Rajesh V. Lalla

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy

Mucositis is a highly significant, and sometimes dose‐limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis.

A systematic review of oral fungal infections in patients receiving cancer therapy

PurposeThe aims of this systematic review were to determine, in patients receiving cancer therapy, the prevalence of clinical oral fungal infection and fungal colonization, to determine the impact on quality of life and cost of care, and to review current management strategies for oral fungal infections.MethodsThirty-nine articles that met the inclusion/exclusion criteria were independently reviewed by two calibrated reviewers, each using a standard form. Information was extracted on a number of variables, including study design, study population, sample size, interventions, blinding, outcome measures, methods, results, and conclusions for each article. Areas of discrepancy between the two reviews were resolved by consensus. Studies were weighted as to the quality of the study design, and recommendations were based on the relative strength of each paper. Statistical analyses were performed to determine the weighted prevalence of clinical oral fungal infection and fungal colonization.ResultsFor all cancer treatments, the weighted prevalence of clinical oral fungal infection was found to be 7.5% pre-treatment, 39.1% during treatment, and 32.6% after the end of cancer therapy. Head and neck radiotherapy and chemotherapy were each independently associated with a significantly increased risk for oral fungal infection. For all cancer treatments, the prevalence of oral colonization with fungal organisms was 48.2% before treatment, 72.2% during treatment, and 70.1% after treatment. The prophylactic use of fluconazole during cancer therapy resulted in a prevalence of clinical fungal infection of 1.9%. No information specific to oral fungal infections was found on quality of life or cost of care.ConclusionsThere is an increased risk of clinically significant oral fungal infection during cancer therapy. Systemic antifungals are effective in the prevention of clinical oral fungal infection in patients receiving cancer therapy. Currently available topical antifungal agents are less efficacious, suggesting a need for better topical agents.

Systematic review of agents for the management of gastrointestinal mucositis in cancer patients

PurposeThe aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis.MethodsA systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of 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, and no guideline possible.ResultsA total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing Lactobacillus spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence.ConclusionsThis updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates.

Systematic review of basic oral care for the management of oral mucositis in cancer patients.

PurposeThe purpose of this project was to evaluate research in basic oral care interventions to update evidence-based practice guidelines for preventing and treating oral mucositis (OM) in cancer patients undergoing radio- or chemotherapy.MethodsA systematic review of available literature was conducted by the Basic Oral Care Section of the Mucositis Study Group of MASCC/ISOO. Seven interventions—oral care protocols, dental care, normal saline, sodium bicarbonate, mixed medication mouthwash, chlorhexidine, and calcium phosphate—were evaluated using the Hadorn (J Clin Epidemiol 49:749–754, 1996) criteria to determine level of evidence, followed by a guideline determination of one of the following: recommendation, suggestion, or no guideline possible, using Somerfield’s (Classic Pap Cur Comments 4:881–886, 2000) schema.ResultsFifty-two published papers were examined by treatment population (radiotherapy, chemotherapy, and hematopoietic stem cell transplant) and by whether the intervention aimed to prevent or treat OM. The resulting practice suggestions included using oral care protocols for preventing OM across all treatment modalities and age groups and not using chlorhexidine mouthwash for preventing OM in adults with head and neck cancer undergoing radiotherapy. Considering inadequate and/or conflicting evidence, no guidelines for prevention or treatment of OM were possible for the interventions of dental care, normal saline, sodium bicarbonate, mixed medication mouthwash, chlorhexidine in patients receiving chemotherapy or hematopoietic stem cell transplant, or calcium phosphate.ConclusionsThe evidence for basic oral care interventions supports the use of oral care protocols in patient populations receiving radiation and/or chemotherapy and does not support chlorhexidine for prevention of mucositis in head and neck cancer patients receiving radiotherapy. Additional well-designed research is needed for other interventions to improve the amount and quality of evidence guiding future clinical care.

Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients

PurposeThe aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients.MethodsA systematic review of the available literature was conducted. The body of evidence for the use of each agent, in each setting, was assigned a level of evidence. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible.ResultsA recommendation was developed in favor of patient-controlled analgesia with morphine in hematopoietic stem cell transplant (HSCT) patients. Suggestions were developed in favor of transdermal fentanyl in standard dose chemotherapy and HSCT patients and morphine mouth rinse and doxepin rinse in head and neck radiation therapy (H&N RT) patients. Recommendations were developed against the use of topical antimicrobial agents for the prevention of mucositis. These included recommendations against the use of iseganan for mucositis prevention in HSCT and H&N RT and against the use of antimicrobial lozenges (polymyxin–tobramycin–amphotericin B lozenges/paste and bacitracin–clotrimazole–gentamicin lozenges) for mucositis prevention in H&N RT. Recommendations were developed against the use of the mucosal coating agent sucralfate for the prevention or treatment of chemotherapy-induced or radiation-induced OM. No guidelines were possible for any other agent due to insufficient and/or conflicting evidence.ConclusionAdditional well-designed research is needed on prevention and management approaches for OM.

Emerging evidence on the pathobiology of mucositis

BackgroundConsiderable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely.MethodsPanel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011.ResultsRecent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology.ConclusionThe ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

Urban legends: recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is the most common idiopathic intraoral ulcerative disease in the USA. Aphthae typically occur in apparently healthy individuals, although an association with certain systemic diseases has been reported. Despite the unclear etiopathogenesis, new drug trials are continuously conducted in an attempt to reduce pain and dysfunction. We investigated four controversial topics: (1) Is complex aphthosis a mild form of Behçets disease (BD)? (2) Is periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome a distinct medical entity? (3) Is RAS associated with other systemic diseases [e.g., celiac disease (CD) and B12 deficiency]? (4) Are there any new RAS treatments? Results from extensive literature searches, including a systematic review of RAS trials, suggested the following: (1) Complex aphthosis is not a mild form of BD in North America or Western Europe; (2) Diagnostic criteria for PFAPA have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; (4) Thirty-three controlled trials published in the past 6 years reported some effectiveness, although potential for bias was high.

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

PurposeThis 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.MethodsA 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.ResultsTwenty-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.ConclusionsThe 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.

Anti-inflammatory agents in the management of alimentary mucositis

BackgroundAlimentary mucositis is a significant complication of cancer therapy, with important clinical and economic implications.Materials and methodsIn June 2005, the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology conducted an evidence-based review of the literature on alimentary mucositis. The goal of this literature review was to update previously published guidelines for the management of mucositis.ResultsThis article reports the findings of the subgroup charged with reviewing the literature related to anti-inflammatory interventions. Considerable preclinical and clinical evidence suggests that the use of anti-inflammatory agents may be a promising approach to reduce the severity of mucositis. However, there was not enough evidence to support any new guidelines advocating the use of any specific anti-inflammatory intervention.ConclusionThus, there is a need for well-designed clinical trials evaluating the use of anti-inflammatory agents in the management of mucositis.

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

PurposeThe 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.MethodsA 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.ResultsThirty 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.ConclusionReview 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.