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Cryotherapy and keratinocyte growth factor may be beneficial in preventing oral mucositis in patients with cancer, and sucralfate is effective in reducing its severity
RESEARCH
CRITICAL
SUMMARIES
Cryotherapy and keratinocyte growth factor may be beneficial in preventing oral mucositis in patients with cancer, and sucralfate is effective in reducing its severity A critical summary of Worthington HV, Clarkson JE, Bryan G, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011;(4):CD000978. Shukan Kanuga, DDS, MSD Systematic review conclusion. Ten interventions were beneficial in preventing or reducing the severity of oral mucositis associated with cancer treatment. Both cryotherapy (ice chips) and keratinocyte growth factor (palifermin) used separately were the most beneficial in preventing oral mucositis. Sucralfate was effective in reducing the severity of mucositis. Critical summary assessment. Ten interventions with varying levels of evidence had some benefits that helped prevent or reduce the severity of mucositis compared with placebos or no treatment. Evidence quality rating. Limited.
Clinical question. In patients with cancer who are undergoing therapy, which interventions prevent or reduce the severity of oral mucositis compared with placebos or no treatment? Review methods. The reviewers searched seven electronic databases for articles published from 1950 through February 2011. They included only articles found by hand searching carried out by the Cochrane Collaboration. The Cochrane Collaboration also translated non–English-language articles that met the inclusion criteria. The reviewers contacted authors and experts in the field concerning additional published and unpublished trials. Two reviewers independently searched the titles and abstracts of all articles. They
included only randomized controlled trials (RCTs) in the review. Study participants were people with cancer who were receiving radiotherapy, chemotherapy or targeted therapies. The authors considered any intervention prescribed as prophylaxis for oral mucositis to be an active intervention, and they considered placebo, another active intervention or no treatment to be a control. Mucositis as measured on a four-point scale (ranging from “none” to “severe”) was the primary outcome measure. Oral hygiene measures, relief of pain, febrile episodes and xerostomia were some of the 21 secondary outcome measures. The reviewers assessed the trials for their risk of bias (high, low and unclear) and heterogeneity.
Main results. The authors included 131 RCTs for the review, all of which included data on assessment of mucositis. Investigators in 36 of the trials compared an active intervention with no treatment, and investigators in 87 trials used a placebo. There were 43 interventions and 10,514 recruited patients in the studies in which investigators assessed oral mucositis and its treatment with acyclovir, allopurinol mouthrinse, aloe vera, chlorhexidine, cryotherapy, dental stent, histamine gel, oral care, povidone iodine, prednisone and zinc sulfate. The reviewers deemed that 27 studies (21 percent) had adequate sequence generation and classified them as being at low risk of bias for this domain. They also deemed that the remaining 104 studies (79 percent) had an unclear risk of bias. Investigators in 19 studies (15 percent) used adequate methods of allocation concealment, and the reviewers, therefore, classified them as being at low risk of bias. There was evidence of a benefit associated with the use of cryotherapy for each of the three outcome categories of mucositis (absent versus present [0 versus ≥ 1],
Dr. Kanuga is a pediatric dentist in private practice, West Hills, Calif., and Valencia, Calif., and a lecturer, Pediatric Dentistry, School of Dentistry, University of California Los Angeles. She also is an evidence reviewer for the American Dental Association. Address reprint requests to Dr. Kanuga at 20640 Pesaro Way, Porter Ranch, Calif. 91326, e-mail [email protected].
928 JADA 144(8) http://jada.ada.org August 2013 Copyright © 2013 American Dental Association. All Rights Reserved.
RESEARCH
mild versus moderate or severe [0-1 versus ≥ 2] and moderate versus severe [0-2 versus ≥ 3]) and in the prevention of mucositis with substantial heterogeneity related to the diversity of clinical conditions and treatments. Keratinocyte growth factor was beneficial in preventing all categories of mucositis.
Conclusions. There is some evidence regarding the effectiveness of cryotherapy and keratinocyte growth factor in preventing mucositis, and there is weaker evidence regarding the use of aloe vera, amifostine, glutamine, granulocyte colony-stimulating factor, honey, laser, polymixin/tobramycin/
Commentary
Importance and context. Cancer treatments are associated with short- and long-term adverse effects. Mucositis is a major oral adverse effect that is associated with certain types of cancer therapy. It manifests as pain and discomfort, thereby affecting the quality of life of the patients receiving treatment. Managing these oral adverse effects remains a challenge despite the use of a variety of agents to prevent them, treat them or both. Strengths and weaknesses of the systematic review. The strengths of the review included a thorough and comprehensive search of the literature by means of multiple electronic databases, search of non–English-language literature, contacting experts, use of unpublished literature and use of two independent reviewers. The reviewers had established a priori inclusion and exclusion criteria with primary and secondary outcome measures. The reviewers also provided the characteristics of the included studies in a table that included data regarding participants, interventions and outcomes from the original studies. They thoroughly assessed the scientific quality of the included studies in terms of risk of bias and heterogeneity of results, as well as the effect of these factors on the resulting evidence. They determined that there were too few trials to conduct a sensitivity analysis. The reviewers did not state any conflicts of interest. Strengths and weaknesses of the evidence. All of the included studies were RCTs regarding interventions used to prevent oral mucositis in patients receiving cancer treatment. These trials, however, were at high or unclear risk of bias. Although the facts that cryotherapy
CRITICAL
SUMMARIES
amphotericin lozenges or paste and sucralfate being beneficial in preventing mucositis in patients with cancer who are receiving treatment. There was some evidence that sucralfate reduced the severity of mucositis. No sources of funding for this systematic review were listed.
and keratinocyte growth factor were beneficial in preventing mucositis and that sucralfate was beneficial in reducing the severity of mucositis were established on the basis of some evidence, the evidence for using other interventions was weaker because the trials had a high or unclear risk of bias. The substantial heterogeneity related to the variety of clinical conditions and treatments made it difficult to assess the multiple outcome variables. Implications for dental practice. On the basis of limited evidence, cryotherapy and keratinocyte growth factor can prevent mucositis in patients receiving treatment for cancer, and sucralfate can reduce its severity. The other interventions studied had weaker evidence for being beneficial in preventing or reducing mucositis because of high or unclear risk of bias. Cryotherapy may be a practical and economical intervention compared with keratinocyte growth factor, which not only is an expensive oncology-related drug but also requires intravenous administration and has multiple systemic adverse effects, so a collaborative medical-dental effort should be used to address the patient’s options regarding these interventions. n Disclosure. Dr. Kanuga did not report any disclosures. These summaries, published under the auspices of the American Dental Association Center for Evidence-Based Dentistry, are prepared by practitioners trained in critical appraisal of published systematic reviews who work under the mentorship of experts. The summaries are not intended to, and do not, express, imply or summarize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as guided by their clinical judgment and by patient needs. For more information on the evidence quality rating provided above and additional critical summaries, please visit http://ebd.ada.org.
JADA 144(8) http://jada.ada.org August 2013 929 Copyright © 2013 American Dental Association. All Rights Reserved.
CRITICAL
SUMMARIES
Cryotherapy and keratinocyte growth factor may be beneficial in preventing oral mucositis in patients with cancer, and sucralfate is effective in reducing its severity A critical summary of Worthington HV, Clarkson JE, Bryan G, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011;(4):CD000978. Shukan Kanuga, DDS, MSD Systematic review conclusion. Ten interventions were beneficial in preventing or reducing the severity of oral mucositis associated with cancer treatment. Both cryotherapy (ice chips) and keratinocyte growth factor (palifermin) used separately were the most beneficial in preventing oral mucositis. Sucralfate was effective in reducing the severity of mucositis. Critical summary assessment. Ten interventions with varying levels of evidence had some benefits that helped prevent or reduce the severity of mucositis compared with placebos or no treatment. Evidence quality rating. Limited.
Clinical question. In patients with cancer who are undergoing therapy, which interventions prevent or reduce the severity of oral mucositis compared with placebos or no treatment? Review methods. The reviewers searched seven electronic databases for articles published from 1950 through February 2011. They included only articles found by hand searching carried out by the Cochrane Collaboration. The Cochrane Collaboration also translated non–English-language articles that met the inclusion criteria. The reviewers contacted authors and experts in the field concerning additional published and unpublished trials. Two reviewers independently searched the titles and abstracts of all articles. They
included only randomized controlled trials (RCTs) in the review. Study participants were people with cancer who were receiving radiotherapy, chemotherapy or targeted therapies. The authors considered any intervention prescribed as prophylaxis for oral mucositis to be an active intervention, and they considered placebo, another active intervention or no treatment to be a control. Mucositis as measured on a four-point scale (ranging from “none” to “severe”) was the primary outcome measure. Oral hygiene measures, relief of pain, febrile episodes and xerostomia were some of the 21 secondary outcome measures. The reviewers assessed the trials for their risk of bias (high, low and unclear) and heterogeneity.
Main results. The authors included 131 RCTs for the review, all of which included data on assessment of mucositis. Investigators in 36 of the trials compared an active intervention with no treatment, and investigators in 87 trials used a placebo. There were 43 interventions and 10,514 recruited patients in the studies in which investigators assessed oral mucositis and its treatment with acyclovir, allopurinol mouthrinse, aloe vera, chlorhexidine, cryotherapy, dental stent, histamine gel, oral care, povidone iodine, prednisone and zinc sulfate. The reviewers deemed that 27 studies (21 percent) had adequate sequence generation and classified them as being at low risk of bias for this domain. They also deemed that the remaining 104 studies (79 percent) had an unclear risk of bias. Investigators in 19 studies (15 percent) used adequate methods of allocation concealment, and the reviewers, therefore, classified them as being at low risk of bias. There was evidence of a benefit associated with the use of cryotherapy for each of the three outcome categories of mucositis (absent versus present [0 versus ≥ 1],
Dr. Kanuga is a pediatric dentist in private practice, West Hills, Calif., and Valencia, Calif., and a lecturer, Pediatric Dentistry, School of Dentistry, University of California Los Angeles. She also is an evidence reviewer for the American Dental Association. Address reprint requests to Dr. Kanuga at 20640 Pesaro Way, Porter Ranch, Calif. 91326, e-mail [email protected].
928 JADA 144(8) http://jada.ada.org August 2013 Copyright © 2013 American Dental Association. All Rights Reserved.
RESEARCH
mild versus moderate or severe [0-1 versus ≥ 2] and moderate versus severe [0-2 versus ≥ 3]) and in the prevention of mucositis with substantial heterogeneity related to the diversity of clinical conditions and treatments. Keratinocyte growth factor was beneficial in preventing all categories of mucositis.
Conclusions. There is some evidence regarding the effectiveness of cryotherapy and keratinocyte growth factor in preventing mucositis, and there is weaker evidence regarding the use of aloe vera, amifostine, glutamine, granulocyte colony-stimulating factor, honey, laser, polymixin/tobramycin/
Commentary
Importance and context. Cancer treatments are associated with short- and long-term adverse effects. Mucositis is a major oral adverse effect that is associated with certain types of cancer therapy. It manifests as pain and discomfort, thereby affecting the quality of life of the patients receiving treatment. Managing these oral adverse effects remains a challenge despite the use of a variety of agents to prevent them, treat them or both. Strengths and weaknesses of the systematic review. The strengths of the review included a thorough and comprehensive search of the literature by means of multiple electronic databases, search of non–English-language literature, contacting experts, use of unpublished literature and use of two independent reviewers. The reviewers had established a priori inclusion and exclusion criteria with primary and secondary outcome measures. The reviewers also provided the characteristics of the included studies in a table that included data regarding participants, interventions and outcomes from the original studies. They thoroughly assessed the scientific quality of the included studies in terms of risk of bias and heterogeneity of results, as well as the effect of these factors on the resulting evidence. They determined that there were too few trials to conduct a sensitivity analysis. The reviewers did not state any conflicts of interest. Strengths and weaknesses of the evidence. All of the included studies were RCTs regarding interventions used to prevent oral mucositis in patients receiving cancer treatment. These trials, however, were at high or unclear risk of bias. Although the facts that cryotherapy
CRITICAL
SUMMARIES
amphotericin lozenges or paste and sucralfate being beneficial in preventing mucositis in patients with cancer who are receiving treatment. There was some evidence that sucralfate reduced the severity of mucositis. No sources of funding for this systematic review were listed.
and keratinocyte growth factor were beneficial in preventing mucositis and that sucralfate was beneficial in reducing the severity of mucositis were established on the basis of some evidence, the evidence for using other interventions was weaker because the trials had a high or unclear risk of bias. The substantial heterogeneity related to the variety of clinical conditions and treatments made it difficult to assess the multiple outcome variables. Implications for dental practice. On the basis of limited evidence, cryotherapy and keratinocyte growth factor can prevent mucositis in patients receiving treatment for cancer, and sucralfate can reduce its severity. The other interventions studied had weaker evidence for being beneficial in preventing or reducing mucositis because of high or unclear risk of bias. Cryotherapy may be a practical and economical intervention compared with keratinocyte growth factor, which not only is an expensive oncology-related drug but also requires intravenous administration and has multiple systemic adverse effects, so a collaborative medical-dental effort should be used to address the patient’s options regarding these interventions. n Disclosure. Dr. Kanuga did not report any disclosures. These summaries, published under the auspices of the American Dental Association Center for Evidence-Based Dentistry, are prepared by practitioners trained in critical appraisal of published systematic reviews who work under the mentorship of experts. The summaries are not intended to, and do not, express, imply or summarize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as guided by their clinical judgment and by patient needs. For more information on the evidence quality rating provided above and additional critical summaries, please visit http://ebd.ada.org.
JADA 144(8) http://jada.ada.org August 2013 929 Copyright © 2013 American Dental Association. All Rights Reserved.