Worthington, H.V., Clarkson, J.E., Bryan, G., Furness, S., Glenny, A.M., Littlewood, A., … Khalid, T. (2011). Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews (Online), 4(4), CD000978.

To evaluate the evidence for prophylactic agents in management of oral mucositis in patients with cancer receiving treatment

Databases searched were MEDLINE, CANCERLIT, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), System for Information on Grey Literature in Europe (SIGLE), and the Cochrane Database.

An extensive list of search terms and strategies used per database was provided in the article.

Studies were included in the review if they

• Were randomized controlled trials (RCTs).
• Compared an intervention to a placebo or no treatment.

A total of 383 references were retrieved. Risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were categorized as low, unclear, or high risk of bias. Studies were labeled using the GRADES system for evaluating quality of evidence.

• The final number of studies included in the review was 131.
• The total sample size across all studies was 10,514 with an across-study sample range of 12–301. 
• Studies involved a variety of cancers and patients receiving chemotherapy, radiation therapy, or both.

• Patients were in the active antitumor treatment phase of care.
• This study has clinical applicability to pediatrics.

• Only 8% of studies included were seen to have a low risk of bias. 
• Studies included a variety of treatments such as acyclovir, allopurinol rinse, aloe vera, amifostine, antibiotic paste, systemic antibiotics, axulene, benzydamine, beta carotene, chamomile, chewing gum, Chinese herbs, chlorhezidine, cryotherapy, epidermal growth factor, glutamine, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enymes, indigo wood root, intestinal trefoil factor, keratinocyte growth factor, laser, anti-inflammatory drugs, oral care, pentoxifylline, pilocarpine, polymixin/tobramycin/amphotericin (PTA), traumeel, sucralfate, zinc sulphate, and povidone iodine. 
• From all analyses, at least moderately strong evidence of benefit was found for cryotherapy (RR = 0.74, 95% confidence interval [CI] 0.57–0.95, p = 0.02) for any mucositis and for keratinocyte growth factor (RR = 0.82, 95% CI 0.71–0.94, p = .0005) for any mucositis. 
• Weak and unreliable evidence for potential benefit was found with aloe vera, amifostine, glutamine, G-CSF, honey, laser, polymixin/tobramycin, amphotericin lozenges, and sucralfate.
• A substantial body of evidence showed no benefit of chlorhexidine.

Findings support the benefits of cryotherapy and keratinocyte growth factor. The low quality of evidence in most of the other interventions points to the need for ongoing, well-designed research in this area. The presentation of findings in many publications made meta-analysis impossible.

The rationale for the authors' summaries of findings was not entirely clear. Similar RR ratio results with similar evidence quality levels were identified differently in terms of potential benefit. Although the review was inclusive and extensive, interpretation of results was inconsistent. High heterogeneity existed in most interventions, and most studies were either at high or unclear risk of bias with low GRADES scoring. Studies did not always differentiate between mucositis and candidiasis, which would affect recommendations.

This article suggests strong support for use of cryotherapy and keratinocyte growth factor for mucositis prevention. It suggests possible benefit from aloe vera, amifostine, IV glutamine, G-CSF, honey, laser, and antibiotic lozenges. Sucralfate may reduce the severity of mucositis. These findings should be interpreted with caution, given the relatively low quality of overall evidence and high heterogeneity across studies included in meta-analysis, as well as the fact that treatments and sample characteristics were highly varied.