The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies.

Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.

Recent advances in cancer therapy-associated oral mucositis.

Oral mucositis (OM) is a common and debilitating toxicity of cancer treatments - chemotherapy, radiotherapy, hematopoietic cell transplant, or combinations. OM is associated with severe oral pain and has negative impacts on patient function and quality of life. Additionally, OM has accompanying systemic complications that may have critical implications. These local and systemic consequences can alter cancer treatment, and add an economic burden. This review covers the clinical presentation and course of OM, differential diagnosis, clinical and economic impacts, pathogenesis, risk factors, assessment measures, biomarkers and prediction of OM, management, research advances in the development of new drugs and treatments, and big data.

Clinical use of photobiomodulation for the prevention and treatment of oral mucositis: the real-life experience of MASCC/ISOO members.

AIM: To assess clinical use and patient outcome of photobiomodulation (PBM) for oral mucositis (OM) prevention and treatment among specialized practitioners. METHODS: A poll was emailed to the members of the Mucositis Study Group of MASCC/ISOO. The PBM parameters used by the respondents were analyzed using exploratory statistical methods to identify combinations of PBM parameters (patterns) that characterize the variance in the protocols (principal component analysis). RESULTS: Responses were received from 101 MSG members, with 78 providing analyzable data. Most of the responders were dental practitioners or oral medicine specialists. PBM was used by 59% of the responders for OM or targeted therapy stomatitis. Technical parameters varied widely. Most responders used wavelengths ∼650 nm intra-orally. The spot-size and distance from the tissue were the main factors driving the variation. All PBM users noted that PBM relieved pain, either immediately or a delayed effect. High likelihood of pain relief (measured as responder's report of pain relief in 67-100% of patients) was reported by 22% and 19% of PBM users for immediate pain relief and delayed pain relief, respectively. The most common reported barriers to using PBM were financial considerations, time constraints, lack of training or experience and concern about the potential for malignant transformation or increased risk of cancer recurrence. CONCLUSIONS: The use of PBM for OM prevention or treatment is in early phases of adoption in practices, facing some obstacles to implement it. A wide variation in technical parameters was found. Nonetheless, responses indicate that PBM provided pain relief.

Confounding factors in the assessment of oral mucositis in head and neck cancer.

Treatment of locally advanced head and neck carcinoma not amenable for surgical resection or resected with high-risk features is usually based on (chemo-)radiation treatment. Oral mucositis represents one of the main side effects of (chemo-)radiation, with an important impact on quality of life and causing approximately 20% of early interruption of treatment, leading to a suboptimal dose administered. Treatment and prevention of oral mucositis have a central role in the therapeutic pathways of head and neck cancer patients but remains quite challenging. Although extensive research is conducted to identify interventions for the management of mucositis, very few interventions had sufficient evidence to generate an international expert consensus. This may be partially explained by confounding factors that could influence the development and assessment of oral mucositis. Little is known about the confounding factors of oral mucositis, which, if not well balanced in an experimental study, could lead to non-solid results. The current paper aims to review the main oral mucositis confounding factors related to head and neck cancer patients.

Clinicians' experience with topical benzydamine and morphine for the management of oral mucositis: adverse effects and barriers.

INTRODUCTION: Among the evidence-based agents outlined in the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) mucositis guidelines, benzydamine and morphine are advised for the management of oral mucositis (OM) in certain cancer patients. This study is aimed to collect information from a group of highly experienced healthcare professionals in the field of oral mucositis about their clinical experience with these agents. METHODS: A survey questionnaire about the clinical experience with topical benzydamine and morphine to manage oral mucositis and their related adverse effects (AEs) was electronically distributed to the members of the Mucositis Study Group of MASCC/ISOO. RESULTS: Eighty-eight entries were recorded (response rate 25%), and 54 entries submitted complete questionnaires about the drug-related AE (completion rate 65%) and were used for the data analysis. Of the respondents, 44% and 27.7% prescribed benzydamine and morphine to manage their patients' oral mucositis, respectively. Lack of availability in the respondent's country was the common reason for not prescribing benzydamine and morphine (18.9% and 5.4%, respectively); however, a large portion of the respondents indicated that 'another reason' stopped them from prescribing these agents (51.3% and 73%, respectively). AEs to benzydamine or morphine were observed by 25.9% and 12.9% of respondents, respectively, with mild numbness and tingling as the most common drug-related AE for both agents. CONCLUSION: The use of topical benzydamine and morphine for the management of OM varies between countries. While relatively common, the AEs related to these agents are mild. Mitigating the barriers for prescribing them may increase their use.

The impact of the COVID-19 outbreak on supportive care for oral mucositis: current concepts and practice.

The outbreak of coronavirus disease 2019 (COVID-19) markedly affected the way healthcare professionals approach patients with cancer worldwide, not only in terms of therapeutic decision-making but also in terms of supportive care. With the rapid appearance of signs and symptoms and the need of close re-assessment, standard management of oral mucositis has been challenged by physical distancing and limited resources due to the global crisis. Building on the clinical experience developed during the acute phase by members of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), the implications of COVID-19 on the prevention, assessment, and treatment of mucositis are critically reported. Inspired by the restructuring of supportive care measures in response to the pandemic, suggestions for new models of approaching acute side effects are also discussed.

Oral white lesion in patients post-hematopoietic stem cell transplantation: a case series demonstrating the diagnostic dilemma.

The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.

Oral verruciform xanthoma in chronic graft-versus-host disease patients.

BACKGROUND: Verruciform xanthoma (VX) is an uncommon benign epithelial lesion which mainly appears in inflamed oral epithelium. In this study, our aim was to present new cases of oral VX (OVX) in chronic graft-versus-host disease (cGVHD) and review the literature. METHODS: We conducted a retrospective chart review of cGVHD patients (2012-2019) to reveal cases of OVX. The demographics, medical background, clinical presentation, treatment provided, and follow-up were obtained. Additionally, Medline was searched using the terms "graft-versus-host disease," "verruciform xanthoma," and "oral." Of the articles, the above-mentioned demographic and clinical features were retrieved. RESULTS: The patient pool included 133 oral cGVHD patients. Three cGVHD patients (males, aged 15-49 years, post-hematologic malignancy) were diagnosed with OVX. All patients had oral mucosal lichenoid lesions, but not in close proximity to the VX lesion. Medline searches revealed 9 cases of OVX in cGVHD patients reported in the literature. Eleven of the 12 patients had oral mucosal lichenoid lesions. Four patients had multiple OVX lesions. All lesions were asymptomatic. Six patients had lesions in the masticatory mucosa (hard palate and gingiva) and 4 patients had lesions in the buccal mucosa. CONCLUSIONS: To the best of our knowledge, this is the largest published OVX in cGVHD series, including 12 patients. It appears that despite the higher prevalence in cGVHD patients relative to the general population, OVXs do not necessarily develop in sites with lichenoid lesions. It is advised that clinicians be familiar with the clinical and histological features in order to consider OVX in the differential diagnosis of oral lesions in cGVHD patients.

MASCC/ISOO clinical practice guidelines for the management of mucositis: sub-analysis of current interventions for the management of oral mucositis in pediatric cancer patients.

OBJECTIVE: The aim of this sub-analysis was to highlight the MASCC/ISOO clinical practice guidelines for the management of oral mucositis (OM) in pediatric patients and to present unique considerations in this patient population. METHODS: This sub-analysis of the pediatric patient population is based on the systematic review conducted by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISSO) published in 2019/2020. Studies were scored and assigned a level of evidence based on previously published criteria. Data regarding adverse effects and compliance was collected from the original publications. RESULTS: A total of 45 papers were included and assessed in this sub-analysis, including 21 randomized controlled trials (RCTs). Chewing gum was demonstrated to be not effective in preventing OM in pediatric cancer patients in 2 RCTs. The efficacy of all other interventions could not be determined based on the available literature. CONCLUSION: There is limited or conflicting evidence about interventions for the management of OM in pediatric cancer patients, except for chewing gum which was ineffective for prevention. Therefore, currently, data from adult studies may need to be extrapolated for the management of pediatric patients. Honey and photobiomodulation therapy in this patient population had encouraging potential. Implementation of a basic oral care protocol is advised amid lack of high level of evidence studies.

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

BACKGROUND: Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. 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 the management of mucositis. METHODS: The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in patients who have cancer.

Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To update the clinical practice guidelines for the use of growth factors and cytokines for the prevention and/or treatment of oral mucositis (OM). 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 (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: recommendation, suggestion, and no guideline possible. RESULTS: A total of 15 new papers were identified within the scope of this section and were merged with 51 papers that were reviewed in the previous guidelines update. Of these, 14, 5, 13, 2, and 1 were randomized controlled trials about KGF-1, G-CSF, GM-CSF, EGF, and erythropoietin, respectively. For the remaining agents there were no new RCTs. The previous recommendation for intravenous KGF-1 in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy and TBI-based regimens is confirmed. The previous suggestion against the use of topical GM-CSF for the prevention of OM in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation remains unchanged. CONCLUSIONS: Of the growth factors and cytokines studied for the management of OM, the evidence supports a recommendation in favor of KGF-1 and a suggestion against GM-CSF in certain clinical settings.

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

PURPOSE: To update the clinical practice guidelines for the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and/or treatment of oral mucositis (OM). 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 (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 9 new papers were identified within the scope of this section, adding to the 62 papers reviewed in this section previously. A new Suggestion was made for topical 0.2% morphine for the treatment of OM-associated pain in head and neck (H&N) cancer patients treated with RT-CT (modification of previous guideline). A previous Recommendation against the use of sucralfate-combined systemic and topical formulation in the prevention of OM in solid cancer treatment with CT was changed from Recommendation Against to No Guideline Possible. Suggestion for doxepin and fentanyl for the treatment of mucositis-associated pain in H&N cancer patients was changed to No Guideline Possible. CONCLUSIONS: Of the agents studied for the management of OM in this paper, the evidence supports a Suggestion in favor of topical morphine 0.2% in H&N cancer patients treated with RT-CT for the treatment of OM-associated pain.

Systematic review of oral cryotherapy for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To update the 2013 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines on oral cryotherapy for the management of oral mucositis (OM) caused by cancer therapies. METHODS: A systematic review was conducted by the Mucositis Study Group of MASCC/ISOO. The evidence for each intervention for specific cancer treatment modalities was assigned a level of evidence (LoE). The findings were added to the database used to develop the 2013 MASCC/ISOO clinical practice guidelines. Based on the LoE, the guidelines were set as: recommendation, suggestion, or no guideline possible. RESULTS: A total of 114 papers were identified: 44 from PubMed and 70 from Web of Science. After abstract triage and merging with the 2013 database, 36 papers were reviewed. The LoE for prevention of OM with oral cryotherapy in patients undergoing autologous hematopoietic stem cell transplant using high-dose melphalan conditioning protocols was upgraded, and the guideline changed to recommendation. Additionally, the recommendation for prevention of OM with oral cryotherapy in patients receiving bolus 5-fluorouracil for the treatment of solid tumors was confirmed. No guidelines were possible for other clinical settings. CONCLUSIONS: The evidence supports recommendations for the use of oral cryotherapy for the prevention of OM for either (i) patients undergoing autologous hematopoietic stem cell transplant with high-dose melphalan conditioning protocols or (ii) patients receiving bolus 5-fluorouracil chemotherapy.

Systematic review of natural and miscellaneous agents, for the management of oral mucositis in cancer patients and clinical practice guidelines - part 2: honey, herbal compounds, saliva stimulants, probiotics, and miscellaneous agents.

OBJECTIVE: To update the clinical practice guidelines for the management of oral mucositis (OM) that were developed by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). This part focuses on honey, herbal compounds, saliva stimulants, probiotics, and miscellaneous agents. METHODS: A systematic review was conducted by the Mucositis Study Group of MASCC/ISOO. The body of evidence for each intervention, in each clinical setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, one of the following guidelines were determined: Recommendation, Suggestion, No Guideline Possible. RESULTS: A total of 78 papers were identified within the scope of this section, of which 49 were included in this review and merged with nine publications that were reported in the previous guidelines update. A new Suggestion was made for honey (combined topical and systemic delivery) for the prevention of OM in head and neck cancer patients receiving radiotherapy with or without chemotherapy. A new Suggestion clarified that chewing gum is not effective for the prevention of OM in pediatric patients with hematological or solid cancer treated with chemotherapy. No guideline was possible for other interventions. CONCLUSIONS: Numerous natural products and herbal remedies were studied for the management of OM. Of the agents reviewed in this systematic review, a guideline in favor was made for honey (combined topical and systemic), while a guideline against was made for chewing gum. Additional research is warranted to clarify the potential of other interventions.

Oral mucosal changes associated with primary diseases in other body systems.

Systemic diseases may manifest in the oral cavity. This chapter reviews the oral mucosal pathology in blood diseases, gastrohepatic diseases, kidney diseases, immunologic and connective tissue diseases, endocrine diseases, pulmonary diseases, nutritional deficiencies, dermatologic diseases, as well as cancer-associated oral mucosal conditions. The oral mucosa is one of the most commonly affected tissues and may present with unique clinical appearances. Oral mucosal involvement may be the first presentation of the systemic disease or reflect activity or progression of the primary condition. Therefore, it is of importance to be familiar with oral mucosal manifestations of these systemic diseases.

Development of the MASCC/ISOO clinical practice guidelines for mucositis: an overview of the methods.

New studies and literature continue to emerge on the management of mucositis secondary to cancer therapy. The evidence-based clinical practice guidelines for mucositis were first published in 2004 and updated in 2007 and 2014 by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The existing 2014 guidelines for mucositis are being updated in line with new literature to inform clinical practice. This paper describes the materials and methods employed for the comprehensive updates to the guidelines for managing mucositis.

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review.

INTRODUCTION: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing. OBJECTIVE: To review characteristics of ONJ in cancer patients receiving non-antiresorptives. METHODS: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. RESULTS: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications. CONCLUSIONS: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To systematically review the literature and update the evidence-based clinical practice guidelines for the use of photobiomodulation (PBM), such as laser and other light therapies, for the prevention and/or treatment of oral mucositis (OM). 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) using PubMed and Web of Science. We followed the MASCC methods for systematic review and guidelines development. The rigorously evaluated evidence for each intervention, in each cancer treatment setting, was assigned a level-of-evidence (LoE). Based on the LoE, one of the following guidelines was determined: Recommendation, Suggestion, or No Guideline Possible. RESULTS: Recommendations are made for the prevention of OM and related pain with PBM therapy in cancer patients treated with one of the following modalities: hematopoietic stem cell transplantation, head and neck (H&N) radiotherapy (without chemotherapy), and H&N radiotherapy with chemotherapy. For each of these modalities, we recommend 1-2 clinically effective protocols; the clinician should adhere to all parameters of the protocol selected. Due to inadequate evidence, currently, No Guideline Possible for treatment of established OM or for management of chemotherapy-related OM. The reported clinical settings were extremely variable, limiting data integration. CONCLUSIONS: The evidence supports the use of specific settings of PBM therapy for the prevention of OM in specific patient populations. Under these circumstances, PBM is recommended for the prevention of OM. The guidelines are subject to continuous update based on new published data.

Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: The aim of this systematic review was to update the clinical practice guidelines for the use of anti-inflammatory agents in the prevention and/or treatment of oral mucositis. METHODS: A systematic review was conducted by the Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC/ISOO) subcommittee on mucositis guideline update. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the clinical practice guidelines published in 2014. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guidelines. RESULTS: A total of 11 new papers across five interventions were examined. The recommendation for the use of benzydamine mouthwash for the prevention of radiotherapy-induced mucositis remained unchanged. New suggestion for the use of the same for prevention of mucositis associated with chemoradiotherapy was made. No guideline was possible for any other anti-inflammatory agents due to inadequate and/or conflicting evidence. CONCLUSIONS: Of the anti-inflammatory agents studied for oral mucositis, the evidence supports the use of benzydamine mouthwash in the specific populations listed above. Additional well-designed research is needed on other (class of agents) interventions and in other cancer treatment settings.

Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: The aim of this study was to update the clinical practice guidelines for the use of basic oral care (BOC) interventions for the prevention and/or treatment of oral mucositis (OM). 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. The findings were added to the database used to develop the 2013 MASCC/ISOO clinical practice guidelines. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. RESULTS: A total of 17 new papers across six interventions were examined and merged with a previous database. Based on the literature, the following guidelines were possible. The panel suggests that the implementation of multi-agent combination oral care protocols is beneficial for the prevention of OM during chemotherapy, head and neck (H&N) radiation therapy (RT), and hematopoietic stem cell transplantation (Level of Evidence III). The panel suggests that chlorhexidine not be used to prevent OM in patients undergoing H&N RT (Level of Evidence III). No guideline was possible for professional oral care, patient education, saline, and sodium bicarbonate, and expert opinion complemented these guidelines. CONCLUSIONS: The evidence supports the use of multi-agent combination oral care protocols in the specific populations listed above. Additional well-designed research is needed on the other BOC interventions prior to guideline formulation.