13/89 19/89 0.68 [ 0.36, 1.30 ]


Damon 2004 5/44 37/53 0.16 [ 0.07, 0.38 ]

3 GM-CFS versus sucralfate

Saarilahti 2002 19/21 18/19 0.96 [ 0.80, 1.14 ]

4 Keratinocyte: 50 mg versus 25 mg

Freytes 2004 7/14 9/14 0.78 [ 0.40, 1.49 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.3. Comparison 2 Comparisons between active interventions, Outcome 3 Mucositis (0-2 versus

3+).





n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Cryotherapy: 30 min versus 60 minRocke 1993 6/89 10/89 0.60 [ 0.23, 1.58 ]


Damon 2004 0/44 10/53 0.06 [ 0.00, 0.95 ]

3 GM-CSF versus sucralfate

Saarilahti 2002 6/21 10/19 0.54 [ 0.24, 1.21 ]

4 Keratinocyte: 50 mg versus 25 mg

Freytes 2004 1/14 3/14 0.33 [ 0.04, 2.83 ]

0.1 0.2 0.5 1 2 5 10






Analysis 3.1. Comparison 3 Side effects, Outcome 1 Amifostine.


Comparison: 3 Side effects

Outcome: 1 Amifostine

Study or subgroup Treatment Control log [risk ratio] risk ratio Weight risk ratio


1 Survival at 24 months

Brizel 2000 36 30 0.131 (0.133) 100.0 % 1.14 [ 0.88, 1.48 ]

Subtotal (95% CI) 100.0 % 1.14 [ 0.88, 1.48 ]



2 Recurrence at 18 months after cancer treatment

Antonadou 2002 22 23 -0.3567 (0.572) 25.4 % 0.70 [ 0.23, 2.15 ]

Brizel 2000 80 88 0.0953 (0.218) 74.6 % 1.10 [ 0.72, 1.69 ]

Subtotal (95% CI) 100.0 % 1.04 [ 0.70, 1.55 ]



3 Incomplete response to radiotherapy

Antonadou 2002 22 23 -0.8675 (0.782) 29.5 % 0.42 [ 0.09, 1.94 ]

Koukourakis 2000 12 12 -0.1863 (0.447) 70.5 % 0.83 [ 0.35, 1.99 ]

Subtotal (95% CI) 100.0 % 0.70 [ 0.33, 1.50 ]



4 Delay to radiotherapy

Koukourakis 2000 19 20 -0.821 (0.425) 100.0 % 0.44 [ 0.19, 1.01 ]

Subtotal (95% CI) 100.0 % 0.44 [ 0.19, 1.01 ]



5 Hypotension

Antonadou 2002 22 23 1.9879 (1.48) 4.9 % 7.30 [ 0.40, 132.77 ]

Brizel 2000 148 153 2.23 (1.48) 4.9 % 9.30 [ 0.51, 169.14 ]

Buentzel 2006 66 64 0.8294 (0.314) 57.3 % 2.29 [ 1.24, 4.24 ]

Hwang 2004 30 30 0.5878 (0.494) 32.9 % 1.80 [ 0.68, 4.74 ]

Subtotal (95% CI) 100.0 % 2.32 [ 1.40, 3.84 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )





(. . . Continued



6 Nausea

Antonadou 2002 22 23 1.141 (1.61) 11.4 % 3.13 [ 0.13, 73.45 ]

Bourhis 2000 12 12 1.0986 (1.59) 11.7 % 3.00 [ 0.13, 67.69 ]

Brizel 2000 148 153 1.4207 (1.12) 22.7 % 4.14 [ 0.46, 37.18 ]

Buentzel 2006 66 64 -0.0305 (0.685) 54.2 % 0.97 [ 0.25, 3.71 ]

Subtotal (95% CI) 100.0 % 1.69 [ 0.61, 4.67 ]



7 Vomiting

Antonadou 2002 22 23 1.141 (1.61) 30.9 % 3.13 [ 0.13, 73.45 ]

Bourhis 2000 12 12 1.0986 (1.6) 31.3 % 3.00 [ 0.13, 69.03 ]

Brizel 2000 148 153 2.8662 (1.45) 37.8 % 17.57 [ 1.02, 301.31 ]

Subtotal (95% CI) 100.0 % 5.95 [ 1.03, 34.29 ]



0.1 0.2 0.5 1 2 5 10


A P P E N D I C E S

Appendix 1. Cochrane Oral Health Group Trials Register search strategy

((neoplasm* OR leukemia OR leukaemia OR leukaemia OR lymphoma* OR plasmacytoma OR “histiocytosis malignant” OR retic-uloendotheliosis OR “sarcoma mast cell” OR “Letterer Siwe disease” OR “immunoproliferative small intestine disease” OR “Hodgkindisease” OR “histiocytosis malignant” OR “bone marrow transplant*” OR cancer* Or tumor* OR tumour* OR malignan* OR neu-tropeni* OR carcino* OR adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemo*) AND (stomatitisOR “Stevens Johnson syndrome” OR “candidiasis oral” OR mucositis OR (oral AND (cand* OR mucos* OR fung*)) OR mycosisOR mycotic OR thrush))

Appendix 2. CENTRAL search strategy

(For this update, the search strategy was revised to include the MeSH term MUCOSITIS which was introduced in 2006.)#1.NEOPLASMS explode all trees (MeSH)#2.LEUKEMIA explode all trees (MeSH)#3.LYMPHOMA explode all trees (MeSH)#4.RADIOTHERAPY explode all trees (MeSH)#5.BONE MARROW TRANSPLANTATION explode all trees (MeSH)#6.(neoplasm* or cancer* or carcino* or malignan*)#7.(leukemi* or leukaemi*)#8.(tumour* or tumor*)#9.neutropeni*





#10.adenocarcinoma*

#11.lymphoma*#12.(radioth* or radiat* or irradiat* or radiochemo*)#13.(bone next marrow next transplant*)#14.(chemo* or radiochemo*)#15.(#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14)#16.STOMATITIS explode all trees (MeSH)#17. MUCOSITIS (MeSH)#18.CANDIDIASIS ORAL single term (MeSH)#19.stomatitis#20.(stevens next johnson next syndrome)#21.mucositis#22.(oral near cand*)#23.(mouth near cand*)

#24.(oral and fung*)#25.(mouth and fung*)#26.(mycosis or mycotic or thrush)#27.(#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26)#28.(#15 and #27)

Appendix 3. MEDLINE (OVID) search strategy

1. exp NEOPLASMS/2. exp LEUKEMIA/3. exp LYMPHOMA/4. exp RADIOTHERAPY/

5. Bone Marrow Transplantation/6. neoplasm$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]7. cancer$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]8. (leukaemi$ or leukemi$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drugmanufacturer name, device trade name]9. (tumour$ or tumor$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manu-facturer name, device trade name]10. malignan$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]11. neutropeni$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturername, device trade name]

12. carcino$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]13. adenocarcinoma$.mp. [mp=title, abstract, subject headings, drug trade name,original title,device manufacturer, drug manufacturername, device trade name]14. lymphoma$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturername, device trade name]15. (radioth$ or radiat$ or irradiat$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer,drug manufacturer name, device trade name]16. (bone adj marrow adj5 transplant$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer,drug manufacturer name, device trade name]17. chemo$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]18. or/1-17





19. exp STOMATITIS/

20. MUCOSITIS21. CANDIDIASIS, ORAL/22. stomatitis.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]23. mucositis.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name,device trade name]24. (oral and cand$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturername, device trade name]25. (oral adj6mucos$).mp. [mp=title,abstract, subject headings,drug tradename, original title, device manufacturer, drugmanufacturername, device trade name]26. (oral and fung$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturername, device trade name]27. (mycosis or mycotic).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manu-

facturer name, device trade name]28. or/19-2729. 18 and 28Cochrane/OHG search filter for MEDLINE (OVID):1. RANDOMIZED CONTROLLED TRIAL.pt.2. CONTROLLED CLINICAL TRIAL.pt.3. RANDOMIZED CONTROLLED TRIALS.sh.4. RANDOM ALLOCATION.sh.5. DOUBLE BLIND METHOD.sh.6. SINGLE BLIND METHOD.sh.7. CROSS-OVER STUDIES.sh.8. MULTICENTER STUDIES.sh.9. (“multicentre stud$” or “multicentre trial$” or “multicenter stud$” or “multicenter trial$” or “multi-centre stud$” or “multi-centre

trial$” or “multi-center stud$” or “multi-center trial$” or “multi-site trial$” or “multi-site stud$”).ti,ab.10. MULTICENTER STUDY.pt.11. latin square.ti,ab.12. (crossover or cross-over).ti,ab.13. (split adj (mouth or plot)).ti,ab.14. or/1-1315. (ANIMALS not HUMAN).sh.16. 14 not 1517. CLINICAL TRIAL.pt.18. exp CLINICAL TRIALS/19. (clin$ adj25 trial$).ti,ab.20. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.21. PLACEBOS.sh.

22. placebo$.ti,ab.23. random$.ti,ab.24. RESEARCH DESIGN.sh.25. or/17-2426. 25 not 1527. 16 OR 26





Appendix 4. EMBASE (OVID) search strategy

1. exp NEOPLASM/2. exp LEUKEMIA/3. exp LYMPHOMA/4. exp RADIOTHERAPY/5. exp bone marrow transplantation/6. (neoplasm$ orcancer$ or leukemi$or leukaemi$or tumour$ or tumor$or malignan$ or neutropeni$ or carcino$ or adenocarcinoma$or lymphoma$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturername]7. (radioth$ or radiat$ or irradiat$ or radiochemo$).mp. [mp=title, abstract, subject headings, drug trade name, original title, devicemanufacturer, drug manufacturer name]8. (bone marrow adj3 transplant$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drugmanufacturer name]9. chemo$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]10. or/1-911. exp Stomatitis/12. Thrush/13. (stomatitis or mucositis or (oral and candid$) or (oral adj4 mucositis) or (oral and fung$) or mycosis or mycotic or thrush).mp.[mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]14. or/11-1315. 10 and 14Filter for EMBASE (OVID):1. random$.ti,ab.2. factorial$.ti,ab.3. (crossover$ or cross over$ or cross-over$).ti,ab.4. placebo$.ti,ab.

5. (doubl$ adj blind$).ti,ab.6. (singl$ adj blind$).ti,ab.7. assign$.ti,ab.8. allocat$.ti,ab.9. volunteer$.ti,ab.10. CROSSOVER PROCEDURE.sh.11. DOUBLE-BLIND PROCEDURE.sh.12. RANDOMIZED CONTROLLED TRIAL.sh.13. SINGLE BLIND PROCEDURE.sh.14. or/1-1315. ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/16. HUMAN/17. 16 and 15

18. 15 not 1719. 14 not 18





Appendix 5. CANCERLIT (PubMed Cancer Subset) search strategy

((neoplasm* OR leukemia OR leukaemia OR leukaemia OR lymphoma* OR plasmacytoma OR “histiocytosis malignant” OR retic-uloendotheliosis OR “sarcoma mast cell” OR “Letterer Siwe disease” OR “immunoproliferative small intestine disease” OR “Hodgkindisease” OR “histiocytosis malignant” OR “bone marrow transplant*” OR cancer* Or tumor* OR tumour* OR malignan* OR neu-tropeni* OR carcino* OR adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemotherap*) AND (stom-atitis OR “Stevens Johnson syndrome” OR “candidiasis oral” OR mucositis OR (oral AND (candid* OR mucos* OR fung*)) OR mycosis OR mycotic OR thrush))

AND(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh]OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (“clinical trial” [tw]OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw] )) OR (placebos [mh] OR placebo*[tw] OR random* [tw] OR research design [mh:noexp]) NOT (animals [mh] NOT human [mh]))

Appendix 6. SIGLE search strategy

((neoplasm* OR leukemia OR leukaemia OR leukaemia OR lymphoma* OR plasmacytoma OR histiocytosis malignant OR reticu-loendotheliosis OR sarcoma mast cell OR Letterer Siwe disease OR immunoproliferative small intestine disease OR Hodgkin diseaseOR histiocytosis malignant OR bone marrow transplant* OR cancer* Or tumor* OR tumour* OR malignan* OR neutropeni* OR carcino* OR adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemo*)

AND(stomatitis OR Stevens Johnson syndrome OR candidiasis oral OR mucositis OR (oral AND (cand* OR mucos* OR fung*)) OR mycosis OR mycotic OR thrush)

Appendix 7. LILACS search strategy

( www.bireme.org)RCT filter (source www.centrocochranedobrasil.org)((Pt randomized controlled trial OR Pt controlledclinical trial OR Mh randomized controlledtrials OR Mh random allocation OR Mhdouble-blind method OR Mh single-blind method) AND NOT (Ct animals AND NOT (Ct human and Ct animal)) OR (Pt clinicaltrial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$))OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animals AND NOT (Ct humanand Ct animals)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animals AND NOT (Ct human and Ct animals)))

ANDMh NEOPLASMS OR Tw neoplasm$ OR Tw cancer$ OR Tw carcinoma$ OR Tw tumour$ OR Tw tumor$ OR Tw malignan$OR Tw carcino$ OR Tw nuetropeni$ OR Tw adenocarcinoma$ OR Mh leukemia OR Tw leukaemia$ OR Tw leukemi$ OR Tw

lymphoma$ OR Tw “bone marrow transplantation” OR Tw “bone marrow transplant$” OR Tw radiotherapy OR Tw radioth$ OR Tw radiat$ OR Tw irradiat$ OR Tw radiochemo$ OR Tw chemo$

ANDMh stomatitis OR Tw stomatitis OR Mh Candidiasis-Oral OR Tw “oral candidiasis” OR (Tw candida$ AND (Tw mouth OR Tw oral)) OR Tw mucositis OR ((Tw oral OR mouth) AND Tw fung$) OR (Tw oral AND Tw candidiasis$)



http://www.bireme.org/

http://www.centrocochranedobrasil.org/

http://www.centrocochranedobrasil.org/

http://www.bireme.org/



Appendix 8. CINAHL search strategy

As MEDLINE.

W H A T ’ S N E W

Last assessed as up-to-date: 20 August 2007.

16 June 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 1, 1998

Review first published: Issue 1, 2000

21 August 2007 New citation required and conclusions have changed Substantive amendment. This substantial update with a

search only 14 months after the previous one includes18 new included studies, bringing the total of numberof studies up to 89. There are four new interventions in-cluded, bringing the total number of interventions to 33.

C O N T R I B U T I O N S O F A U T H O R S

Helen Worthington (HW) and Jan Clarkson (JC) wrote the protocol and review. HW co-ordinated the review and wrote the letters

to authors. HW and JC independently and in duplicate assessed the eligibility of trials, extracted data and assessed the quality of thetrials. Tim Eden (OE) provided advice on cancer, its treatment and the interventions included in the review and checked the data. HW conducted the statistical analysis.

D E C L A R A T I O N S O F I N T E R E S T

None known.





S O U R C E S O F S U P P O R T

Internal sources

• The University of Manchester, UK.• Chief Scientists Office, Scottish Executive, UK.• NHS Education for Scotland, UK.• University of Dundee, UK.

External sources

• NIDCR grant ref 1 DE016950-01, USA.

N O T E S

The title of the protocol was originally ’Oral care for patients with cancer treated with chemotherapy (excluding head and neck cancer).’

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antifungal Agents [∗therapeutic use]; Antineoplastic Agents [∗adverse effects]; Candidiasis, Oral [etiology; ∗prevention & control];Cryotherapy; Drugs, Chinese Herbal [therapeutic use]; Ice; Mouth Mucosa; Neoplasms [drug therapy; radiotherapy]; RandomizedControlled Trials as Topic; Stomatitis [etiology; ∗prevention & control]

MeSH check words

Humans

Documents

Interventions for Preventing Oral Mucositis for Patients With