A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis

Purpose  

The purpose of this study is to review the effects of low-level laser therapy (LLLT) in the prevention and treatment of cancer therapy-induced oral mucositis (OM).     

Individualized pharmacological treatment of oral mucositis pain in patients with head and neck cancer receiving radiotherapy

Purpose  

Pain is a prominent symptom in radiotherapy-induced oral mucositis (OM). This study assesses the effect of pharmacological treatment in head and neck cancer patients with OM-induced pain and swallowing difficulties.     

Prevalence of clinically relevant oral mucositis in outpatients receiving myelosuppressive chemotherapy for solid tumors

Purpose  

Chemotherapy-induced oral mucositis (CIOM) is a common side effect of cancer therapy that may lead to significant morbidity and interfere with the treatment plan. The present prospective, cross-sectional study intended to describe the prevalence of clinically relevant CIOM (CRCIOM) in outpatients receiving chemotherapy for solid tumors.     

Systematic review of amifostine for the management of oral mucositis in cancer patients

Purpose

The aim of this study was to review the available literature from 1966 until December 31, 2010 and define clinical practice guidelines for the use of amifostine for the prevention and treatment of oral mucositis in cancer patients.

Methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for the use of amifostine, in each cancer treatment setting was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible.

Results

Thirty papers were reviewed for evidence on amifostine as an intervention for oral mucositis. No guideline was possible for amifostine in any cancer treatment setting due to inadequate and conflicting evidence.

Conclusion

Review of the amifostine studies for the prevention and treatment of oral mucositis has found insufficient evidence to support its use in any cancer treatment setting for this purpose. Additional well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.     

Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients

Purpose

The aim of this project was to review the available literature and define clinical practice guidelines for the use of anti-inflammatory agents for the prevention and treatment of oral mucositis in cancer patients.

Materials and methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for use of each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible.

Results

Forty-one papers were reviewed. There was sufficient evidence to recommend the use of benzydamine mouthwash for the prevention of oral mucositis in head and neck cancer patients receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy. A new suggestion was developed against the use of misoprostol mouthwash for the prevention of oral mucositis in head and neck cancer patients receiving radiation therapy. Positive results were reported for some other anti-inflammatory agents. However, no guidelines were able to be developed for any other agents due to insufficient and/or conflicting evidence.

Conclusions

The use of anti-inflammatory agents continues to be a promising strategy for the prevention and treatment of oral mucositis. Additional well-designed studies are needed to examine the use of this class of agents for oral mucositis.     

Topische Schmerztherapie bei oraler Mukositis

Background

The pain provoked by mucositis is often described as the most excruciating symptom of cancer treatment. It often causes reduced ingestion, malnutrition, and sometimes postponement or withdrawal of the therapy. For health care providers, adequate pain treatment is a major challenge. The aim of this article is to present an overview of studies on the topical treatment of mucositis pain.

Methods

A systematic search was performed in PubMed with the keywords “mucositis” “pain” and “topical” or “local”. In addition, reference lists and relevant websites were scanned for appropriate literature.

Results

A total of 47 articles were included. There is only scarce evidence for the topical treatment of mucositis pain. The most convincing studies tested opioids, corticoids and benzydamine. For the other substances, too few studies were performed, the results were contradictory, or the study quality was low.

Conclusion

Based on the information gathered in this systematic search of the literature, topical treatment of mucositis pain today is based on empiricism and not on scientific evidence.     

Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution

Purpose

CAM2028, a vehicle that forms a bioadhesive lipid barrier when applied to the oral mucosa, was developed as a carrier system for local delivery of benzydamine, an NSAID used for pain relief in oral mucositis. This trial compared the analgesic effect of CAM2028 plus benzydamine (CAM2028-benzydamine) with unmedicated CAM2028 (CAM2028-control) for the treatment of oral mucositis in patients with head-and-neck cancer.

Methods

Thirty-eight study participants were enrolled during their 3rd to 4th week of radiation therapy. Participants were required to have symptomatic oral mucositis (WHO Grade 2 or above) at screening and pain scores of at least 6 on an 11-point Likert scale at screening and on each day before treatment with study medication. After undergoing radiation, patients were administered a single dose of CAM2028-control or CAM2028-benzydamine 2 days apart, in a randomized crossover fashion. Pain was assessed over the following 8 h.

Results

With both treatments, patients experienced a mean 40 % decrease in pain intensity at 6 h (the primary study endpoint). Both treatments resulted in significant pain relief within 5 min of application that was evident during the entire 8-h assessment period. There was no difference in pain relief between the two interventions at any time point. Both treatments were safe and well tolerated.

Conclusions

CAM2028-benzydamine and CAM2028-control were both efficacious in reducing pain in patients with oral mucositis related to radiation therapy for head-and-neck cancer. Analgesic effects of both medications were immediate, clinically significant, and persistent for up to 8 h.     

Low body mass index as a risk factor of moderate to severe oral mucositis in oral cancer patients with radiotherapy

Purpose

The association between body mass index (BMI) and oral mucositis in oral cancer patients receiving radiotherapy is unclear. This study examined whether low BMI could be a risk factor for oral mucositis in oral cancer patients receiving radiotherapy.

Methods

Between April 2007 and March 2011, a total of 33 inpatients with oral cancer receiving radiotherapy were recruited. They were followed from the beginning of radiotherapy to discharge from hospital. All patients had no mucositis when radiotherapy started. The odds ratio (OR) and 95?% confidence interval (CI) of BMI for incident grade 2 and grade 3 mucositis were calculated by use of univariable logistic regression models.

Results

All patients developed oral mucositis (grade 1 in 39.4?%, grade 2 in 30.3?%, grade 3 in 30.3?%), with the maximum grade occurring at an average of 32.4?days. Compared with normal BMI (≥22.0), the OR of low BMI (<22.0) for moderate to severe mucositis was 9.07 (95?% CI, 1.72-47.68).

Conclusions

Low BMI may be a risk factor of moderate to severe oral mucositis.     

Self-reported experience of mucositis in cancer patients who underwent conditioning regimen and stem cell transplantation

Purpose  

This study was done to evaluate the frequency and severity of mucositis in the early period of stem cell transplantation (SCT) and the relation of conditioning regimens with mucositis.     

Development and initial evaluation of electronic Children's International Mucositis Evaluation Scale (eChIMES) for children with cancer

Purpose

We previously developed a pediatric-specific measure of oral mucositis named the Children's International Mucositis Evaluation Scale (ChIMES). Availability as an electronic version may improve self-report response rates. The objectives were to develop an electronic version of ChIMES (eChIMES) and to determine whether the instrument is easy to use, understandable, and suitable for measuring mucositis among children and adolescents with cancer.

Methods

Development of eChIMES was on an iPad; the initial version was piloted with ten children to refine instructions for use and presentation. A crosssectional study then was conducted and included English-speaking children and adolescents 8–18 years of age receiving active treatment for cancer. Participants were shown eCHIMES and were asked to complete it. Questions elicited whether they found eChIMES easy or difficult to use, easy or difficult to understand, and suitable (a good way) for children with cancer to monitor mucositis. Outcomes were rated using five-point ordinal scales.

Results

Following the development and initial refinement of eChIMES, 40 children were enrolled. Median age was 12.4 (range, 8.0 to 17.8)?years. The instrument was found to be easy or very easy to use and understood by 40 (100 %) and 38 (95 %) participants, respectively. The application was considered suitable or very suitable for measuring mucositis by 37 (92 %).

Conclusions

We found that eChIMES was easy to use, understandable, and suitable for monitoring mucositis among children with cancer. Incorporation into clinical trials may improve the ability to compare and evaluate interventions for mucositis.     

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients

Purpose

The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy.

Methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible.

Results

Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60???g/kg per day for 3?days prior to conditioning treatment and for 3?days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence.

Conclusions

Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.     

Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study

Goals  

Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis.     

Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen

Goals of work  

Severe oral mucositis induced by allogeneic hematopoietic cell transplantation (HCT) is associated with intolerable pain and risk of systemic bacteremia infection. Differences between conventional HCT and reduced-intensity regimens for allogeneic HCT (RIST) may influence the occurrence and severity of oral mucositis. Here, we evaluated oral mucositis in patients undergoing RIST and compared the results with those in conventional allogeneic HCT patients to facilitate predictive measures for mucositis.     

Progress of oral care and reduction of oral mucositis—a pilot study in a hematopoietic stem cell transplantation ward

Purpose  

Oral mucositis is a common symptomatic complication associated with hematopoietic stem cell transplantation (HCT). We use simple strategies aimed to reduce oral mucositis by keeping the oral cavity clean and moist. Here, we report on the progress of oral care and the changes in the degree of oral mucositis. The purpose of this pilot study is to evaluate the effects of our strategies on the prevalence and the severity of oral mucositis.     

Systematic review of natural agents for the management of oral mucositis in cancer patients

Purpose

The aim of this study was to review the available literature and define clinical practice guidelines for the use of natural agents for the prevention and treatment of oral mucositis.

Methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible.

Results

A total of 49 papers across 15 interventions were examined. A new suggestion was developed in favor of systemic zinc supplements administered orally in the prevention of oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation (Level III evidence). A recommendation was made against the use of intravenous glutamine for the prevention of oral mucositis in patients receiving high-dose chemotherapy prior to hematopoietic stem cell transplant (Level II evidence). No guideline was possible for any other agent, due to inadequate and/or conflicting evidence.

Conclusions

Of the various natural agents reviewed here, the available evidence supported a guideline only for two agents: a suggestion in favor of zinc and a recommendation against glutamine, in the treatment settings listed above. Well-designed studies of other natural agents are warranted.     

A randomized placebo-controlled trial of manuka honey for radiation-induced oral mucositis

Background

Few treatments have the potential to reduce the severity of radiation-induced mucositis in head and neck cancer patients. Some small studies have suggested that organic honey may be a useful preventive treatment.

Methods

This investigator-initiated double-blind randomized placebo-controlled trial investigated whether honey reduced the severity of radiation-induced oral mucositis (ROM). One hundred six head and neck cancer patients from the Vancouver and Sudbury Cancer Centers in Canada were randomized to swish, hold, and swallow either 5 ml of irradiated organic manuka honey or a placebo gel, four times a day throughout radiation treatment, plus seven more days. Severity of oral mucositis according to the Radiation Therapy Oncology Group (RTOG), World Health Organization (WHO), and Oral Mucositis Assessment Scale scales, weight, and subjects' symptom severity and quality of life were assessed weekly. Sialometry was performed at baseline and at the last study visit.

Results

One hundred six patients were recruited. Twenty-four did not attend any mucositis assessments. One was removed from the study because of off-study consumption of store-bought manuka honey. The remaining 81 patients had at least one mucositis assessment and were included in the analysis. Sixty-two percent of subjects received concurrent chemotherapy; 81 % were male. The groups were well-matched, and blinding was excellent. Dropouts were mostly due to nausea and were similar in both arms, with 78 % being able to tolerate the study products for more than 1 week. The dropout rate was 57 % in those who received honey and 52 % in those who received placebo gel. The dropout rate in those who had concurrent chemotherapy was 59 % and in those who only received radiation was 47 %. There was no statistically significant difference between the honey and placebo arms in any of the outcome indicators. Those who completed the study in both treatment arms had low rates of RTOG greater than or equal to grade 3 mucositis; 35 % in the honey group and 43 % in the placebo group.

Conclusion

Despite promising earlier reports, manuka honey was not tolerated well by our patients and, even when used as directed, did not have a significant impact on the severity of ROM.     

Evaluation of nutritional status in head and neck radio-treated patients affected by oral mucositis: efficacy of class IV laser therapy

Purpose

To retrospectively evaluate the role of class IV laser therapy in the amelioration of nutritional status of patients affected by oral mucositis due to radiotherapy of the head and neck region during oncological treatment.

Methods

Sixty-three oncological patients were included in this study. All patients were affected by tumors in the head and neck region and had developed oral mucositis during radiotherapy. Forty-two patients had been treated by high-power laser therapy whereas 21 patients had been managed with traditional medications. Data collection included weight measurement (kilogram) and body mass index (BMI) calculation (mass (kilogram)/(height) (square meter)) on the first and last day of radiotherapy. In addition, gender, age, pathology, and the kind of oncological treatment have been considered.

Results

Laser-treated patients decreased less in BMI during radiotherapy (p?=?0.000). Patients treated by combined oncological treatments (radiotherapy and/or chemotherapy and/or surgery) had a higher weight loss during radiotherapy (p?=?0.015). According to a multivariate regression analysis, the only variable which significantly influenced the reduction of BMI was laser treatment (p?=?0.000).

Conclusions

Laser therapy is actually considered one of the recommended remedies for the healing of oral mucositis due to cancer treatments. Healing of mucositis can deeply influence the feeding capacity of patients, through reduction of pain and improvement of chewing and swallowing capacities. It also allows lowering the costs for hospitalization and supportive care. Laser therapy should become part of nutritional interventions in oncological patients affected by oral mucositis.     

Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy

Purpose

This systematic review analyzed the strength of the literature and defined clinical practice guidelines for the use of oral cryotherapy for the prevention and/or treatment of oral mucositis caused by cancer therapy.

Methods

A systematic review on relevant oral cryotherapy studies indexed prior to 31 December 2010 was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) using OVID/MEDLINE, with publications selected for review based on defined inclusion and exclusion criteria. Findings from the reviewed studies were integrated into guidelines based on the overall level of evidence for each intervention. Guidelines were classified into three types: recommendation, suggestion, or no guideline possible.

Results

Twenty-two clinical studies and two meta-analyses were analyzed. Results were compared with the MASCC/ISOO guidelines published in 2007. The recommendation for the use of oral cryotherapy to prevent oral mucositis in patients receiving bolus fluorouracil (5-FU) was maintained, in agreement with the 2007 guidelines. A suggestion for use of oral cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan as conditioning regimen with or without total body irradiation for HCST was revised from the 2007 guidelines. No guideline was possible for any other intervention, due to insufficient evidence.

Conclusions

The evidence continues to support the use of oral cryotherapy for prevention of oral mucositis in patients receiving bolus 5-FU chemotherapy or high-dose melphalan. This intervention is consistent with the MASCC/ISOO guidelines published in 2007. The literature is limited by the fact that utilization of a double-blind study design is not feasible. Future studies that compare efficacy of oral cryotherapy with other mucositis agents in patients receiving chemotherapy with relatively short plasma half-lives would be useful.     

In Vivo Effects of Immunomodulators in a Murine Model of Fluorouracil-Induced Mucositis

Background

Fluorouracil (5-FU) is a pyrimidine analogue used as a cancer treatment. Its toxic side effects, including mucositis, are reported to occur in 40% of the treated patients. Because of the inflammatory component of mucositis, we explored the possibility of modulating this condition with an immunomodulatory agent and a tumor necrosis factor-α inhibitor.

Objective

The aim of this study was to evaluate the effect of 2 immunosuppressive agents, etanercept and cyclosporine, in a murine model of 5-FU–induced mucositis.

Methods

To study the short-term effects of 5-FU on mucositis, cyclosporine and etanercept were administered to mice after an injection of 5-FU. The animals (n = 8) were euthanized at 6 hours post-challenge. Hematoxylin and eosin–stained histologic sections of the small intestine were examined for signs of apoptosis. To further examine the potential of cyclosporine in the treatment of 5-FU–induced mucositis in a longer duration, the animals (N = 15) were given 2 challenges of 5-FU within 6 hours. All mice were dosed daily until day 9 with either cyclosporine (100 mg/kg) or phosphate-buffered saline (PBS).

Results

Six hours after 5-FU challenge, 25 mg/kg etanercept and 50 mg/kg cyclosporine had no effect on 5-FU–induced apoptosis (P > 0.05). However, 100 mg/kg cyclosporine significantly reduced the cumulative level of apoptosis >41.6% of the intestinal crypt surface (P < 0.05). During long-term observation, all mice began to lose weight at a rate of approximately 0.8 g/day after 5-FU exposure. The rates of weight loss and survival were not affected by cyclosporine treatment. The diarrhea onset began on day 4 with 46.7% of the PBS-treated mice showing signs of diarrhea compared with 53.3% in the cyclosporine group. The diarrhea score for both groups plateaued on day 7, with a cumulative score of 41 for the PBS group and 50 for the cyclosporine group. Cyclosporine treatment did not affect the diarrhea onset day or severity compared with the PBS-treated group (P > 0.05).

Conclusions

Our data indicated that etanercept is not a suitable treatment for 5-FU–induced mucositis. Despite decreased apoptosis in the gut, cyclosporine did not affect the severity of the diarrhea or survival. Therefore, we concluded that cyclosporine treatment was only effective in mediating the short-term apoptotic events in the intestines but has no long-term effect on the animals' survival and diarrhea.     

Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients

Background

The aim of this study was to review the available literature and define clinical practice guidelines for the use of laser and other light therapies for the prevention and treatment of oral mucositis.

Methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible.

Results

A new recommendation was made for low-level laser (wavelength at 650?nm, power of 40?mW, and each square centimeter treated with the required time to a tissue energy dose of 2?J/cm² (2?s/point)) for the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation conditioned with high-dose chemotherapy, with or without total body irradiation. A new suggestion was made for low-level laser (wavelength around 632.8?nm) for the prevention of oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer. No guideline was possible in other populations and for other light sources due to insufficient evidence.

Conclusions

The increasing evidence in favor of low-level laser therapy allowed for the development of two new guidelines supporting this modality in the populations listed above. Evidence for other populations was also generally encouraging over a range of wavelengths and intensities. However, additional well-designed research is needed to evaluate the efficacy of laser and other light therapies in various cancer treatment settings.