Interventions for treating oral mucositis for patients with cancer receiving treatment

Jan E Clarkson; Helen V Worthington; Susan Furness; Martin McCabe; Tasneem Khalid; Stefan Meyer

doi:10.1002/14651858.CD001973.pub4

. 2010 Aug 4;2010(8):CD001973. doi: 10.1002/14651858.CD001973.pub4

Interventions for treating oral mucositis for patients with cancer receiving treatment

Jan E Clarkson ¹, Helen V Worthington ^2,^✉, Susan Furness ³, Martin McCabe ⁴, Tasneem Khalid ⁵, Stefan Meyer ⁶

PMCID: PMC6669240 PMID: 20687070

Abstract

Background

Treatment of cancer is increasingly effective but associated with short and long term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them.

Objectives

To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both.

Search methods

Electronic searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 1 June 2010), CENTRAL via The Cochrane Library (to Issue 2, 2010), MEDLINE via OVID (1950 to 1 June 2010), EMBASE via OVID (1980 to 1 June 2010), CINAHL via EBSCO (1980 to 1 June 2010), CANCERLIT via PubMed (1950 to 1 June 2010), OpenSIGLE (1980 to 1 June 2010) and LILACS via the Virtual Health Library (1980 to 1 June 2010) were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.

Selection criteria

All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life.

Data collection and analysis

Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation, blindness and withdrawals. Risk of bias assessment was carried out on six domains. The Cochrane Collaboration statistical guidelines were followed and risk ratio (RR) values calculated using fixed‐effect models (less than 3 trials in each meta‐analysis).

Main results

Thirty‐two trials involving 1505 patients satisfied the inclusion criteria. Three comparisons for mucositis treatment including two or more trials were: benzydamine HCl versus placebo, sucralfate versus placebo and low level laser versus sham procedure. Only the low level laser showed a reduction in severe mucositis when compared with the sham procedure, RR 5.28 (95% confidence interval (CI) 2.30 to 12.13).

Only 3 comparisons included more than one trial for pain control: patient controlled analgesia (PCA) compared to the continuous infusion method, therapist versus control, cognitive behaviour therapy versus control. There was no evidence of a difference in mean pain score between PCA and continuous infusion, however, less opiate was used per hour for PCA, mean difference 0.65 mg/hour (95% CI 0.09 to 1.20), and the duration of pain was less 1.9 days (95% CI 0.3 to 3.5).

Authors' conclusions

There is limited evidence from two small trials that low level laser treatment reduces the severity of the mucositis. Less opiate is used for PCA versus continuous infusion. Further, well designed, placebo or no treatment controlled trials assessing the effectiveness of interventions investigated in this review and new interventions for treating mucositis are needed.

Keywords: Humans, Analgesics, Analgesics/therapeutic use, Anti‐Ulcer Agents, Anti‐Ulcer Agents/therapeutic use, Low‐Level Light Therapy, Low‐Level Light Therapy/methods, Mouth Diseases, Mouth Diseases/etiology, Mouth Diseases/therapy, Neoplasms, Neoplasms/drug therapy, Neoplasms/radiotherapy, Oral Ulcer, Oral Ulcer/etiology, Oral Ulcer/therapy, Pain, Pain/etiology, Pain Management, Randomized Controlled Trials as Topic, Stomatitis, Stomatitis/etiology, Stomatitis/therapy

Interventions for treating oral mucositis for patients with cancer receiving treatment

Using a low level laser may reduce the severity of ulcers caused by cancer treatment. Treatments for cancer can cause severe ulcers (sores) in the mouth. These can be painful and slow to heal. The review found some evidence that using a laser relieves or cures the ulcers. Morphine can control the pain. Although using morphine automatically on a constant drip, or self controlled use, provide similar relief, people use less morphine when they are controlling it themselves.

Background

Treatment of malignant diseases with cytotoxic chemotherapy or radiotherapy or both, is becoming increasingly more effective but it is associated with short and long term side effects. Among the clinically important acute side effects is disruption in the function and integrity of the oral mucosa. The consequences of this include severe ulceration (oral mucositis) and fungal infection of the mouth (oral candidiasis). These disease and treatment induced complications may also produce oral discomfort and pain, poor nutrition, delays in administration of chemotherapy or radiotherapy, reductions in the doses of chemotherapy drugs, increased length of inpatient stays and associated economic costs and in some patients life threatening infection (septicaemia in neutropenic patients).

Oral complications remain a major source of illness despite the use of a variety of agents to prevent them. There are variations in usage between cancer centres in terms of the mouthcare regimen used. Compliance with recommended use of product is variable and there are conflicting reports of the effectiveness of prophylactic agents. The qualitative and quantitative benefits, side effects and costs of oral therapies are of importance to the cancer teams responsible for the treatment of patients.

There have been several traditional reviews published and most of these present a general discussion for both chemotherapy and radiotherapy induced oral side effects (De Pauw 1997; Denning 1992; Knox 2000; Lortholary 1997; Plevova 1999; Shaw 2000; Stevens 1995; Symonds 1998; Verdi 1993; White 1993). The conclusions drawn and recommendations made vary from advocating a particular therapy to recommending oral care procedures that have not been systematically investigated. Five systematic reviews, which were not Cochrane reviews, have focused on the prevention and treatment of oral mucositis in patients with cancer. One older review published in 1998 concluded that for most strategies reviewed there is insufficient evidence to draw any conclusions regarding their effectiveness (Kowanko 1998). The other three more recent reviews focused on patients with head and neck cancer only (Shih 2002; Sutherland 2001; Trotti 2003), and two were unable to draw definite conclusions regarding the effectiveness of any of the agents tested, however in the Sutherland 2001 review the main analysis combined all the interventions in one meta‐analysis and found a beneficial effect of prophylactic interventions. This pooling of interventions is impossible to interpret and therefore not helpful.

A systematic review looking at antimicrobial therapy to prevent or treat mucositis identified 31 prospective trials (not just randomised trials) of which 13 reported some benefit. The review concludes that there is no clear pattern emerging regarding the benefit or otherwise of antimicrobial use to manage mucositis, and there is limited evidence supporting the use of antimicrobial agents for reducing oral mucositis (Donnelly 2003).

Another review looked at granulocyte macrophage‐colony stimulating factor (GM‐CSF) for the prevention and treatment of oral mucositis (Fung 2002). This review included studies of different types including some with historical controls. The authors conclude that although there are published studies, these studies are limited and the use of systemic or topical GM‐CSF cannot be recommended for prevention or treatment of mucositis.

This review is part of a series of four Cochrane reviews looking at the prevention and treatment of oral mucositis and oral candidiasis in patients with cancer receiving treatment (Worthington 2007a; Clarkson 2007; Worthington 2007b). The review for the prevention of oral mucositis (Worthington 2007b) found 11 out of the 33 interventions investigated showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions with more than one trial were amifostine, Chinese medicine, hydrolytic enzymes and ice chips (cryotherapy). Interventions with only one study were: benzydamine, calcium phosphate, etoposide bolus, honey, iseganan, oral care and zinc sulphate. This review is currently being updated and will be published in 2010.

Objectives

To assess the effectiveness of interventions (which may include placebo or no treatment) for the treatment of oral mucositis or its associated pain for patients with cancer receiving chemotherapy or radiotherapy or both. The following null hypotheses were tested, against alternative hypotheses of a difference, for comparisons between groups treated for mucositis.

There is no difference in the proportion of patients with improvement in mucositis after treatment for mucositis.
There is no difference in the proportion of patients with mucositis eradicated after treatment for mucositis.
There is no difference in the proportion of patients with severe mucositis (≥grade 3) after treatment for mucositis
There is no difference in the mean number of days taken to heal.
There is no difference in the mean pain scores after treatment or analgesia for mucositis.

The review is divided into two parts, one concerning interventions for the treatment of mucositis and one concerning the control of the pain in patients with mucositis. In this review we also addressed the hypothesis of no difference between groups treated for mucositis for the following outcomes if data were available from studies which included a primary outcome:

relief of dysphagia (problems during eating);
incidence of systemic infection;
amount of analgesia;
days stay in hospital;
cost of oral care;
patient quality of life.

The following subgroup analyses were proposed a priori:

cancer type (head and neck, other solid tumours, leukaemia, and mixed);
cancer treatment type;
age group (children, adults, children and adults).

Methods

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials (RCTs) were eligible for inclusion in this review.

Types of participants

Anyone with cancer who is receiving chemotherapy or radiotherapy or both and has oral mucositis.

Types of interventions

Active agents: any intervention for the treatment of oral mucositis or its associated pain. Control: may be placebo, no treatment, or another active intervention.

Types of outcome measures

The following outcomes were considered in this review:

Mucositis at different levels of severity
Days to heal (mean)
Oral pain scores or categories
Relief of dysphagia
Incidence of systemic infection
Amount of analgesia
Days stay in hospital
Cost of oral care
Patient quality of life.

Search methods for identification of studies

This review is part of a series of four reviews on the prevention and treatment of oral candidiasis and oral mucositis in patients with cancer, and the same search strategies were used for all four reviews. The searches attempted to identify all relevant trials irrespective of language. Papers not in English were translated by members of The Cochrane Collaboration. Sensitive search strategies were developed for each database using a combination of free text and MeSH terms. The MEDLINE and CANCERLIT searches combined the subject search with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomized trials in MEDLINE: sensitivity maximising version (2009 revision) as referenced in Chapter 6.4.11.1 and detailed in boxes 6.4a and 6.4.c of The Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009] (Higgins 2009). The EMBASE and CINAHL searches were combined with sensitive search strategies developed by the Cochrane Oral Health Group for identifying RCTs. The LILACs subject search was combined with the Brazilian Cochrane Centre search strategy for identifying RCTs in LILACS.

Electronic searching ‐ the databases searched were: Cochrane Oral Health Group Trials Register (to 1 June 2010) (see Appendix 1) Cochrane Pain, Palliative and Supportive Care (PaPaS) Group Trials Register (to 1 June 2010) (see Appendix 1) Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library 2010, Issue 2, 1 June 2010) (see Appendix 2) MEDLINE and MEDLINE Pre‐indexed via OVID (1950 to 1 June 2010) (see Appendix 3) EMBASE via OVID (1980 to 1 June 2010) (see Appendix 4) CINAHL via EBSCO (1980 to 1 June 2010) (see Appendix 5) CANCERLIT via PubMed (1950 to 1 June 2010) (see Appendix 6) OpenSIGLE (1980 to 1 June 2010) (see Appendix 7) LILACS via The Virtual Health Library (see Appendix 8).

Only handsearching carried out by The Cochrane Collaboration was included in the search (see master list www.cochrane.org).

The controlled trials database (www.controlled‐trials.com) was also searched to identify ongoing and completed trials and to contact trialists for further information about these trials.

The reference list of related review articles and all articles obtained were checked for further trials. Authors of trial reports and specialists in the field known to the review authors were written to concerning further published and unpublished trials.

The review will be updated every 2 years using the Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT and LILACS. The search of OpenSIGLE was discontinued as this database ceased being updated in 2005.

Data collection and analysis

Selection of studies

The titles and abstracts (when available) of all reports identified through the searches were scanned by two review authors. Full reports were obtained for trials appearing to meet the inclusion criteria or for which there was insufficient information in the title and abstract to make a clear decision. The full reports obtained from all the electronic and other methods of searching were assessed independently, in duplicate, by two review authors to establish whether the trials met the inclusion criteria or not. Disagreements were resolved by discussion.

Data extraction and management

Data were extracted by two review authors independently using specially designed data extraction forms. The characteristics of the trial participants, interventions and outcomes for the included trials are presented in the study tables. Mucositis may be dichotomised at different levels of severity. In order to maximise the availability of similar outcome data, we recorded the number of patients in each category of mucositis usually on a 0 to 4 scale, and used the following dichotomies: 0 versus 1+, 0‐1 versus 2+, 0‐2 versus 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 in order 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. Authors of full study reports and abstracts identified were contacted for clarification or for further information.

Assessment of risk of bias in included studies

This was conducted using the recommended approach for assessing risk of bias in studies included in Cochrane reviews (Higgins 2009). It is a two‐part tool, addressing the six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and ‘other issues’). Each domain includes one or more specific entries in a ‘Risk of bias’ table. Within each entry, the first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry. This is achieved by answering a pre‐specified question about the adequacy of the study in relation to the entry, such that a judgement of ‘Yes’ indicates low risk of bias, ‘No’ indicates high risk of bias, and ‘Unclear’ indicates unclear or unknown risk of bias.

The domains of sequence generation, allocation concealment, incomplete outcome data and selective outcome reporting are each addressed in the tool by a single entry for each study. For blinding two entries were used because assessments need to be made separately for a) patients and carers and b) outcome assessor. The final domain (‘other sources of bias’) was assessed as a single entry for studies as a whole.

The risk of bias assessment was undertaken independently and in duplicate by two review authors as part of the data extraction process.

Summarising risk of bias for a study:

After taking into account the additional information provided by the authors of the trials, studies were grouped into the following categories. We assumed that the risk of bias was the same for all outcomes and each study was assessed as follows:

Risk of bias	Interpretation	Within a study	Across studies
Low risk of bias.	Plausible bias unlikely to seriously alter the results.	Low risk of bias for all key domains.	Most information is from studies at low risk of bias.
Unclear risk of bias.	Plausible bias that raises some doubt about the results.	Unclear risk of bias for one or more key domains.	Most information is from studies at low or unclear risk of bias.
High risk of bias.	Plausible bias that seriously weakens confidence in the results.	High risk of bias for one or more key domains.	The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.

		Experimental		Control		RR/MD (95%CI)	P value
		Events/ Mean (SD)	Total	Events/Mean (SD)	Total
Allopurinol mouthwash versus placebo (Porta 1994)	Improvement in mucositis	19	22	3	22	RR 6.33 (2.18, 18.37)	0.0007
	Mucositis eradicated	9	22	0	22	RR 19.00 (1.17, 307.63)	0.04
	Time to heal mucositis (days)	4 (1.16)	22	8.5 (2.82)	22	MD ‐4.50 (‐5.77, ‐3.23)	< 0.001
Chlorhexidine versus salt and soda (Dodd 2000)	Mucositis eradicated	51	67	49	71	RR 1.10 (0.90, 1.35)	0.35
	Time to heal mucositis (days)	6.6 (2.57)	51	7.0 (2.99)	49	MD ‐0.40 [‐1.49, 0.69]	0.47
	Average pain scores	11.3 (20.1)	32	14.8 (19.8)	31	MD ‐3.50 [‐13.35, 6.35]	0.49
Gelclair versus sucralfate and mucaine (Barber 2007)	Mild to moderate mucositis	3	10	6	10	RR 0.50 [0.17, 1.46]	0.21
GM‐CSF versus no treatment (Mascucci 2005)	Improvement in mucositis at 14 days	11	29	4	22	RR 2.09 [0.77, 5.68]	0.15
	Improvement in mucositis at end of radiotherapy	14	32	3	29	RR 4.23 (1.35, 13.24)	0.01
GM‐CSF versus placebo (Valcarcel 2000)	Time to heal mucositis (days)	11.4 (4.00)	16	12.5 (3.4)	19	MD ‐1.10 (‐3.59, 1.39)	0.39
GM‐CSF versus povidone iodine (Henja 2001)	Time to heal mucositis (days)	2.8 (0.7)	15	6.3 (1.1)	16	MD ‐3.50 [‐4.14, ‐2.86]	< 0.001
GM‐CSF versus antimycotic mouthwash (Papila 2003)	Time to heal mucositis (days)	3.95 (2.01)	20	6.35 (3.44)	20	MD ‐2.40 [‐4.15, ‐0.65]	0.007
Human placental extract versus Disprin^TM (Kaushal 2001)	Improvement in mucositis	36	60	8	60	RR 4.50 [2.29, 8.86]	< 0.001
‘Magic’ versus salt and soda (Dodd 2000)	Mucositis eradicated	42	62	49	71	RR 0.98 [0.78, 1.24]	0.88
	Time to heal mucositis (days)	7.17 (2.57)	42	7.00 (2.99)	49	MD 0.17 [‐0.97, 1.31]	0.77
	Average pain scores	14.2 (19.8)	26	14.8 (19.8)	31	MD ‐0.60 [‐10.92, 9.72]	0.91
Phenytoin mouthrinse versus placebo (Baharvand 2010)	Average pain scores	1.5 (2.4)	6	3.2 (1.2)	6	MD ‐1.70 [‐3.85, 0.45]	0.12
	Quality of Life	51.7 (4.8)	6	66.8 (12.8)	6	MD ‐15.10 [‐26.04,‐4.16]	0.007
Polyvariant intramuscular immunoglobulin versus placebo (Schedler 1994)	Improvement in mucositis	31	39	18	41	RR 1.81 [1.24, 2.65]	0.002
Sucralfate versus placebo (Chiara 2001)	Improvement in mucositis	14	17	15	17	RR 0.93 [0.71, 1.24]	0.63
Sucralfate versus salt and soda (Dodd 2003)	Time to heal mucositis (days)	70.8 (28.9)	13	57.7 (22.5)	15	MD 13.10 [‐6.30, 32.50]	0.19
	Average pain intensity	2.1 (1.1)	14	2.4 (0.9)	15	MD ‐0.30 [‐1.03, 0.43]	0.42
Tetrachlorodecaoxide versus placebo (Malik 1997)	Improvement in mucositis	29	32	22	30	RR 1.24 [0.97, 1.58]	0.09
Vitamin E versus (not true) placebo (Wadleigh 1992)	Mucositis eradicated	6	9	1	9	RR 6.00 [0.89, 40.31]	0.07
Vitamin E (topical) versus vitamin E (swallowed) at 5 days (El‐Housseiny 2007)	Improvement in mucositis	28	30	2	33	RR 15.40 [4.01, 59.21]	< 0.001
	Mucositis eradicated	24	30	0	33	RR 53.74 [3.41, 846.84]	0.005
Alfentanil (PKPCA) versus morphine (PKPCA) (Hill 1992)	Average pain scores	48.0 (52.0)	12	48.0 (20.0)	16	MD 0.00 [‐31.01, 31.01]	1.00
	Daily mean opiate intake per hour	2.3 (2.8)	12	6.2 (4.0)	16	MD ‐3.90 [‐6.42, ‐1.38]	0.002
Hydromorphone (PCA) versus morphine (PCA)) (Coda 1997)	Average pain scores	48.9 (19.9)	27	48.3 (17.5)	29	MD 0.60 (‐9.24, 10.44)	0.90
Sufentanil (PCA) versus morphine (PCA) (Coda 1997)	Average pain scores	53.7 (16.0)	31	48.3 (17.5)	29	MD 5.40 [‐3.10, 13.90)	0.21
Opioid versus antidepressant (Ehrnrooth 2001)	Average pain scores	33.5 (17.7)	20	52.6 (20.1)	19	MD ‐19.10 [‐31.01, ‐7.19]	0.002
Morphine (PKPCA) versus morphine (PCA) (Hill 1991)	Average pain scores	48.0 (19.0)	15	66.0 (22.0)	20	MD ‐18.00 [‐31.62, ‐4.38]	0.01
	Daily mean opiate intake per hour	6.4 (3.9)	15	2.8 (1.8)	20	MD 3.60 [1.47, 5.73)	0.0009
PCA versus staff controlled (pethidine) (Zucker 1998)	Average pain scores	41.0 (24.0)	10	62.032.0	10	MD ‐21.00 [‐45.79, 3.79]	0.10
	Daily mean opiate intake per hour	17.0 (7.0)	10	21.0 (7.0)	10	MD ‐4.00 [‐10.14, 2.14)	0.20
Diclofenic versus placebo (Kostrica 2002)	Average pain scores	0.75 (1.17)	32	1.05 (1.17)	34	MD ‐0.30 [‐0.86, 0.26]	0.30
Therapist versus control (Syrjala 1992)	Daily mean opiate intake per hour	1.86 (5.0)	12	1.66 (5.4)	10	MD 0.20 [‐4.18, 4.58	0.93
Relaxation and imagery versus control (Syrjala 1995)	Average pain scores	45.56 (23.7)	23	53.78 (23.25)	23	MD ‐8.22 [‐21.79, 5.35]	0.24
Cognitive behaviour versus control (Syrjala 1992)	Daily mean opiate intake per hour	1.46 (3.98)	11	1.66 (5.4)	10	MD ‐0.20 [‐4.29, 3.89]	0.92
Hypnosis versus control (Syrjala 1992)	Average pain scores	23.0 (31.1)	12	33.5 (29.9)	10	MD ‐10.50 [‐36.05, 15.05]	0.42
	Daily mean opiate intake per hour	1.21 (3.78)	12	1.66 (5.4)	10	MD ‐0.45 [‐4.42, 3.52]	0.82

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Average pain score	3	113	Mean Difference (IV, Fixed, 95% CI)	‐2.49 [‐12.28, 7.29]
2 Daily mean opiate intake per hour	3	113	Mean Difference (IV, Fixed, 95% CI)	‐0.65 [‐1.20, ‐0.09]
3 Duration of pain control	3	113	Mean Difference (IV, Fixed, 95% CI)	‐1.87 [‐3.49, ‐0.25]

Date	Event	Description
6 July 2010	New search has been performed	New searches up to 01 June 2010.
6 July 2010	New citation required and conclusions have changed	5 new included studies, 8 new excluded studies. Risk of bias assessments completed on all included studies. Added new outcome: proportion of patients with mild/moderate mucositis. Review restructured to reflect many of comparisons have only one trial and to downgrade this. 4 new authors.
17 June 2008	Amended	Converted to new review format.
16 February 2007	New citation required and conclusions have changed	Substantive amendment. In this update we have added 1 included and 28 excluded studies.

Methods	Location: Iran. Number of centres: Multicentre. Funding source: Unclear. Recruitment period: December 2006 to May 2007.
Participants	Inclusion: Adults undergoing chemotherapy who developed oral mucositis Gr 2 or worse, with no other systemic disease, life expectancy at least 6 months. Exclusion: Other concomitant disease, heavy smoker, severe psychological disorder. 14 randomised, 12 completed.
Interventions	GpA (6) Phenytoin, 0.5% (50:50 mixture sodium phenytoin and phenytoin powder), 10 ml given 4 times daily, swished around mouth and spat out. GpB (6) Placebo 10 ml 4 times daily, swished around mouth and spat out.
Outcomes	Assessed at baseline, 1 week and 2 weeks after start of treatment. VAS scores for pain, Mucositis score NCI Common Toxicity Criteria (0 to 4 scale), duration of mucositis (not used as data presented in a format not suitable for pooling).
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	'Patients were assigned to case and control groups randomly and separately at each department. Sampling method was performed on a multi‐central, non‐probable (easy to access) basis.'
Allocation concealment?	Unclear risk	Not mentioned.
Blinding of participants/carers?	Low risk	Patients and nurses blinded to treatment group.
Blinding of outcome assessors?	Unclear risk	Ppatients self assessed pain and QoL, unclear who conducted the mucositis assessments.
Incomplete outcome data addressed?	Unclear risk	2/14 randomised were subsequently excluded because they were 'uncooperative' ‐ no details given. It is not stated which group these were from, but if both exclusions were from the same group, this would represent 25% drop out from that group and a significant risk of bias.
Free of selective reporting?	Low risk	Reported mucositis scores, duration of mucositis, pain and quality of life.
Free of other bias?	Low risk

Methods	Location: United Kingdom. Number of centres: Two. Funding source: Not stated. Recruitment period: September 2004 to April 2005.
Participants	Adults aged 18 years and over, with at least Grade 1 OM and when they felt they were no longer receiving adequate pain control via simple analgesic, receiving daily doses of radiotherapy to the head and neck. 20 eligible, 20 randomised.
Interventions	GpA (10) Gelclair, 4x in the 24 hour study (30 min to 1 hour before eating/drinking and before bedtime, swished around mouth and spat out). GpB (10) Standard care 10 ml 4x in 24 hour study (30 min to 1 hour before eating/drinking sucralfate and Mucaine swished around mouth and swallowed) (30 min to 1 hour before eating/drinking).
Outcomes	Assessed at baseline, 1 hour, 3 hours and 24 hours post treatment. VAS scores for pain (not used as only 24 hour assessment), Pain on speaking, Mucositis score NCI Common Toxicity Criteria (0‐4 scale). Secondary outcome ‐ extent to which ability to swallow is influenced by pain (odynophagia).
Notes	Outcomes assessed by nurse specialists blinded to group allocation. No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "computer generated random allocation sequence for the 2 centres was prepared by Exeter clinical research radiographer".
Allocation concealment?	Low risk	Quote: "radiographer accessed the randomisation list by telephone to determine the patients group allocation".
Blinding of participants/carers?	High risk	Comment: Not possible to blind patients and carers because one product 'swish and spit' and the other 'swish and swallow'.
Blinding of outcome assessors?	Low risk	Quote: "single blind trial with the administering nurse specialist being unaware as to what medication had been issued".
Incomplete outcome data addressed?	Low risk	Quote: "one patient despite their eagerness to participate fell asleep during the course of the trial and did not take their Sucralfate and Mucaine before the 24‐h assessment" "The missing 24‐h scores were substituted with 3‐h assessment scores". Comment: Unlikely to influence results.
Free of selective reporting?	High risk	Comment: Despite intention to report mucositis it was not reported apart from at baseline.
Free of other bias?	Unclear risk	Small pilot study which lacks power. At baseline there are differences between the groups that may have influenced the results. Intervention group had more severe OM (6/10 vs 3/10), and included all patients with enteral feeding and support. 3/10 in control group and 1/10 of intervention group had concomitant chemotherapy during trial. Funding unclear.

Methods	Location: Italy. Number of centres: One. Funding source: Not stated. Recruitment period: Not stated.
Participants	Inclusion: Adults with histopathologically confirmed diagnosis of malignancy, WHO performance status </=2 chemotherapy induced stomatitis at any time during chemotherapy treatment with any antiblastic drug alone, or in combination. Exclusion: Previous or concomitant radiotherapy to oral mucosa. 40 enrolled and randomised, 34 completed.
Interventions	GrA (n = 20) sucralfate gel (1 gr) (5 ml) applied over mucosa, 3 times daily. Evaluated after 1 or 2 weeks and at time of next course of chemotherapy. GrB (n = 20) placebo (in identical sachets with identical taste, colour and consistency to sucralfate) (5 ml) applied over mucosa, 3 times daily. Evaluated after 1 or 2 weeks and at time of next course of chemotherapy.
Outcomes	Complete response to treatment, VAS scores for pain but data not reported. Mucositis not resolved at 14 days is used.
Notes	"No sample size was calculated".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	'Randomised' no further details given.
Allocation concealment?	Unclear risk	Not reported.
Blinding of participants/carers?	Low risk	Quote: "....double blind placebo controlled...." Quote: "Drug or placebo were provided in individual sachets of 5 ml with identical taste, colour and consistency".
Blinding of outcome assessors?	Low risk	Quote: "....double blind placebo controlled...."
Incomplete outcome data addressed?	Low risk	Withdrawals and exclusions clearly described and balanced in each group (2 in each group non‐compliant and 1 in each group withdrew due to taste disturbances). 15% lost to follow up.
Free of selective reporting?	Low risk	Eradication and improvement of mucositis reported.
Free of other bias?	Unclear risk	No information on funding.

Methods	Location: Seattle, USA. Number of centres: One. Funding source: Not stated. Recruitment period: March 1991 to July 1993. Eligible patients had oral mucositis and had been on opioids for at least 2 days.
Participants	Inclusion: Patients undergoing bone marrow transplant for haematological malignancies or breast cancer, who were treated with total body irradiation or busulphan, who developed oral mucositis and stayed on study for at least 2 days. Exclusion: History of adverse reaction to opioid analgesics, moderate to severe hepatic, renal or pulmonary diseases, those currently taking opioids for other purposes, history of opioid, alcohol or cocaine abuse. 119 enrolled and randomised, 97 completed at least 2 days of treatment.
Interventions	Gr A (n = 39) Patient controlled analgesia (PCA) morphine 5 mg/ml for at least 2 days. Gr B (n = 40) PCA hydromorphone 1 mg/ml for at least 2 days. Gr C (n = 40) PCA sufentanil 5 μg/ml for at least 2 days. In all groups PCA was set to deliver bolus doses equivalent to 15 μg/kg morphine sulphate, with a 10 min lockout period. If increasing the demand for bolus doses was not sufficient to control pain, a baseline continuous infusion (CI) was added at a rate of approx 50% of the average rate during the previous 24 hour period. Patients were given the option of a higher CI rate during the night in order to minimise the demand for bolus doses during sleep.
Outcomes	Average pain VAS score (0 to 100) for days 2 to 5. Number who discontinued as drug not working.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "....randomised using a computer generated randomisation scheme".
Allocation concealment?	Low risk	Not reported.
Blinding of participants/carers?	Low risk	Quote: "....randomised double blind study". Quote: "study opioids were supplied by the pharmacy service and were coded 30 ml PCA vials that were labelled 5mg/ml morphine sulphate".
Blinding of outcome assessors?	Low risk	Quote: "....randomised double blind study".
Incomplete outcome data addressed?	Unclear risk	19/119 (16%) patients randomised had < 2 days of treatment and were therefore not considered evaluable (9, 6 & 4 in groups A, B & C respectively). See below. Of the 100 patients who had at least 2 days of treatment, 69/100 completed the study and a further 31/97 were excluded ‐ 11 due to side effects of treatment (2, 6 & 3 in groups A, B & C respectively), 8 due to inadequate pain relief (1, 0 & 7 respectively) and 12 due to BMT complications (1, 5 & 6 respectively) for total withdrawal/exclusion rates of randomised participants of 13/39 (33%), 17/40 (43%) and 20/40 (50%) in groups A, B & C respectively. Results are reported for the 'evaluable' patients (30, 34 & 36 in groups A, B & C respectively).
Free of selective reporting?	Low risk	Many outcomes described and reported.
Free of other bias?	Unclear risk	Baseline characteristics given for 'evaluable' patients only. Some randomised patients had less than 2 days treatment and were excluded because they did not develop mucositis (4, 1 & 2 in groups A, B & C), stopped treatment due to side effects (4, 1 & 2 in groups A, B & C), protocol violation (1, 3 in groups A & B) or died (1 in Gr B). Likely that prognostic factors were distributed differently in these patients. Funding unclear.

Methods	Location: Turkey. Number of centres: One. Funding source: Not stated. Recruitment period: February 2002 to September 2005.
Participants	Children aged 1 to 14 years with solid tumours, hospitalised for induction chemotherapy, who had large contiguous oral mucositis lesions, neutrophil count </= 1000/mm³, were taking systemic opioids and prophylactic antibiotics. 40 eligible, 40 randomised.
Interventions	Gp A (n = 20) Debridement of oral lesions + standard care. Gp B (n = 20) Standard care only.
Outcomes	Time to complete healing of lesions, mean mucositis scores at 6 days using WHO scale. 0 to 3 scale for pain included opiate use and presence of ulcers so not used in meta analysis. No specific information given on withdrawals or losses to follow‐up. Oral assessments conducted by two trained calibrated dentists. Can only report results without using the data.
Notes	Outcome data collected by oral examinations performed by 'two calibrated dentists' three times per week. Total number of oral examination performed was 960 in Gp A and 980 in Gp B. No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Children were randomly assigned...." Quote: "....were assigned one by one into two groups according to the intervention administered". Comment: Unclear as to method of sequence generation ‐ possibly alternation?
Allocation concealment?	Unclear risk	Not reported.
Blinding of participants/carers?	High risk	Not really possible to blind patients or carers.
Blinding of outcome assessors?	Unclear risk	Not mentioned.
Incomplete outcome data addressed?	Unclear risk	No information given.
Free of selective reporting?	Unclear risk	No information given.
Free of other bias?	Unclear risk	Groups well balanced at baseline. Unclear funding.

Methods	Location: San Francisco, USA. Number of centres: Not stated (23 referral centres). Funding source: Chlorhexidine mouthwash provided by Proctor and Gamble. Recruitment period: Not stated. Patient had mucositis confirmed by clinician.
Participants	Inclusion: Adults over 18 years, undergoing stomatotoxic chemotherapy, who could read & write English, were mentally capable of understanding research protocol, had Karnofsky Performance Status >/= 60%. Eilers Oral Assessment Guide score >/=10, and physician assessed & documented oral mucositis. Exclusion: Concurrent RT to head & neck, diagnosed with AIDS or leukaemia, undergoing bone marrow transplant. 299 eligible, 200 randomised, 142 completed.
Interventions	Gr A Chlorhexidine mouthwash 0.12% 20 ml in mouth, swish for 20 seconds, 4 times/day for 12 days. Gr B Salt & Soda mouthwash (1 teaspoon each in 1 pint water) 20 ml in mouth, swish for 20 seconds, 4 times/day for 12 days. Gr C Magic mouthwash (lidocaine 0.5%, diphenhydramine HCL 0.25 ml, Aluminium hydroxide 14.75 ml) 20 ml in mouth, swish for 20 seconds, 4 times/day for 12 days. All patients were instructed in PROSELF Mouth Aware (PSMA) programme of oral hygiene ‐ new toothbrush for each CT cycle, regular & thorough brushing, daily flossing, regular oral assessment using Oral Assessment Guide, training to recognise mouth lesions requiring nurse assessment.
Outcomes	Patient soreness rating on 0 (no soreness) to 10 (very sore) scale for 7 days, day 7 used. Mucositis oral assessment guide used by patients dichotomised as eradicated or not. The mean time to cessation of symptoms (SD) is also used.
Notes	0 to 10 scale converted VAS scale to 0 to 100. No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: 'randomised double blind clinical trial".
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	Low risk	Quote: 'double blind'. Quote: "Intervention nurses who performed initial oral assessments and the telephone contacts with the patients were blind to the group assignments". Comment: Although one mouthwash contained a suspension and caused oral numbness, one caused discolouration of teeth & gums and one clear solution we consider it to be blind.
Blinding of outcome assessors?	Low risk	Quote: 'double blind'. Comment: Outcomes assessed by patients.
Incomplete outcome data addressed?	High risk	58/200 (29%) of those randomised were excluded. 47 (24%) because they were hospitalised, too nauseated, too ill, or didn't like taste or numbness caused by mouthwash (likely to be more unwell that those included). A further 11 patients took more than 12 days to report cessation of OM symptoms. The treatment group allocation of these 58 is not given but "no significant difference in demographic characteristics between 142 patients who reported cessation of signs & symptoms of mucositis within 12 days and those who didn't .... and proportion similar in 3 mouthwash groups (P = 0.52).
Free of selective reporting?	Unclear risk	Comment: Pain can only be measured by the patient which is subjective. No other outcomes reported.
Free of other bias?	Unclear risk	Unclear.

Methods	Location: Denmark. Number of centres: One. Funding source: Not stated. Recruitment period: January 1995 to January 1999.
Participants	Inclusion: Adults undergoing radiotherapy with curative intent for head & neck cancer (biopsy verified squamous cell carcinoma of larynx, pharynx or oral cavity) with radiation induced pain not managed with acetaminophen. Exclusion: Cancer related pain before the initiation of radiotherapy, ongoing treatment with opioids, tricyclics, or non‐steroidal anti‐inflammatory drug, or known contraindications to tricyclics. 86 eligible, 43 enrolled and randomised and 39 completed.
Interventions	Gr A (n = 22) oral morphine chloride (5 mg x 6) additional doses of 5 mg each, plus stimulant laxative. Gr B (n = 21) oral nortriptyline (tricyclic antidepressant) (25 mg x 2). Patients on nortriptyline had the dose increased by 25 mg every second day, until pain relief or intolerable side effects were experienced (up to max dose of 150 mg/day). Acetaminophen was used for breakthrough pain in nortriptyline group. Patients with insufficient pain relief were offered supplementary medication from the opposite treatment arm.
Outcomes	VAS pain scores at 1, 2 weeks after randomisation and 2 weeks after end of radiotherapy. The 7 day scores are used.
Notes	Danish version of McGill Pain Questionnaire. Sample size calculation reported: to detect a 10 mm difference in VAS score for pain (smallest clinically significant difference) assuming a standard deviation of 0.2 in VAS score, with α = 0.05 and β = 0.1 a total of 43 patients was required to detect this difference.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "'in a randomised design".
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	High risk	Different frequency for interventions.
Blinding of outcome assessors?	High risk	Not mentioned.
Incomplete outcome data addressed?	Low risk	Post randomisation exclusions and withdrawals described and reasons given. Equal numbers in both groups. Two patient in each arm considered in evaluable. 9% lost to follow‐up.
Free of selective reporting?	Low risk	Primary and secondary outcomes described and reported.
Free of other bias?	High risk	Patients with insufficient pain relief were offered supplementary medication from the other treatment arm. 11/21 (52%) of patients in Gr2 had morphine as well as nortriptyline (mean time to morphine 13.4 +/‐ 8.4 days). None of the morphine group took nortriptyline.

Methods	Location: Egypt. Number of centres: One (one treatment centre but two recruitment centres). Funding source: Not stated. Recruitment period: Not stated.
Participants	Children under 12 years with mucositis, cancer type unclear but receiving chemotherapy. 80 eligible, 80 randomised (40 to each group), 63 completed.
Interventions	Gp A 100 IU Vitamin E capsule either emptied into mouth or chewed, twice daily. Gp B 100 IU Vitamin E capsule swallowed twice daily.
Outcomes	Mucositis severity scores by WHO criteria, improvement of mucositis at 5 days.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "patients were randomly assigned".
Allocation concealment?	Unclear risk	No mention of allocation concealment.
Blinding of participants/carers?	High risk	One group were instructed to swallow capsule, the other group instructed to either chew it or have contents emptied into mouth by carer.
Blinding of outcome assessors?	High risk	Not mentioned.
Incomplete outcome data addressed?	High risk	In Gp A 3 patients non compliant with treatment, 6 died & 3 lost to follow‐up (30% excluded from analysis), in Gp B 2 patients non compliant with treatment (analysed in Gp A), 2 died & 3 lost to follow‐up (18% excl from analysis). Data analysed on 28/40 (70%) patients randomised to Gp A plus the 2 from Gp B, and 33/40 (83%) randomised to Gp B. Possible that incomplete outcome data may have influenced results.
Free of selective reporting?	Unclear risk	Comment: Planned to follow patients followed for 5 days. Comment in discussion that some of the Gp B patients 'improved later', suggesting that the relative effects may be different after longer follow‐up.
Free of other bias?	High risk	Comment: Differences between groups at baseline. Severity of mucositis (Gp A median severity score 3, Gp B median severity score 2). Distribution of mucositis sites different in each group. "On treatment" analysis, more patients excluded from analysis in Gp A, and non compliant patients in Gp B added to Gp A.

Methods	Location: Belgium. Number of centres: One. Funding source: Not stated. Recruitment period: Not stated. Two studies reported, one prevention and one treatment of OM.
Participants	Adults with haematological malignancies and grade 1 or 2 OM induced by chemotherapy +/‐ radiotherapy prior to stem cell transplantation. 37 patients seemed eligible, 36 randomised, 18 to each group.
Interventions	GpA (18) low energy laser (LEL) on alternate working days (approx 3 sessions of 6 mins per week delivering 2 J/cm² to each lesion) GpB (18) sham illumination (laser switched off) on alternate working days (approx 3 sessions of 6 mins per week)
Outcomes	Primary ‐ time to development of grade 3 OM using EORTC scale. Secondary ‐ success of treatment (no lesions >/= Gr 3). Number with grade 3 OM after 7 days.
Notes	3 additional outcome measures added retrospectively: development of oesophageal mucositis, presence of diarrhoea, development of septicaemia. Sample size calculation for expected rates of OM at 7 days of 10% intervention and 60% control, 20 patients per group will give 90% power for 2‐sided log rank test and significance level of 5%.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "Randomised". Clarified by e‐mail from authors.
Allocation concealment?	Low risk	Not mentioned but clarified as sealed envelopes in e‐mail from authors.
Blinding of participants/carers?	Low risk	Therapists and nurses doing pretreatment assessments not blinded (for safety/ethical reasons), but patients were blinded.
Blinding of outcome assessors?	Low risk	Quote: "independent qualified healthcare professional observer (blinded to the treatment administered)".
Incomplete outcome data addressed?	Low risk	Outcome data complete for primary and secondary outcomes. 1 patient missing from retrospective outcome data in each group. 6% loss to follow‐up.
Free of selective reporting?	Low risk	Planned primary and secondary outcomes reported as well as additional retrospectively added outcomes. Acknowledged the 'methodological limitation not to have planned this data collection and analysis at the beginning of the trial'.
Free of other bias?	Low risk	Comment: All patients analysed in the groups to which they were randomised (ITT) and groups were comparable at baseline ‐ so probably.

Methods	Location: Vienna, Austria. Number of centres: One. Funding source: Not stated. Recruitment period: March 1998 to June 1999.
Participants	Inclusion: Patients with WHO grade 1 to 3 oral mucositis following 5 FU based chemotherapy. Patients were > 19 years of age, could read & understand German, had WHO Performance Status < 3. Exclusion: History of adverse reactions to G‐CSF, or GM‐CSF, or iodine, severe concomitant diseases including hyperthyroidism, dermatitis herpetiformis or need for systemic G‐CSF or GM‐CSF for neutropenia. 31 recruited and randomised and completed.
Interventions	Gr A (n = 15) GM‐CSF (Malgramostim) mouthwash three times daily (400 ug molgramostim dissolved in 250 ml water. Patients were instructed to wash mouths with 25 ml and keep in mouth for 3 min, then rinse and repeat 10 times within 30 mins). Gr B (n = 16) Antiseptic mouthwash (Povidone iodine) 4 ml povidone‐iodine in 125 ml water was used 6 times daily. This was kept in mouth for 3 mins. Patients received 4 daily tablets of amphotericin B, 10 mg (AA regimen). All patients with oral mucositis exceeding grade 2 were offered topical lidocaine 6 times daily.
Outcomes	Mean duration of therapy until complete remission.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Randomisation performed without stratification according to a balanced block randomisation procedure carried out by a third investigator".
Allocation concealment?	Unclear risk	No details given.
Blinding of participants/carers?	High risk	Quote " Physicians were not blinded but the patients were as to the efficacy of any of the chosen regimes". Comment: Different mouthwashes for different frequencies plus only one group received amphotericin B tablets.
Blinding of outcome assessors?	High risk	Quote " Physicians were not blinded but the patients were as to the efficacy of any of the chosen regimes".
Incomplete outcome data addressed?	Unclear risk	All patients completed. 2/16 (12%) patients in control group did not provide final OM score.
Free of selective reporting?	Unclear risk	Unclear.
Free of other bias?	High risk	Significant differences between groups at baseline for the following prognostic factors age group, WHO performance status, smoking status, oral hygiene. May have influenced results. 4 patients in control arm did not receive treatment but ITT analysis conducted.

Methods	Location: India. Number of centres: One. Funding source: Not stated. Recruitment period: August 1997 to March 1999.
Participants	Inclusion: Adults who developed oral mucositis after radiotherapy for histologically proven squamous cell carcinoma of head and neck. Exclusion: Patients with early head and neck cancer suitable for brachytherapy, those on palliative radiotherapy, had previous radiotherapy of chemotherapy, those with concurrent chemotherapy or those with distant metastases. 120 randomised and completed.
Interventions	Gr A (n = 60) Human placental extract (Placentrex) 2 ml IM, 5 times weekly for 3 weeks. Gr B (n = 60) Disprin™ gargle, 1 tablet in a cup of water, 3 times daily 0.5 mg/ml betamethasone oral drops, 8 drops 3 times daily. Both groups received Betadine™ antiseptic mouthwashes three times daily.
Outcomes	Progression of mucositis to grade 3, improvement in dysphasia, decrease in pain (data not used). All evaluated 2 times weekly, but unclear over what time period. Interruption of radiotherapy due to severe radiation reactions. To include the data we included the patients who did not get worse with the mucositis improved outcome.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "randomised" ‐ no details given.
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	High risk	Comment: Interventions given differently.
Blinding of outcome assessors?	High risk	Not mentioned.
Incomplete outcome data addressed?	Low risk	All randomised patients included in analysis. 0% drop‐outs.
Free of selective reporting?	Unclear risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Placentrex given for 3 weeks ‐ ?duration of control group treatment.

Methods	Location: New York, USA. Number of centres: One. Funding source: DuPont Pharmaceuticals provided the medications used in the trial. Recruitment period: Not stated. Randomised, double blind. Patients who complained of mouth or throat pain were eligible. Unclear information on withdrawals. 60% lost to follow‐up.
Participants	Adults with head and neck cancer receiving radiation therapy to oral pharyngeal regions, complaining of throat or mouth pain. 67 randomised, 37 received benzydamine and 30 placebo. Results for mucositis given for days 2/3, for 33 in benzydamine and 28 in placebo groups, with loss to follow‐up of 11% and 7% respectively.
Interventions	Gr A Benzydamine chloride rinse/gargle 1.5 mg/ml used every 3 hours during the day. Gr B Placebo.
Outcomes	Improvement in mucositis up 2/3 days, assessed by clinician. Specific criteria not given but mucositis is presented on 1 to 4 scale with 1 = none, 2 = slight; 3 = moderate and 4 = severe. At baseline there were 2 patients in the benzydamine group and 1 patient in the placebo group with no mucositis and these patients have been excluded from our analysis. We dichotomised 4 point scale as mucositis not improved by day 2/3. Relief from pain on swallowing also reported.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "randomised". No details given.
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	Low risk	Quote: "double blind".
Blinding of outcome assessors?	Low risk	Quote: "double blind".
Incomplete outcome data addressed?	High risk	Less than half of those randomised were evaluated for some outcomes on day 2. No explanation given. 60% lost to follow‐up for some outcomes. drop‐outs for mucositis 9%.
Free of selective reporting?	High risk	Only some of planned outcomes reported for some of the participants.
Free of other bias?	Unclear risk	Unclear.

Methods	Location: Czech Republic. Number of centres: One. Funding source: Not stated. Recruitment period: March 2000 to March 2001.
Participants	Inclusion: Adults over 18 years with head and neck cancer receiving radiation treatment with minimum dose of 40 Gy, who develop oral mucositis, are on routine supportive treatment for OM, are likely to return for assessment, have a life expectancy > 6 months, not pregnant, on contraception (as appropriate). Eligible patients had mucositis in large parts of mouth. Exclusion: Those who have participated in clinical trial in previous 4 weeks, a history of liver or kidney disease, gastrointestinal ulcers, are 'non‐compliant', intolerant of diclofenac, have inadequate oral hygiene. 77 randomised, 69 included in efficacy analysis by clinician, 66 in efficacy analysis assessment by patient.
Interventions	Gr A (n = 39) Diclofenac (free acid 0.074%) mouthwash, 15 ml, three times daily for 2 to 6 weeks. Gr B (n = 38) placebo mouthwash, 15 ml, three times daily for 2 to 6 weeks.
Outcomes	Patient assessment for pain ‐ 0 absent; 1 slight; 2 moderate; 3 severe. Dysphagia has 5 point scale. Assessments for both presented in figures giving mean values for each day from day 0 to 28, and end of treatment. Day 7 used in the analysis.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "randomised using randomisation numbers".
Allocation concealment?	Unclear risk	No information reported.
Blinding of participants/carers?	Low risk	Quote: "double blind".
Blinding of outcome assessors?	Low risk	Quote: "double blind".
Incomplete outcome data addressed?	Low risk	Post randomisation exclusions clearly described for each group.10% lost to follow‐up.
Free of selective reporting?	Low risk	Planned outcome measure described and reported.
Free of other bias?	Unclear risk	No information on funding.

Methods	Location: Brazil. Number of centres: One. Funding source: Supported by Cancer Institute in Brazil. Recruitment period: October 2005 to May 2006.
Participants	Incusion: Children over 3 years with mixed cancer. All completed study 9 randomised to laser and 12 to sham.
Interventions	low level laser GaAlAs instrument by photon laser II with continuous 830 nm wavelength, 100 mW power versus sham. Treatment time = energy x surface area/power. Energy density of 4 J/cm² was delivered to the mucositis lesions. Duration 7 days. Dentist who applied the laser did not participate in the evaluation. Patients received pain control and symptomatic treatment according to severity of OM.
Outcomes	OM by a dentist blinded to the intervention. OM was measured 0 to 4 scale (National Cancer Institute Common Toxicity Criteria version 2 at baseline and every day until complete healing).
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "placebo controlled randomised trial". Quote: "patients were randomised by computer code generation in two groups".
Allocation concealment?	Unclear risk	No information.
Blinding of participants/carers?	Low risk	Participants were, carers were not.
Blinding of outcome assessors?	Low risk	Comment: Different to laser provider.
Incomplete outcome data addressed?	Low risk	No drop outs ‐ 0%.
Free of selective reporting?	Low risk	Very clear outcome outcome reporting.
Free of other bias?	Low risk	Comment: Probably.

Methods	Location: USA. Number of centres: Multicentre (actual number unclear). Funding source: Grants from the US Public Health Service and the National Cancer Institute. Recruitment period: January to December 1994.
Participants	Adults with mixed cancer receiving first cycle 5FU based chemotherapy. Patients who complained of mouth or throat pain were eligible. 135 eligible, 50 enrolled, 50 completed.
Interventions	Placebo versus sucralfate solution 1 g/30 ml. Rinse 4 times/day for median of 7 days.
Outcomes	Daily patient reported maximum over 7 days (0 to 4 scale). Clinical evaluation of mucositis by healthcare provider ("in a manner commonly used in cancer trials usually judged by historical means") 4/5 weeks after chemotherapy on WHO 0 to 4 scale. Mucositis not resolved used.
Notes	All patients had ice chips during chemotherapy. Power calculation reported: Anticipated that 50% of those recruited would report stomatitis. Actual % less, (38%) so accrual continued till 50 patients reported stomatitis providing a 73% power to detect a 1‐grade decrease in stomatitis, 85% power to detect a 1.5‐grade decrease & 95% power to detect a 2‐grade decrease, via a one‐sided Wilcoxon test with a 2.5% error rate.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Patients were stratified and randomised...."
Allocation concealment?	Unclear risk	No details given.
Blinding of participants/carers?	Low risk	Quote: "Double blind".
Blinding of outcome assessors?	Low risk	Quote: "Double blind".
Incomplete outcome data addressed?	Low risk	131 patients randomised but only 50/131 developed stomatitis and underwent therapy. However all randomised patients who developed stomatitis included in analysis. None lost to follow‐up 0%.
Free of selective reporting?	Low risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Unclear.

Methods	Location: Pakistan. Number of centres: One. Funding source: Brooks Pharmaceutical co supplied the TCDO and placebo. Recruitment period: Not stated. Randomised, double blind. Eligible patients had mucositis on entry. None lost to follow‐up.
Participants	Adults with mixed cancer, with oral mucositis WHO grades 2 to 4, induced by chemotherapy in preceding 2 weeks, including those given prophylactic nystatin or antiseptic mouthwash. 62 eligible, 62 randomised , 62 completed.
Interventions	GrA (n = 32) TCDO (tetrachlorodecaoxide). 10 ml twice daily, swish then swallow. Maximum 7 days. GrB (n = 30) placebo 10 ml twice daily, swish then swallow. Maximum 7 days
Outcomes	Objective clinical mucositis improvement by day 3 using WHO criteria on 0 to 4 scale, mucositis not improved by day 3 used. Symptomatic improvement by patient of oral pain and ability to eat by day 3.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "double blind placebo controlled randomised trial".
Allocation concealment?	Unclear risk	No information.
Blinding of participants/carers?	Low risk	Quote: "Double blind". Comment: TCDO and placebo supplied in identical containers.
Blinding of outcome assessors?	Low risk	Quote: "Double blind".
Incomplete outcome data addressed?	Low risk	All randomised patients included in analysis.
Free of selective reporting?	Low risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Comment: Some pharmaceutical funding.

Methods	Location: Sweden. Number of centres: Five. Funding source: Unrestricted grant from Schering Plough AB, Stockholm. Duration: End of radiotherapy.
Participants	Adults with recently detected head and neck cancer, who were about to undergo radiotherapy. 92 patients were entered onto database and randomised. Only 62 developed mucositis scores > 1.5. 61 included an end point. 10 patients had only 1 evaluation. 51 analysed for mucositis outcome.
Interventions	GrA: Recombinant human granulocyte monocyte‐colony stimulating factor GM‐CSF (Molgramostim, Leucomax, Schering‐Plough, Sweden) 4 g/kg/d sc. By injection every day (including radiotherapy free days) from when oral mucositis scored reached 1.5 until full radiotherapy dose was given. 'Conventional care' as well. GrB: 'Conventional care' ‐ details not provided.
Outcomes	Improvement in mucositis scores assessed as change of 1 unit from baseline (this was a mean value over several sites). Assessment at 1, 2 and end of radiotherapy. Additional side effects: nutritional status, weight loss. Pain and difficulty eating were assessed but data not presented (pain and difficulty eating incorporated in mucositis scores).
Notes	Power calculation "Assuming a binomial distribution 2x39 patients were needed to achieve a power of 80%, or 2 x 52 for a power of 90%, to reject the hypothesis of equal success probabilities, using a 2 sided test at the significance level of 5% (normal approximation)".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Randomisation performed centrally at start of radiotherapy 'according to a computer generated code in blocks of 10.' Only those who subsequently developed OM score greater than 1.5 entered the study.
Allocation concealment?	Low risk	'Treatment allocation at centres performed using sealed envelopes'.
Blinding of participants/carers?	High risk	Quote: "multicentre open randomised phase III study".
Blinding of outcome assessors?	Low risk	Outcome assessment conducted by a physician or dentist blinded to treatment allocation.
Incomplete outcome data addressed?	Low risk	Comment: Randomised patients accounted for: 21/92 (11 and 10 in GrA & Gr B respectively) patients did not enter treatment because they did not develop OM score > 1.5. A further 5 patients in each group excluded from analysis due to insufficient documentation, leaving 61/71 evaluable patients. 51 patients included in primary outcome. 28% drop‐outs (based on those who were eligible). 3 and 7 patients from GM‐CSF & control groups respectively did not have data for primary endpoint (after 2 weeks).
Free of selective reporting?	Low risk	Planned outcomes reported.
Free of other bias?	Unclear risk	Unclear.

PERMALINK

Interventions for treating oral mucositis for patients with cancer receiving treatment

Jan E Clarkson

Helen V Worthington

Susan Furness

Martin McCabe

Tasneem Khalid

Stefan Meyer

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Interventions for treating oral mucositis for patients with cancer receiving treatment

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Summarising risk of bias for a study:

Figure 1.

Figure 2.

Measure of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Characteristics of the trial setting and investigators

Characteristics of the participants

Characteristics of the interventions

Treatment of mucositis

Control of mucositis pain

Characteristics of outcome measures

Treatment of mucositis

Control of mucositis pain

Risk of bias in included studies

Effects of interventions

Treatment of mucositis

Table 1.

Benzydamine HCl versus placebo

Analysis 1.1.

Sucralfate versus placebo

Analysis 3.1.

Laser versus sham treatment

Analysis 2.1.

Control of mucositis pain

Patient controlled analgesia (PCA) versus continuous infusion delivery of morphine

Analysis 4.1.

Analysis 4.2.

Analysis 4.3.

Therapist versus control

Analysis 5.1.

Cognitive behaviour therapy versus control

Analysis 6.1.

Discussion

Authors' conclusions

Feedback

Low level laser, 9 August 2010

Summary

Reply

Contributors

Acknowledgements

Appendices

Appendix 1. Cochrane Oral Health Group's Trials Register; Cochrane Pain, Palliative & Supportive Care Group's Trials Register search strategy

Appendix 2. The Cochrane Central Register of Controlled Clinical Trials (CENTRAL) search strategy

Appendix 3. MEDLINE via OVID search strategy (including MEDLINE Pre‐Indexed)

Methods	Location: Liverpoool, United Kingdom. Number of centres: One. Funding source: Not stated. Recruitment period: February 1995 to August 1997.
Participants	Inclusion: Patients undergoing conditioning chemotherapy in preparation for bone marrow transplant or autologous transplant of peripheral blood stem cells (cyclophosphamide/TBI, high dose melphalan or BEAM). 81 screened, 65 randomised, 43 sought treatment for severe mucositis pain when non‐opioids were ineffective, 35 completed.
Interventions	GrA (n = 33) Diamorphine by PCA 0.8 mg bolus + 2 mg/hour (max) to max of 96 mg/24 hour for 14 days. GrB (n = 32) Diamorphine by continuous infusion, 24 mg in 24 hour (with requested doses increases up to a max dose of 96 mg/24 hour) for up to 14 days.
Outcomes	Average pain VAS score (0 to 100) day 7 taken. Mean opiate use mg per hour for day 7. The mean duration of morphine (days) ‐ we have converted the standard errors to standard deviations.
Notes	All patients, on 2 occasions, received prophylactic amphotericin lozenges, nystatin, chlorhexidine, oral acyclovir, oral ciprofloxacin and colistin. No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "serial sealed envelopes containing computer generated random treatment allocation".
Allocation concealment?	Low risk	Quote: "serial sealed envelopes containing computer generated random treatment allocation".
Blinding of participants/carers?	High risk	Interventions given differently.
Blinding of outcome assessors?	High risk	Self assessment.
Incomplete outcome data addressed?	Low risk	Comment: only 45/65 (66%) of those randomised required treatment for mucositis. 8 patients who received treatment were subsequently excluded from analysis (4 in Gr A failed attempt at PCA and 1 needed diamorphine for 'other pain', and 3 in Gr B needed diamorphine for 'other pain'). 18% drop‐outs.
Free of selective reporting?	Low risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Not all randomised participants required opioid treatment for severe mucositis pain. No funding mentioned.

Methods	Location: Germany. Number of centres: One. Funding source: Unclear. Recruitment period: Unclear.
Participants	Inclusion: Adults with Grade 1 or 2 mucositis after undergoing radiotherapy for head and neck cancer who had Karnofsky Performance Status > 50%. Exclusion: Previous radiotherapy, pervious therapy for oral mucositis, recent chemotherapy, skin or mucosal defects.
Interventions	Gr B (n = 39) Polyvalent immunoglobulin (160 mg/ml) 10 ml IM on day ), then 5 ml on days 2 & 4. Gr B (n = 42) Placebo (10% human albumin) 10 ml IM on day ), then 5 ml on days 2 & 4.
Outcomes	EORTC grade did not reduce to 0 or 1 used in review.
Notes	Double blind study up to day 7. Both groups received nystatin. Power calculation ‐ not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "A randomised double blind study".
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	Low risk	Double blind.
Blinding of outcome assessors?	Low risk	Double blind.
Incomplete outcome data addressed?	Low risk	Only one dropout from placebo group due to poor general health 1% drop out.
Free of selective reporting?	Unclear risk	Unclear.
Free of other bias?	Unclear risk	Unclear funding.

Methods	Location: USA. Number of centres: One. Funding source: Grants from National Cancer Institute (CA 38522) American Cancer Society (Institutional grant IN‐24), Biomedical Research Support Grant (RR‐05346). Recruitment period: Not stated. Randomised patients and assessor not blinded.
Participants	Inclusion: Adults with haematological malignancy or lymphoma having BMT, who spoke English and were aged > 18 years. Patients had oral mucositis with pain. 67 enrolled, 45 completed.
Interventions	Gr A (n = 18) HYP Hypnosis ‐ 2 training sessions prior to treatment twice weekly sessions for 5 weeks. Gr B (n = 17) CB Cognitive Behavioural coping skills,cognitive restructuring, & relaxation ‐ 2 training sessions prior to treatment twice weekly sessions for 5 weeks. Gr C (n = 16) TCC Therapist contact control group ‐ therapist met with patients for a chat but no new coping skills were taught ‐ 2 training sessions prior to treatment twice weekly sessions for 5 weeks. Gr D (n = 16) TAU Treatment as usual group ‐ received 'standard interventions for nausea, pain and emesis.
Outcomes	Average pain VAS score mean over week 3. Average mean opiate use per day for week 3.
Notes	Average mean opiate use per day was converted to hourly rate by dividing by 24. No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Patients were randomised to one of 4 intervention groups".
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	High risk	Interventions delivered differently.
Blinding of outcome assessors?	High risk	Self assessment.
Incomplete outcome data addressed?	Low risk	Reasons for post randomisation withdrawal and exclusions given for each group and balanced across groups. (17 patients too ill to continue & 5 had missing data (HYP 6, CB 6, TCC 4, TAU 6 respectively). 33% withdrew.
Free of selective reporting?	Low risk	planned outcomes described and reported.
Free of other bias?	Unclear risk	Quote: "During random assignment a marked sex difference occurred between groups".

Methods	Location: Seattle USA. Number of centres: One. Funding source: NCI Grants (38552 & 57807). Recruitment period: Not stated.
Participants	Inclusion: English speaking adults undergoing bone marrow transplant, aged > 18 years, with leukaemia, myelodysplasia or lymphoma. Had to receive 2 outpatient training sessions and remain well enough to participate for 1 month after their bone marrow transplant. Exclusion: Those actively practising imagery. 161 randomised, 94 completed.
Interventions	Gr A: R&I relaxation & imagery training. Gr B: CB cognitive /behavioural coping skills training. Gr C: TS therapist support. Gr D: TAU treatment as usual (no training). 2 training sessions prior to treatment, then twice weekly sessions for 5 weeks. All patients received standard interventions for pain, nausea and emesis.
Outcomes	Average pain VAS score mean day 6 to 26.
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Randomised patients to one of four intervention conditions. Randomisation was stratified for conditioning regimen (CT), whether patients had total body irradiation, and gender".
Allocation concealment?	Unclear risk	No information given.
Blinding of participants/carers?	Low risk	Quote: "Patients blinded to content of other intervention groups. They were told the content only for the intervention they received".
Blinding of outcome assessors?	Low risk	Quote: "These research assistants were blind to the randomisation of the patients".
Incomplete outcome data addressed?	Unclear risk	67/161 = 42% did not complete the study. Details reasons given in Table 2 and reasons and numbers similar in each group. However authors acknowledge that this introduces a risk of bias and have attempted to deal with this in the analysis.
Free of selective reporting?	Low risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Baseline characteristics not given by allocated treatment group ‐ uncertainty as to whether randomisation resulted in balanced groups and/or high proportion of non completers caused bias.

Methods	Location: Barcelona, Spain. Number of centres: One. Funding source: rhGM‐CSF (Molgramastin) supplied by Schering Plough. Recruitment period: October 1998 to March 2001.
Participants	Inclusion: Adults with WHO grade 3 to 4 oral mucositis who had haematological malignancies undergoing stem cell transplantation. 41 patients recruited, 35 completed.
Interventions	GrA (n = 18) rhGM‐CSF 400 ug of rhGM‐CSF dissolved in 200 ml saline solution, mouthrinse to be used for 30 mins, three times daily, for 5 days. Swish and spit. GrB (n = 23) placebo (saline solution only), mouthrinse to be used for 30 mins, three times daily, for 5 days. Swish and spit.
Outcomes	Overall duration of mucositis (days) is used. Reduction in at least 1 grade of mucositis, need for PCA morphine (however there were significantly more already needing this in the placebo group at the beginning of the treatment protocol).
Notes	No power calculation reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Quote: "Double blind randomised controlled trial". Quote: "Both patient randomisation and drug prepartion were performed in the pharmacy department".
Allocation concealment?	Unclear risk	No further details given.
Blinding of participants/carers?	Low risk	Double blind. Quote: "Active and placebo mouthrinses looked and tasted identical".
Blinding of outcome assessors?	Low risk	Double blind.
Incomplete outcome data addressed?	Unclear risk	6/41 (15%) excluded post randomisation, reasons (3 died, 2 refused, 1 required ventilation). 16/18 in Gr A & 19/23 Gr B completed treatment SF.
Free of selective reporting?	Low risk	Planned outcomes described and reported.
Free of other bias?	Unclear risk	Unclear.

Study	Reason for exclusion
Agüeros 2004	Abstract, insufficient information (I).
Allison 1995	Not RCT (sucralfate plus fluconazole).
Atkins 2004	Abstract, insufficient information.
Awada 2004	Not RCT and mucositis not primary outcome.
Barker 1991	No useable data, only medians given (sucralfate versus diphenhydramine syrup/kaolin‐pectin).
Beltran 1990	Abstract, insufficient information (bencidamide mouthwash versus placebo).
Biswal 2002	Abstract, insufficient information (PCA versus CI).
Biswal 2003	Prevention not treatment of mucositis (honey).
Bondi 1997	No useable data, outcome looks at progression of mucositis (tobramycin polymyxin E amphotericin versus diphenhydramine).
Carnel 1990	No useable data, unclear how many patients in each group (lidocaine 1% cocaine versus dyclonine hydrochloride versus diphenhydramine kaolin‐pectin versus placebo).
Cerchietti 2002	No relevant outcomes (morphine mouthwash versus 'magic' mouthwash).
Cerchietti 2003	Problems with design and no mucositis outcomes in form which can be used in the review.
Chambers 2006	Abstract, insufficient information (RK‐0102 oral rinse).
Chapman 1997	No useable data, severity scores given (morphine versus hydromorphone).
Cheng 2004	Prevention of mucositis not treatment.
Collins 1996	No relevant outcomes (morphine versus hydromorphone).
Collova 2004	Abstract, insufficient information.
Connor 1996	Abstract, insufficient information (PCA versus CI).
Crawford 1994	Abstract, insufficient information.
Domenge 1999	Abstract, insufficient information (fluconazole versus amphotericin B).
Ehrnrooth 1999	Abstract, insufficient information (morphine versus tricyclic antidepressant).
Eren 2007	Study published in turkish language with English abstract. Unit of randomisation is chemotherapy cycles not patients (rGM ‐ CSF versus standard care comprising chlorhexidine + sodium bicarbonate + Vitamin E + mycostatin + ranitidine).
Evans 1998	Abstract, insufficient information (GM‐CSF versus placebo).
Evensen 2001	Prevention not treatment of mucositis (Na‐sucrose octasulfate versus placebo).
Ferretti 1987	Abstract, insufficient information (chlorhexidine versus placebo).
Foote 1996	Abstract, insufficient information (antibiotic lozenge‐tobramycin, polymyxin, amphotericin B versus placebo).
Giles 2002	Abstract, insufficient information.
Giles 2004	Prevention of mucositis not treatment.
Girdler 1995	No useable data, number of ulcers and area covered, means but no SDs (epidermal growth factor versus placebo).
Gobetti 1999	Abstract, insufficient information.
Haritha 2009	Abstract, insufficient information (oral morphine).
Hejna 2000	Abstract, insufficient information (GM‐CSF mouthwashes).
Kin‐Fong Cheng 2006	Not eligible as excluded patients with severe (> 2) oral mucositis.
Kostler 2005	Not RCT.
Labbate 2003	Not RCT (contacted authors to check but no reply to e‐mail 10/8/06).
Lever 1987	Study halted early ‐ protocol violation (benzydamine versus HSC mouthwashes).
Lilleby 2006	Prevention of mucositis not treatment.
Lockhart 2005	Prevention of mucositis not treatment.
Mantovani 2003	Not RCT (GM‐CFS).
Marinoni 1996	Abstract, insufficient information (many interventions).
Meredith 1997	Design only treats when mucositis present but the results include patients not treated (sucralphate versus placebo).
Mitrokhin 2003	Translated from Russian. Not RCT.
Naidu 2005	Data presented within groups (comparing change from baseline) only no comparison between groups (Oral polyherb).
Oguchi 1998	Not RCT (polymer film).
Oshitani 1990	Not RCT (sodium alginate versus no treatment control).
Papila 1999	Unclear if RCT ‐ no reply to letter or e‐mail (sucralfate versus placebo).
Pession 1997	Abstract, insufficient information.
Pouli 1999	Abstract, insufficient information.
Rades 2004	Prevention of mucositis not treatment.
Radmard 2002	Abstract, insufficient information.
Rothwell 1990	No useable data, results presented as means (rinse‐hydrocortisone, nystatin, tetracyclin, diphenhydramine versus placebo).
Schmid 2006	No oral outcome and wrong intervention for mucositis.
Schwerkkoske 1999	Abstract, insufficient information.
Shaiova 2004	No appropriate outcomes and unsure of design.
She 2000	Unclear if RCT and insufficient information.
Shen 2004	Unclear if RCT and insufficient information.
Sprinzl 2001	Trial designed so that allocated patients received intervention on onset of mucositis, however outcomes measured at time from beginning of study. Patients had been on intervention for different times. We felt we could not use the data (GM‐CSF versus hydrocortisone mouthwash).
Stokman 2004	Not RCT.
Su 2004	Abstract, insufficient information.
Svanberg 2004	Abstract, insufficient information.
Teshima 1986	Insufficient information on trial to include and no response to letter (sent in Japanese).
Valcarcel 2002	Abstract, insufficient information.
Vayne‐Bossert 2010	Cross‐over study with carry‐over effect from first to second period. Only 9 patient in cross‐over, too few to undertake first period analysis.
Vela‐Ojeda 1996	Abstract, insufficient information.