Reproduced with permission of JE Clarkson, HV Worthington, OB Eden. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews 2008, Issue 2. Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: 10.1002/14651858.CD001973.pub3.
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 strategy: Computerized searches of Cochrane Oral Health Group’s Trials Register; Cochrane Pain, Palliative and Supportive Care Group’s Trials Register; CENTRAL; MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches June 2006: CENTRAL (The Cochrane Library 2006, Issue 2).
Selection criteria: All randomized 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 hospitalization, 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 randomization, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and risk ratio (RR) values calculated using fixed effect models.
Main results: Twenty-six trials involving 1353 patients satisfied the inclusion criteria. Four agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% confidence interval (CI) 1.06 to 10.49; granulocyte macrophage-colony stimulating factor RR 4.23, 95% CI 1.35 to 13.24; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Three of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and ‘magic’ (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: granulocyte macrophage-colony stimulating factor when compared to povidone iodine, with mean difference −3.5 days (95% CI −4.1 to −2.9) and allopurinol compared to placebo, with mean difference −4.5 days (95% CI −5.8 to −3.2).
Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA: however, more opiate was used with PKPCA.
Authors’ conclusions: There is weak and unreliable evidence that allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.
Mucositis is a common and often inevitable side effect of various types of oncology treatment, particularly head and neck cancer and during conditioning regimens prior to stem cell transplantation. The development of mucositis has important implications in terms of quality of life for patients during treatment due to severe pain and, more importantly, can impact severely on treatment outcomes by comprising cancer treatment and increasing the risk of systemic infection and in some cases, death. The development of mucositis also has significant financial implications for the management of patients during their cancer treatment because of the increased need for hospitalization and use of analgesic medication. The appropriate and effective management of mucositis is therefore a very important factor in improving clinical outcomes for patients.
The aim of this Cochrane Review was to assess the effectiveness of treating oral mucositis or its associated pain in patients receiving chemotherapy and/or radiotherapy for cancer treatment. Only 26 trials out of 84 were considered to be suitable for inclusion into the study. The review found that for the brief list of studies that were included, the evidence for the effectiveness of specific agents was weak and unreliable. The review did, however, report that patient controlled analgesia resulted in less opioid use compared with continuous infusion for pain control. The review highlights the complexities in comparing clinical trials in the area of mucositis research. Clinical mucositis research can involve a wide of variety patients undergoing different treatment regimens, each with different risks of developing mucositis. A broad range of different agents have been investigated, each with different pharmacological modes of action as well as different clinical objectives. Some agents are used to treat mucositis whilst others’ sole aim is to palliate symptoms. Each of these criteria were included in this review. A further complicating factor, also mentioned by the authors of the review, is the use of different scales to measure or score mucositis and measure the effect of interventions. Scales may be study dependent or have specific outcomes, such as general nursing care or oral health care which, although useful in a clinical setting, may make assessment of interventions for mucositis difficult by including other non-related criteria. Furthermore, the review highlighted the issue of lack of clinical assessor training in the trials and interuser variability of scoring scales which can adversely affect the outcome of clinical studies.
Given these many complicating factors and their impact on the selection of papers included in the review, it appears that the selection criteria may have resulted in the omission of studies that supported a range of potentially important interventive measures. Another review of prevention and treatment of mucositis which was undertaken by the Mucositis Study Section of the Multinational Society of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO)1 also used strict criteria for study inclusion but was able to provide a broad range of recommendations for the management of mucositis not considered by the Cochrane Review. Perhaps one of the most important agents was palifermin (keratinocyte growth factor-1). The MASCC/ISOO guidelines recommended the use of palifermin in the clinical setting of patients undergoing high dose chemotherapy and total body irradiation with autologous stem cell transplantation. Other omissions from the Cochrane Review included the potential importance of basic oral care (including dental examinations and treatment prior to the start of cancer therapy for all patients), the potential for cryotherapy in specific clinical situations and the use of benzydamine for the prevention of radiation-induced mucositis.1
The Cochrane Review does indicate the need for more well designed clinical trials of agents in the management of mucositis. This was also highlighted by the MASCC/ISOO guidelines where it was found that in mucositis research there are many small and sometimes non-randomized studies which hamper the ability to evaluate and compare potential agents.2 Ideally robust, well designed, multicentre, placebo-controlled, randomized studies are required to provide this information. In addition, there is also the need for standardized assessment or scoring criteria and adequate training of clinical assessors in trials so that interuser variability is minimized and different trials can be more easily compared.
Whilst the Cochrane Review has limitations and does not provide a great deal of support for the agents included in the review, it does highlight the importance of mucositis in the supportive care of cancer patients. The large range of potential interventions for mucositis also highlights the fact that there is limited information about the pathobiology of mucositis. Once this is better defined, treatments can be targeted toward specific pathways that lead to mucositis, thereby improving clinical outcomes for patients as well as their quality of life during treatment.