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Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy

Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy Abstract Oral mucositis is a common side-effect associated with conventional cancer therapy and has also recently been reported in association with newly emerging cancer therapies. It is characterized as an inflammation of the oral mucous membranes accompanied by many complex mucosal and submucosal changes. Ulcerative oral mucositis can cause significant oral pain, impair nutritional intake, lead to local or systemic infection, and cause significant economic cost. In addition, it may necessitate interruptions in cancer therapy, thus adversely affecting patient prognosis. This review presents the current understanding of the pathogenesis of mucositis and discusses evidence-based clinical management strategies for oral mucositis. In addition, key research questions for future investigation are identified, followed by a discussion of strategies to promote development and funding of the needed research. Mucositis is a common side-effect associated with cancer therapy (chemotherapy and/or radiation therapy) and is characterized as an inflammation of the oral and gastrointestinal mucous membranes accompanied by many complex mucosal and submucosal changes (1–3). Ulcerative mucositis (Figure 1) can have a major impact on delivery of cancer therapy and may cause delay or cessation in the delivery of cancer therapy, which can affect prognosis (4). For example, in chemotherapy patients, a reduction in the dose of the next cycle of chemotherapy was twice as common after cycles with mucositis as it was after cycles without mucositis (23% vs 11%; P < .0001) (5). Additional hospital charges of $42 749 per hematopoietic stem cell transplant (HSCT) patient with oral ulcers have been documented (6). For non-HSCT patients by comparison, the incremental cost of grade 1–2 mucositis is $2725 and can exceed $5000 for grade 3–4 mucositis (5). Figure 1. View largeDownload slide Ulcerative oral mucositis on the buccal mucosa (inside of the cheek) of a patient who was receiving head and neck radiation therapy with concurrent chemotherapy. Figure courtesy of Dr Rajesh V. Lalla. Figure 1. View largeDownload slide Ulcerative oral mucositis on the buccal mucosa (inside of the cheek) of a patient who was receiving head and neck radiation therapy with concurrent chemotherapy. Figure courtesy of Dr Rajesh V. Lalla. The incidence and severity of oral mucositis is dependent on the cancer treatment regimen. For chemotherapy, relevant factors include the chemotherapy drug used, dose, and duration. For radiation therapy, relevant factors include total radiation dose, fractionation schedule, volume of mucosa irradiated, and use of concurrent chemotherapy (7,8). Other proposed risk factors for oral mucositis include low body mass, prolonged neutrophil recovery, and young age (9,10). Mucositis is commonly associated with oral and/or oropharyngeal mucosal pain and thus has a major impact on quality of life (11). Additionally, ulcerations associated with mucositis can become secondarily infected and significantly increase the risk of poly-microbial bacteremia, especially with streptococcal species (12,13). The impact of emerging cancer therapies on oral mucositis incidence, severity, and response to management is under active investigation. Some molecularly targeted agents (such as mTOR inhibitors) are associated with oral ulceration that is quite different from oral mucositis due to conventional chemotherapy or radiation therapy (14–17). Additionally, newer delivery systems for radiation therapy may also affect the incidence and severity of mucositis. This review presents the current understanding of the pathogenesis of oral mucositis secondary to conventional chemotherapy or radiation therapy and discusses evidence-based clinical management strategies. In addition, key research questions for future investigation are identified, followed by a discussion of strategies to promote development and funding of the needed research. Pathobiology: Current Paradigm and New Frontiers The pathobiological basis for cancer regimen-related mucosal toxicity has been the subject of intense study over the past 15 years (8). The historical paradigm that wholly attributed mucositis to direct DNA injury of rapidly dividing basal epithelial “stem” cells has been revised to reflect a broad range of investigational findings that have demonstrated that regimen-induced epithelial toxicities are a consequence of a complex sequence of interacting physical and biological events that involve the cells and tissues of the submucosa and inter-cellular and tissue cross-talk (18). Simultaneously, discoveries detailing pathways and cellular function have continuously contributed to facilitating more granularity to the overall process. The current model of mucositis pathogenesis is comprised of five broad stages (19) (Figure 2). Although compartmentalization of mucositis development into descriptive segments is a convenient way to describe a very dynamic process, the in vivo reality of the molecular, cellular, and tissue events that occur is that the stages overlap and are inter-related rather than compartmentalized and linear. From a clinical perspective, many of the biological events that lead to mucositis are aggressively percolating whereas phenotypic changes of injury are completely absent. Figure 2. View largeDownload slide Five-stage model of the pathobiology of mucositis. Figure courtesy of Dr Stephen T. Sonis. DNA = Deoxyribonucleic acid; IL = Interleukin; NFκB = Nuclear Factor kappa B; ROS = Reactive oxygen species; TNF = Tumor Necrosis Factor. Figure 2. View largeDownload slide Five-stage model of the pathobiology of mucositis. Figure courtesy of Dr Stephen T. Sonis. DNA = Deoxyribonucleic acid; IL = Interleukin; NFκB = Nuclear Factor kappa B; ROS = Reactive oxygen species; TNF = Tumor Necrosis Factor. The initiation phase is characterized by three principal biological events. Direct physical DNA injury results in strand breaks causing clonogenic death of basal epithelial cells. Simultaneously, chemotherapy and radiation indiscriminately trigger a series of biological events in subepithelial tissue and cells (endothelium, fibroblasts, macrophages) in response to oxidative stress and the release of reactive oxygen species and activation of the innate immune response (20) as injured cells release endogenous damage-associated pattern molecules (Chemotherapy and Radiation-Associated Molecular Pattern molecules, or CRAMPs), which then bind to pathogen recognition receptors (21). During the primary damage response phase, chemotherapy, radiation, CRAMPs, the innate immune response, and reactive oxygen species initiate a series of interacting biological events. Transduction pathways prompt the activation of a number of transcription factors, such as Nuclear Factor kappa B (NF-κB), Wnt, p53, p38, and their associated canonical pathways (22). Increasingly, the NF-κB pathway has been identified as playing a pivotal role in facilitating the development of mucositis (23–26) as its activation is associated with apoptosis of normal cells. Chemotherapy, radiation, CRAMPS, and reactive oxygen species can directly or indirectly activate NF-κB. Up to 200 genes may be expressed as a consequence of NF-κB activation. Many of these genes are associated with production of cytokines and cytokine modulators, stress responders (ie, COX-2, inducible NO-synthase, superoxide dismutase), and cell adhesion molecules, many of which have been associated with mucositis (25,27). Because of its key function, it is not surprising that NF-κB also provides an attractive interventional target (28). Radiation and chemotherapy also affect other pathways that may ultimately lead to cell death of basal epithelial stem cells. Among these are the ceramide pathway (29), the toll-like receptor signaling pathway (30), and a number of the kinase pathways (31,32). In addition, connective tissue fibrinolysis initiated as a consequence of cytotoxic therapy stimulates macrophages to produce tissue-damaging matrix metalloproteinases (33). It also seems likely that activation of the NLRP3 inflammasome occurs at the same time. Although not comprehensively studied yet, earlier findings have shown associations between inflammasomes and chemotherapy-induced injury (34). Other studies support this assumption (31,35,36). The early biological events that initiate mucositis precede clinically detectable changes. The consequence of epithelial basal cell damage (the target of biologically medicated injury) is ultimately a loss of renewable epithelium. Although changes in pathway-associated gene expression occur within seconds of radiation or chemotherapy administration, there is a multiple day lag between the damage that is occurring at the molecular and cellular level and its clinical manifestations. In the case of fractionated radiation, the precipitating events that lead to extensive damage are incrementally induced with each radiation exposure. Many of the molecules induced by the primary response have the ability to positively or negatively feedback and alter the local tissue response. This can lead to signal amplification. For example, TNF may positively feedback on NF-κB to amplify its response, and initiate mitogen-activated protein kinase signaling, leading to activation of c-Jun N-terminal Kinase signaling. Although the autonomy of canonical pathways and the genes responsible for their regulation frequently characterize many reports, cross-talk and interaction are the in vivo reality. A crescendo of biological signals causes substantial impairment in the ability of the epithelium to heal, culminating in development of the ulcerative phase of mucositis; this phase is typically clinically the most significant. Despite the failure of anti-microbial treatment strategies to effectively mitigate mucositis development (37,38), a role for the oral microbiome to affect the course of mucositis has become an area of increasing interest (39). Quantitative and qualitative microbiological studies have shown that resident mucosal bacteria increase dramatically (300-fold) during this ulcerative phase, with organisms secondarily colonizing the lesions. These organisms are not simply dormant passengers. Rather, they contribute to the longevity and severity of mucositis by producing cell wall products that penetrate into the submucosa to stimulate resident inflammatory cells, including macrophages, to secrete pro-inflammatory cytokines and other mediators of tissue injury. Furthermore, it is not inconceivable that with regimen-induced breakdown of epithelial tight junctions (40), bacterial cell wall products might penetrate and functionally accelerate both innate immune and inflammasome activities to enhance mucositis development and prolong its course. The final phase of healing usually occurs spontaneously, approximately 2–4 weeks following cessation of the cancer therapy. In response to signaling, which originates in the extracellular matrix of submucosa, the epithelium at the ulcer margins migrates across the lesion. In addition to controlling migration, the extracellular matrix also affects epithelial differentiation and proliferation (41,42). Although much has been learned about the biological events that lead to mucositis, we are a long way from fully understanding how the component events contribute to the process of mucosal injury. But advances to date have opened doors leading to the discovery and on-going clinical development of mechanistically targeted interventions. Equally important has been the ability to leverage the pathobiological elements to clinically applicable biomarkers and predictors of mucositis risk. Patients vary dramatically in individual risk of developing mucositis (the same is true for other regimen-related toxicities). It has become clear that these differences are predominantly genetically driven (43) and biologically based (44), and precancer treatment identification of relevant single polynucleotide can be used to accurately predict patients at risk (45,46). Clinical Management Clinical management of oral mucositis is largely palliative, although several preventive and therapeutic strategies have been studied (47–50). Evidence-based clinical practice guidelines for the management of mucositis have been published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) (51). These guidelines include “recommendations” based on higher levels of evidence and “suggestions” based on lower levels of evidence. They are referred to where applicable in the summary of current clinical approaches for management of oral mucositis presented below. Pain Control Pain due to mucositis negatively affects dietary intake, oral hygiene, and quality of life. Based on expert opinion, mouth rinses containing an anesthetic, such as 2% viscous lidocaine, can provide short-term relief; however, no MASCC/ISOO guideline was possible related to the use of the so called “Magic” or “Miracle” mouthwashes (52). The MASCC/ISOO guidelines suggest that 0.2% morphine mouth rinse and 0.5% doxepin mouth rinse may be effective for pain due to oral mucositis. Topical agents that adhere to the oral mucosa and form a protective coating are also available. Of these, sucralfate is the most widely studied. The MASCC/ISOO guidelines recommend against the use of sucralfate for the prevention or treatment of oral mucositis in patients receiving chemotherapy and also in radiation-induced oral mucositis due to lack of efficacy. Most patients with severe mucositis also require systemic analgesics, including opioids, for satisfactory pain control. The MASCC/ISOO guidelines recommend the use of patient-controlled analgesia with morphine in patients undergoing HSCT and suggest the use of transdermal fentanyl in patients receiving conventional or high-dose chemotherapy (53). It is worth noting that traditional opioids are often less effective than expected for controlling mucositis pain, and there is conflicting evidence for gabapentin. Nutritional Support Nutritional intake can be affected by the mucositis-driven pain associated with eating as well as taste and salivary changes secondary to chemotherapy and/or radiation therapy (54,55). Dietary consultation and weight monitoring is important, especially in patients with severe mucositis. Use of liquid dietary supplements, a gastrostomy tube (for radiation therapy), or total parenteral nutrition (for high-dose chemotherapy regimens) may be warranted. Oral Hygiene Maintenance of good oral hygiene can help reduce the severity of oral mucositis (56–59). In addition, effective oral hygiene practices may reduce the risk of systemic sepsis from oral pathogens. The MASCC/ISOO guidelines suggest the use of a standardized oral care protocol for the prevention of oral mucositis across all cancer treatment modalities (52). Although there are conflicting data on the impact of oral hygiene on oral mucositis, the majority of studies reported a positive effect, supporting a suggestion rather than a stronger recommendation. Cryotherapy Cryotherapy can reduce the severity of oral mucositis in patients receiving bolus doses of chemotherapeutic agents (60–63). The placement of ice chips in the mouth, during the administration of bolus chemotherapy, is thought to reduce delivery of the drug to the oral mucosa by causing local vasoconstriction. The MASCC/ISOO guidelines recommend the use of cryotherapy to reduce oral mucositis in patients receiving bolus doses of 5-fluorouracil and suggest its use in patients receiving high-dose melphalan for HSCT (64). In theory, cryotherapy could be useful to reduce oral mucositis caused by any chemotherapy drug with a short half-life that is administered during a short period of time. Laser and Other Light Therapy Low-level laser therapy can reduce the severity of chemotherapy and radiation-induced oral mucositis (65–69). The mechanism may involve anti-inflammatory and pro-healing effects (70,71). The MASCC/ISOO guidelines recommend the use of low-level laser therapy for the prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT and suggest its use in patients receiving head and neck radiation therapy without concomitant chemotherapy (72). The long-term safety of low-level laser therapy and potential impact on tumor response is still under study. Growth Factors Intravenous recombinant human keratinocyte growth factor-1 (palifermin, Swedish Orphan Biovitrum) significantly reduced incidence of World Health Organization grade 3 and 4 oral mucositis in patients with hematologic malignancies receiving high-dose chemotherapy and total body irradiation for autologous hematopoetic cell transplantation (73). Based on this evidence, the MASCC/ISOO guidelines recommend the use of this growth factor in this specific population (74). Palifermin has been approved by the US Food and Drug Administration (FDA) for patients with hematological malignancies receiving myelotoxic therapies requiring hematopoietic cell support. Two prospective randomized trials showed efficacy in head and neck radiation therapy, but long-term safety data are not available, so this approach remains experimental in that setting (75,76). The safety of epithelial growth factors has not been established in patients with nonhematologic, epithelial malignancies. Anti-Microbial Agents Secondary infection of oral mucositis ulcerations is thought to worsen its severity. Based on this rationale, several topical antimicrobial agents have been examined for oral mucositis, but the results have been disappointing. The MASCC/ISOO guidelines recommend against the routine use of antimicrobial lozenges, chlorhexidine mouth rinse, and iseganan mouth rinse for oral mucositis due to lack of consistent evidence of efficacy (52,53). Anti-Inflammatory Agents Benzydamine hydrochloride mouth rinse reduced the severity of oral mucositis in head and neck cancer patients undergoing radiation therapy of cumulative doses up to 50 Gy, without concomitant chemotherapy (77). Based on this evidence and previous studies, the MASCC/ISOO guidelines recommend use of this agent in patients receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy. However, this agent has not received approval for this use from the US FDA. Furthermore, most head and neck cancer patients receive greater than 50 Gy radiation therapy, often with concomitant chemotherapy. The MASCC/ISOO guidelines also suggest against the use of misoprostol mouth rinse for prevention of oral mucositis in patients receiving head and neck radiation therapy, based on data indicating a lack of efficacy (78). Antioxidants Amifostine (Ethylol, MedImmune, Gaithersburg, MD) is postulated to act as a scavenger of harmful reactive oxygen species (79). Despite reviewing 30 studies on the use of amifostine for oral mucositis in various settings, a MASCC/ISOO guideline could not be established regarding the use of this agent in oral mucositis due to conflicting evidence (80). However, the use of intravenous amifostine was recommended for the prevention of radiation proctitis and suggested for the prevention of esophagitis in patients receiving chemo-radiation for non-small cell lung cancer (81). Amifostine is FDA approved to reduce the incidence of moderate to severe xerostomia in patients receiving postoperative radiation therapy for head and neck cancer where the radiation port includes a substantial portion of the parotid glands. Key Research Questions Despite important advances over the past 15 years relative to mucositis etiopathogenesis, there is only one drug (palifermin) that is approved by the United States FDA for mucositis prevention. Thus, additional research is needed to better understand the molecular pathogenesis of mucosal injury in cancer as well its translation to clinical practice. The following are the key research questions. Definition of Risk Factors for Oral Mucositis The current understanding of risk factors is limited, and the literature is often conflicting. Recent literature has suggested a systems medicine approach to studying risk, involving various areas such as genomics, metabolomics, microbiomics, etc. Interaction Between Tumor, Host, and Anti-Cancer Therapy Much of the toxicity can be ascribed to the type, regimen, and mechanisms of action of the cancer therapy. However, there is emerging evidence that the tumor-host interactions are also important. Modification of Cancer Therapy to Reduce Mucositis Severity Newer cancer therapies such as proton therapy and molecularly targeted agents may be associated with lower risk of mucositis. Careful treatment planning (such as by reducing the volume of mucosa irradiated or the dose of chemotherapy agent) can in some cases reduce the severity of oral mucositis while maintaining efficacy of anti-cancer treatment. Amelioration of Oral Mucositis Without Tumor Protection Many of the pathways involved in the pathogenesis of oral mucositis are comparable to those involved in anti-tumor activity of the drug (mechanism of action = mechanism of toxicity). The concern thus becomes that preventing or downregulating oral mucositis may also lead to tumor protection. The identification and targeting of key network pathways unique to oral mucositis are therefore desirable. Linkage Between Oral Mucositis From Different Treatment Modalities (Chemotherapy, Radiation Therapy, and Targeted Anti-Cancer Therapies) Combination therapy is increasingly common and complicates the modelling. Studies of combined treatment toxicity are limited and should be pursued. With the increased use of combination protocols involving multiple mechanisms, the historical reductionist approach to assessing toxicity of individual agents may not be adequate. Molecular Pathways Associated With Toxicity Clustering Identification of a key pathway that represents the critical link between different toxicities within a cluster could lead to a targeted intervention for amelioration of the collective toxicities within that cluster. Chronic Oral Mucositis and How It Differs From Acute Oral Mucositis A small subset of cancer patients develops chronic oral ulceration; there is, however, limited scientific modelling available at present for this type of oral mucosal injury caused by cancer therapy. Additional research could lead to new insights into both the chronic forms of this lesion as well as the acute component. Strategies to Promote Development and Funding for New Research Limited progress has been made since the National Institutes of Health (NIH)-funded mucosal injury research conference (2000) (82) as well as the NIH-funded conference on emerging oral complications of cancer therapy (2009). It is evident that traditional research strategies (eg, in-series progression of preclinical to clinical trials, silo-based inquiry, and single-source funding) have not kept pace with other areas of investigation. Furthermore, mucosal injury research has lagged behind that of cancer therapeutics, such that knowledge of oral complications of emerging and new cancer therapies is minimal. To progress in understanding of mechanisms of the complex and growing problem of oral complications of cancer treatment, new approaches must be considered to promote and support research in this area. The field can benefit from several productive approaches that have demonstrated success in other research areas (83). Biological as well as technological strategies exist for development of new research approaches and funding opportunities. Biological Strategies Several potential research avenues related to mucosal immunity and susceptibility have not been exploited to date. For example, if an underlying mechanism for mucosal injury is related to immune modulation, then exploring mechanisms and risk factors under investigation for other complex conditions involving mucosal injury such as graft vs host disease, Behcet’s disease, and recurrent aphthous stomatitis could be informative. If injury and potential repair are related to the balance of inflammation, injury, and regeneration, then mucosal injury research can benefit from the advances in stem cell research. Recent focus on the microbiome could also be extended to the more relevant construct of the mucosal-microbiome interaction. Another strategy to leverage the study of the pathophysiology of mucositis related to new cancer treatments is to capitalize on planned oncology studies to investigate in parallel the related condition of interest, such as mucosal toxicity. For example, examining esophageal and oral mucosa and GI mucosa response should be incorporated into existing preclinical safety studies of cancer treatments as well as into early phase I and II human studies. Adaptation of new technologies in use for other conditions should be evaluated, such as innovations in therapeutic delivery for dermatologic and eye conditions: laser therapy, nano-delivery systems, programmed stem cells, and related approaches. Technological Strategies In addition to applying knowledge generated from other areas of scientific inquiry, mucosal researchers can adapt new methodologic approaches. The study of many complex conditions now involves combining strategies to reflect the summed contribution to the condition under study. As discussed in the previous section, risk of mucositis is multifactorial. Its manifestation and perception of such is influenced by the underlying cancer being treated, mechanisms of the treatment regimen(s), and interaction with host immunity and comorbidities (84). These components are all likely modified further by genetic and environmental interactions as well as by the variability in health and health-care standards of both patients and care-givers. Understanding variability in treatment regimens superimposed on the variability of host and the cancer itself necessitates clinical research. There are new methodologic approaches derived from complex data analysis techniques that can be applied to evaluating the intersecting effects of symptom biology, such as cluster analyses that may include impact of symptoms on the condition and manifestation and interaction of toxicities on the overall condition. Dissection of symptoms to underlying biology using genome-wide approaches can yield information on polymorphisms that may affect innate risk and response as well as adaptive variability in gene expression resulting in an individually dynamic pathobiology. Although genomic (genotyping, gene expression, and epigenetic) approaches will be useful for dissecting effects and interactions of the tumor disease, treatment, and host susceptibility factors, currently these studies must involve a large number of subjects. Because methodology improves power with smaller sample sizes, these studies may be linked with those conducted to examine primary mechanisms and toxicities. Complementary studies of a strong predictor in preclinical studies can also be followed-up in phase I/II studies as exploratory analyses. Challenges and Opportunities for Mucositis Research These collective strategies may contribute to identification of potential preventive and therapeutic options. Most importantly, these approaches demand integrated research and interactions between disciplines to form new research teams with complementary expertise to capitalize on opportunities created by major research endeavors such as the human genome project and its “–omic” outgrowths, stem cell research, and powerful new methodologic approaches to complex data analysis (85). Innovation is imperative, not only for discovery, but also for garnering research funding. First and foremost, mucosal injury research must be re-envisioned in the context of current disease epidemiology as well as research assets. Mucosal injury research has suffered from a lack of public and private funding due to the misperception that it relates to orphan diseases that have little public health impact or market share. This view does not incorporate the key fact that an aging population is increasingly being treated for cancer, with therapy-limiting mucosal toxicity affecting a growing proportion of the population. Significantly, advances in research methodologies, new technologies, and creative partnering relationships enhance the feasibility of these proposed strategies through efficiency in conduct as well as economy. Joint funding of proposals with National Cancer Institute, National Institute of Dental and Craniofacial Research, and other institutes with overlapping missions has been considered an approach to leveraging funds. Other examples of recent facilitation of larger scientific endeavors include a growing NIH investment in clinical research networks such as Patient Based Research Networks; the linking of Clinical and Translational Study Award-supported academic sites; and complementary electronic resources, such as Clinical Research Networks. The latter is designed to promote and expand clinical research networks that can rapidly conduct high-quality clinical studies that address multiple research questions across multiple research sites. Collaboration across sites through these mechanisms makes it feasible to increase sample size and generalizability, facilitates standardized data collection methods, and has the potential to promote scientific exchange across programs and study sites. Clinical research networks can be further developed into data repositories to permit modeling of variable interactions such as pharmacogenomics and pharmacoproteomics, gene expression or proteomic changes in human specimens, and patient-reported outcomes, linked to clinical phenotypes. This will ultimately move the field towards population-based rather than clinic-specific research while encouraging standardization of data measures. Such networks are exemplified by NIH initiatives using public-private partnering mechanisms to provide publicly available resources such as PhenX (the Phenotyping and Exposures toolkit: https://www.phenxtoolkit.org) and PROMIS (Patient Reported Outcomes Measurement Information System: http://www.nihpromis.org). An important recent source of funding for oral mucositis research has been industry. There are a number of mechanistically based agents in clinical trials for oral mucositis, mostly in the head and neck cancer population. This increased activity speaks to the market need and provides optimism that effective interventions might be on the way. Lastly, there is scant evidence for many of the available approaches used for prevention, palliation, and therapy (86). Of the studies conducted, many exhibit design flaws such as lack of power or comparison groups and use of a validated and standardized set of instruments for data collection, which, among others, limit the interpretation and application of the results. Thus, rigorous clinical trials of approaches currently in use, as well as those being newly developed, should be conducted to take advantage of the variety of approaches discussed in this section. Taken together, these approaches have the potential to maximize scientific efficiency and cost-effectiveness of the research investment and thus improve the scope and impact of mucosal injury research. Key Points  1. Oral mucositis is a common side-effect of chemotherapy and or/radiation therapy, resulting in pain, difficulty swallowing, and interruptions of cancer therapy. 2. The pathobiology of mucositis is complex and multifactorial. Our understanding of the contributions of the various components to mucosal injury is still incomplete. 3. The clinical management of oral mucositis is largely palliative, although several preventive and therapeutic strategies have been studied. 4. A number of key research areas provide fertile ground for future studies. 5. New approaches must be considered to promote and support research in this area. Notes Affiliations of authors: Section of Oral Medicine, University of Connecticut Health, Farmington, CT (RVL); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Foundational Sciences, East Carolina University School of Dental Medicine, Greenville, NC (SMG); Division of Oral Medicine, Dana-Farber Cancer Institute, Boston, MA (STS); Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX (DIR); Faculty of Health Sciences, University of Adelaide, Adelaide, Australia (DMK). None of the authors reported any conflicts related to this manuscript. The following disclosures were made for financial activities outside this written work: M. Brennan is a consultant for AFYX and Medimmune. D. Keefe is a consultant for Helsinn Healthcare, Mundipharma, Zealand Pharma, and Entrinsic Health Solutions and has stock options for Entrinsic Health Solutions. R. Lalla is a consultant for Alira Health, Biotechspert, Colgate Oral Pharmaceuticals, Eagle Pharma, Galera Therapeutics, Ingalfarma, Leerink, Metlife, Monopar Therapeutics, and SAI Med and has stock in Logic Biosciences. D. Rosenthal is a consultant for Merck. For support see Funding Acknowledgement section of Monograph. References 1 Sonis ST. Oral mucositis . Anticancer Drugs . 2011 ; 22 7 : 607 – 612 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Lalla RV , Peterson DE. Oral mucositis . Dent Clin North Am . 2005 ; 49 1 : 167 – 184, ix . Google Scholar Crossref Search ADS PubMed WorldCat 3 Sroussi HY , Epstein JB , Bensadoun RJ , et al. . 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Personalized medicine for mucositis: Bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis . Oral Oncol . 2011 ; 47 10 : 951 – 955 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Keefe DM , Schubert MM , Elting LS , et al. . Updated clinical practice guidelines for the prevention and treatment of mucositis . Cancer . 2007 ; 109 5 : 820 – 831 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy

JNCI Monographs , Volume 2019 (53) – Aug 1, 2019

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
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10.1093/jncimonographs/lgz011
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Abstract

Abstract Oral mucositis is a common side-effect associated with conventional cancer therapy and has also recently been reported in association with newly emerging cancer therapies. It is characterized as an inflammation of the oral mucous membranes accompanied by many complex mucosal and submucosal changes. Ulcerative oral mucositis can cause significant oral pain, impair nutritional intake, lead to local or systemic infection, and cause significant economic cost. In addition, it may necessitate interruptions in cancer therapy, thus adversely affecting patient prognosis. This review presents the current understanding of the pathogenesis of mucositis and discusses evidence-based clinical management strategies for oral mucositis. In addition, key research questions for future investigation are identified, followed by a discussion of strategies to promote development and funding of the needed research. Mucositis is a common side-effect associated with cancer therapy (chemotherapy and/or radiation therapy) and is characterized as an inflammation of the oral and gastrointestinal mucous membranes accompanied by many complex mucosal and submucosal changes (1–3). Ulcerative mucositis (Figure 1) can have a major impact on delivery of cancer therapy and may cause delay or cessation in the delivery of cancer therapy, which can affect prognosis (4). For example, in chemotherapy patients, a reduction in the dose of the next cycle of chemotherapy was twice as common after cycles with mucositis as it was after cycles without mucositis (23% vs 11%; P < .0001) (5). Additional hospital charges of $42 749 per hematopoietic stem cell transplant (HSCT) patient with oral ulcers have been documented (6). For non-HSCT patients by comparison, the incremental cost of grade 1–2 mucositis is $2725 and can exceed $5000 for grade 3–4 mucositis (5). Figure 1. View largeDownload slide Ulcerative oral mucositis on the buccal mucosa (inside of the cheek) of a patient who was receiving head and neck radiation therapy with concurrent chemotherapy. Figure courtesy of Dr Rajesh V. Lalla. Figure 1. View largeDownload slide Ulcerative oral mucositis on the buccal mucosa (inside of the cheek) of a patient who was receiving head and neck radiation therapy with concurrent chemotherapy. Figure courtesy of Dr Rajesh V. Lalla. The incidence and severity of oral mucositis is dependent on the cancer treatment regimen. For chemotherapy, relevant factors include the chemotherapy drug used, dose, and duration. For radiation therapy, relevant factors include total radiation dose, fractionation schedule, volume of mucosa irradiated, and use of concurrent chemotherapy (7,8). Other proposed risk factors for oral mucositis include low body mass, prolonged neutrophil recovery, and young age (9,10). Mucositis is commonly associated with oral and/or oropharyngeal mucosal pain and thus has a major impact on quality of life (11). Additionally, ulcerations associated with mucositis can become secondarily infected and significantly increase the risk of poly-microbial bacteremia, especially with streptococcal species (12,13). The impact of emerging cancer therapies on oral mucositis incidence, severity, and response to management is under active investigation. Some molecularly targeted agents (such as mTOR inhibitors) are associated with oral ulceration that is quite different from oral mucositis due to conventional chemotherapy or radiation therapy (14–17). Additionally, newer delivery systems for radiation therapy may also affect the incidence and severity of mucositis. This review presents the current understanding of the pathogenesis of oral mucositis secondary to conventional chemotherapy or radiation therapy and discusses evidence-based clinical management strategies. In addition, key research questions for future investigation are identified, followed by a discussion of strategies to promote development and funding of the needed research. Pathobiology: Current Paradigm and New Frontiers The pathobiological basis for cancer regimen-related mucosal toxicity has been the subject of intense study over the past 15 years (8). The historical paradigm that wholly attributed mucositis to direct DNA injury of rapidly dividing basal epithelial “stem” cells has been revised to reflect a broad range of investigational findings that have demonstrated that regimen-induced epithelial toxicities are a consequence of a complex sequence of interacting physical and biological events that involve the cells and tissues of the submucosa and inter-cellular and tissue cross-talk (18). Simultaneously, discoveries detailing pathways and cellular function have continuously contributed to facilitating more granularity to the overall process. The current model of mucositis pathogenesis is comprised of five broad stages (19) (Figure 2). Although compartmentalization of mucositis development into descriptive segments is a convenient way to describe a very dynamic process, the in vivo reality of the molecular, cellular, and tissue events that occur is that the stages overlap and are inter-related rather than compartmentalized and linear. From a clinical perspective, many of the biological events that lead to mucositis are aggressively percolating whereas phenotypic changes of injury are completely absent. Figure 2. View largeDownload slide Five-stage model of the pathobiology of mucositis. Figure courtesy of Dr Stephen T. Sonis. DNA = Deoxyribonucleic acid; IL = Interleukin; NFκB = Nuclear Factor kappa B; ROS = Reactive oxygen species; TNF = Tumor Necrosis Factor. Figure 2. View largeDownload slide Five-stage model of the pathobiology of mucositis. Figure courtesy of Dr Stephen T. Sonis. DNA = Deoxyribonucleic acid; IL = Interleukin; NFκB = Nuclear Factor kappa B; ROS = Reactive oxygen species; TNF = Tumor Necrosis Factor. The initiation phase is characterized by three principal biological events. Direct physical DNA injury results in strand breaks causing clonogenic death of basal epithelial cells. Simultaneously, chemotherapy and radiation indiscriminately trigger a series of biological events in subepithelial tissue and cells (endothelium, fibroblasts, macrophages) in response to oxidative stress and the release of reactive oxygen species and activation of the innate immune response (20) as injured cells release endogenous damage-associated pattern molecules (Chemotherapy and Radiation-Associated Molecular Pattern molecules, or CRAMPs), which then bind to pathogen recognition receptors (21). During the primary damage response phase, chemotherapy, radiation, CRAMPs, the innate immune response, and reactive oxygen species initiate a series of interacting biological events. Transduction pathways prompt the activation of a number of transcription factors, such as Nuclear Factor kappa B (NF-κB), Wnt, p53, p38, and their associated canonical pathways (22). Increasingly, the NF-κB pathway has been identified as playing a pivotal role in facilitating the development of mucositis (23–26) as its activation is associated with apoptosis of normal cells. Chemotherapy, radiation, CRAMPS, and reactive oxygen species can directly or indirectly activate NF-κB. Up to 200 genes may be expressed as a consequence of NF-κB activation. Many of these genes are associated with production of cytokines and cytokine modulators, stress responders (ie, COX-2, inducible NO-synthase, superoxide dismutase), and cell adhesion molecules, many of which have been associated with mucositis (25,27). Because of its key function, it is not surprising that NF-κB also provides an attractive interventional target (28). Radiation and chemotherapy also affect other pathways that may ultimately lead to cell death of basal epithelial stem cells. Among these are the ceramide pathway (29), the toll-like receptor signaling pathway (30), and a number of the kinase pathways (31,32). In addition, connective tissue fibrinolysis initiated as a consequence of cytotoxic therapy stimulates macrophages to produce tissue-damaging matrix metalloproteinases (33). It also seems likely that activation of the NLRP3 inflammasome occurs at the same time. Although not comprehensively studied yet, earlier findings have shown associations between inflammasomes and chemotherapy-induced injury (34). Other studies support this assumption (31,35,36). The early biological events that initiate mucositis precede clinically detectable changes. The consequence of epithelial basal cell damage (the target of biologically medicated injury) is ultimately a loss of renewable epithelium. Although changes in pathway-associated gene expression occur within seconds of radiation or chemotherapy administration, there is a multiple day lag between the damage that is occurring at the molecular and cellular level and its clinical manifestations. In the case of fractionated radiation, the precipitating events that lead to extensive damage are incrementally induced with each radiation exposure. Many of the molecules induced by the primary response have the ability to positively or negatively feedback and alter the local tissue response. This can lead to signal amplification. For example, TNF may positively feedback on NF-κB to amplify its response, and initiate mitogen-activated protein kinase signaling, leading to activation of c-Jun N-terminal Kinase signaling. Although the autonomy of canonical pathways and the genes responsible for their regulation frequently characterize many reports, cross-talk and interaction are the in vivo reality. A crescendo of biological signals causes substantial impairment in the ability of the epithelium to heal, culminating in development of the ulcerative phase of mucositis; this phase is typically clinically the most significant. Despite the failure of anti-microbial treatment strategies to effectively mitigate mucositis development (37,38), a role for the oral microbiome to affect the course of mucositis has become an area of increasing interest (39). Quantitative and qualitative microbiological studies have shown that resident mucosal bacteria increase dramatically (300-fold) during this ulcerative phase, with organisms secondarily colonizing the lesions. These organisms are not simply dormant passengers. Rather, they contribute to the longevity and severity of mucositis by producing cell wall products that penetrate into the submucosa to stimulate resident inflammatory cells, including macrophages, to secrete pro-inflammatory cytokines and other mediators of tissue injury. Furthermore, it is not inconceivable that with regimen-induced breakdown of epithelial tight junctions (40), bacterial cell wall products might penetrate and functionally accelerate both innate immune and inflammasome activities to enhance mucositis development and prolong its course. The final phase of healing usually occurs spontaneously, approximately 2–4 weeks following cessation of the cancer therapy. In response to signaling, which originates in the extracellular matrix of submucosa, the epithelium at the ulcer margins migrates across the lesion. In addition to controlling migration, the extracellular matrix also affects epithelial differentiation and proliferation (41,42). Although much has been learned about the biological events that lead to mucositis, we are a long way from fully understanding how the component events contribute to the process of mucosal injury. But advances to date have opened doors leading to the discovery and on-going clinical development of mechanistically targeted interventions. Equally important has been the ability to leverage the pathobiological elements to clinically applicable biomarkers and predictors of mucositis risk. Patients vary dramatically in individual risk of developing mucositis (the same is true for other regimen-related toxicities). It has become clear that these differences are predominantly genetically driven (43) and biologically based (44), and precancer treatment identification of relevant single polynucleotide can be used to accurately predict patients at risk (45,46). Clinical Management Clinical management of oral mucositis is largely palliative, although several preventive and therapeutic strategies have been studied (47–50). Evidence-based clinical practice guidelines for the management of mucositis have been published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) (51). These guidelines include “recommendations” based on higher levels of evidence and “suggestions” based on lower levels of evidence. They are referred to where applicable in the summary of current clinical approaches for management of oral mucositis presented below. Pain Control Pain due to mucositis negatively affects dietary intake, oral hygiene, and quality of life. Based on expert opinion, mouth rinses containing an anesthetic, such as 2% viscous lidocaine, can provide short-term relief; however, no MASCC/ISOO guideline was possible related to the use of the so called “Magic” or “Miracle” mouthwashes (52). The MASCC/ISOO guidelines suggest that 0.2% morphine mouth rinse and 0.5% doxepin mouth rinse may be effective for pain due to oral mucositis. Topical agents that adhere to the oral mucosa and form a protective coating are also available. Of these, sucralfate is the most widely studied. The MASCC/ISOO guidelines recommend against the use of sucralfate for the prevention or treatment of oral mucositis in patients receiving chemotherapy and also in radiation-induced oral mucositis due to lack of efficacy. Most patients with severe mucositis also require systemic analgesics, including opioids, for satisfactory pain control. The MASCC/ISOO guidelines recommend the use of patient-controlled analgesia with morphine in patients undergoing HSCT and suggest the use of transdermal fentanyl in patients receiving conventional or high-dose chemotherapy (53). It is worth noting that traditional opioids are often less effective than expected for controlling mucositis pain, and there is conflicting evidence for gabapentin. Nutritional Support Nutritional intake can be affected by the mucositis-driven pain associated with eating as well as taste and salivary changes secondary to chemotherapy and/or radiation therapy (54,55). Dietary consultation and weight monitoring is important, especially in patients with severe mucositis. Use of liquid dietary supplements, a gastrostomy tube (for radiation therapy), or total parenteral nutrition (for high-dose chemotherapy regimens) may be warranted. Oral Hygiene Maintenance of good oral hygiene can help reduce the severity of oral mucositis (56–59). In addition, effective oral hygiene practices may reduce the risk of systemic sepsis from oral pathogens. The MASCC/ISOO guidelines suggest the use of a standardized oral care protocol for the prevention of oral mucositis across all cancer treatment modalities (52). Although there are conflicting data on the impact of oral hygiene on oral mucositis, the majority of studies reported a positive effect, supporting a suggestion rather than a stronger recommendation. Cryotherapy Cryotherapy can reduce the severity of oral mucositis in patients receiving bolus doses of chemotherapeutic agents (60–63). The placement of ice chips in the mouth, during the administration of bolus chemotherapy, is thought to reduce delivery of the drug to the oral mucosa by causing local vasoconstriction. The MASCC/ISOO guidelines recommend the use of cryotherapy to reduce oral mucositis in patients receiving bolus doses of 5-fluorouracil and suggest its use in patients receiving high-dose melphalan for HSCT (64). In theory, cryotherapy could be useful to reduce oral mucositis caused by any chemotherapy drug with a short half-life that is administered during a short period of time. Laser and Other Light Therapy Low-level laser therapy can reduce the severity of chemotherapy and radiation-induced oral mucositis (65–69). The mechanism may involve anti-inflammatory and pro-healing effects (70,71). The MASCC/ISOO guidelines recommend the use of low-level laser therapy for the prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT and suggest its use in patients receiving head and neck radiation therapy without concomitant chemotherapy (72). The long-term safety of low-level laser therapy and potential impact on tumor response is still under study. Growth Factors Intravenous recombinant human keratinocyte growth factor-1 (palifermin, Swedish Orphan Biovitrum) significantly reduced incidence of World Health Organization grade 3 and 4 oral mucositis in patients with hematologic malignancies receiving high-dose chemotherapy and total body irradiation for autologous hematopoetic cell transplantation (73). Based on this evidence, the MASCC/ISOO guidelines recommend the use of this growth factor in this specific population (74). Palifermin has been approved by the US Food and Drug Administration (FDA) for patients with hematological malignancies receiving myelotoxic therapies requiring hematopoietic cell support. Two prospective randomized trials showed efficacy in head and neck radiation therapy, but long-term safety data are not available, so this approach remains experimental in that setting (75,76). The safety of epithelial growth factors has not been established in patients with nonhematologic, epithelial malignancies. Anti-Microbial Agents Secondary infection of oral mucositis ulcerations is thought to worsen its severity. Based on this rationale, several topical antimicrobial agents have been examined for oral mucositis, but the results have been disappointing. The MASCC/ISOO guidelines recommend against the routine use of antimicrobial lozenges, chlorhexidine mouth rinse, and iseganan mouth rinse for oral mucositis due to lack of consistent evidence of efficacy (52,53). Anti-Inflammatory Agents Benzydamine hydrochloride mouth rinse reduced the severity of oral mucositis in head and neck cancer patients undergoing radiation therapy of cumulative doses up to 50 Gy, without concomitant chemotherapy (77). Based on this evidence and previous studies, the MASCC/ISOO guidelines recommend use of this agent in patients receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy. However, this agent has not received approval for this use from the US FDA. Furthermore, most head and neck cancer patients receive greater than 50 Gy radiation therapy, often with concomitant chemotherapy. The MASCC/ISOO guidelines also suggest against the use of misoprostol mouth rinse for prevention of oral mucositis in patients receiving head and neck radiation therapy, based on data indicating a lack of efficacy (78). Antioxidants Amifostine (Ethylol, MedImmune, Gaithersburg, MD) is postulated to act as a scavenger of harmful reactive oxygen species (79). Despite reviewing 30 studies on the use of amifostine for oral mucositis in various settings, a MASCC/ISOO guideline could not be established regarding the use of this agent in oral mucositis due to conflicting evidence (80). However, the use of intravenous amifostine was recommended for the prevention of radiation proctitis and suggested for the prevention of esophagitis in patients receiving chemo-radiation for non-small cell lung cancer (81). Amifostine is FDA approved to reduce the incidence of moderate to severe xerostomia in patients receiving postoperative radiation therapy for head and neck cancer where the radiation port includes a substantial portion of the parotid glands. Key Research Questions Despite important advances over the past 15 years relative to mucositis etiopathogenesis, there is only one drug (palifermin) that is approved by the United States FDA for mucositis prevention. Thus, additional research is needed to better understand the molecular pathogenesis of mucosal injury in cancer as well its translation to clinical practice. The following are the key research questions. Definition of Risk Factors for Oral Mucositis The current understanding of risk factors is limited, and the literature is often conflicting. Recent literature has suggested a systems medicine approach to studying risk, involving various areas such as genomics, metabolomics, microbiomics, etc. Interaction Between Tumor, Host, and Anti-Cancer Therapy Much of the toxicity can be ascribed to the type, regimen, and mechanisms of action of the cancer therapy. However, there is emerging evidence that the tumor-host interactions are also important. Modification of Cancer Therapy to Reduce Mucositis Severity Newer cancer therapies such as proton therapy and molecularly targeted agents may be associated with lower risk of mucositis. Careful treatment planning (such as by reducing the volume of mucosa irradiated or the dose of chemotherapy agent) can in some cases reduce the severity of oral mucositis while maintaining efficacy of anti-cancer treatment. Amelioration of Oral Mucositis Without Tumor Protection Many of the pathways involved in the pathogenesis of oral mucositis are comparable to those involved in anti-tumor activity of the drug (mechanism of action = mechanism of toxicity). The concern thus becomes that preventing or downregulating oral mucositis may also lead to tumor protection. The identification and targeting of key network pathways unique to oral mucositis are therefore desirable. Linkage Between Oral Mucositis From Different Treatment Modalities (Chemotherapy, Radiation Therapy, and Targeted Anti-Cancer Therapies) Combination therapy is increasingly common and complicates the modelling. Studies of combined treatment toxicity are limited and should be pursued. With the increased use of combination protocols involving multiple mechanisms, the historical reductionist approach to assessing toxicity of individual agents may not be adequate. Molecular Pathways Associated With Toxicity Clustering Identification of a key pathway that represents the critical link between different toxicities within a cluster could lead to a targeted intervention for amelioration of the collective toxicities within that cluster. Chronic Oral Mucositis and How It Differs From Acute Oral Mucositis A small subset of cancer patients develops chronic oral ulceration; there is, however, limited scientific modelling available at present for this type of oral mucosal injury caused by cancer therapy. Additional research could lead to new insights into both the chronic forms of this lesion as well as the acute component. Strategies to Promote Development and Funding for New Research Limited progress has been made since the National Institutes of Health (NIH)-funded mucosal injury research conference (2000) (82) as well as the NIH-funded conference on emerging oral complications of cancer therapy (2009). It is evident that traditional research strategies (eg, in-series progression of preclinical to clinical trials, silo-based inquiry, and single-source funding) have not kept pace with other areas of investigation. Furthermore, mucosal injury research has lagged behind that of cancer therapeutics, such that knowledge of oral complications of emerging and new cancer therapies is minimal. To progress in understanding of mechanisms of the complex and growing problem of oral complications of cancer treatment, new approaches must be considered to promote and support research in this area. The field can benefit from several productive approaches that have demonstrated success in other research areas (83). Biological as well as technological strategies exist for development of new research approaches and funding opportunities. Biological Strategies Several potential research avenues related to mucosal immunity and susceptibility have not been exploited to date. For example, if an underlying mechanism for mucosal injury is related to immune modulation, then exploring mechanisms and risk factors under investigation for other complex conditions involving mucosal injury such as graft vs host disease, Behcet’s disease, and recurrent aphthous stomatitis could be informative. If injury and potential repair are related to the balance of inflammation, injury, and regeneration, then mucosal injury research can benefit from the advances in stem cell research. Recent focus on the microbiome could also be extended to the more relevant construct of the mucosal-microbiome interaction. Another strategy to leverage the study of the pathophysiology of mucositis related to new cancer treatments is to capitalize on planned oncology studies to investigate in parallel the related condition of interest, such as mucosal toxicity. For example, examining esophageal and oral mucosa and GI mucosa response should be incorporated into existing preclinical safety studies of cancer treatments as well as into early phase I and II human studies. Adaptation of new technologies in use for other conditions should be evaluated, such as innovations in therapeutic delivery for dermatologic and eye conditions: laser therapy, nano-delivery systems, programmed stem cells, and related approaches. Technological Strategies In addition to applying knowledge generated from other areas of scientific inquiry, mucosal researchers can adapt new methodologic approaches. The study of many complex conditions now involves combining strategies to reflect the summed contribution to the condition under study. As discussed in the previous section, risk of mucositis is multifactorial. Its manifestation and perception of such is influenced by the underlying cancer being treated, mechanisms of the treatment regimen(s), and interaction with host immunity and comorbidities (84). These components are all likely modified further by genetic and environmental interactions as well as by the variability in health and health-care standards of both patients and care-givers. Understanding variability in treatment regimens superimposed on the variability of host and the cancer itself necessitates clinical research. There are new methodologic approaches derived from complex data analysis techniques that can be applied to evaluating the intersecting effects of symptom biology, such as cluster analyses that may include impact of symptoms on the condition and manifestation and interaction of toxicities on the overall condition. Dissection of symptoms to underlying biology using genome-wide approaches can yield information on polymorphisms that may affect innate risk and response as well as adaptive variability in gene expression resulting in an individually dynamic pathobiology. Although genomic (genotyping, gene expression, and epigenetic) approaches will be useful for dissecting effects and interactions of the tumor disease, treatment, and host susceptibility factors, currently these studies must involve a large number of subjects. Because methodology improves power with smaller sample sizes, these studies may be linked with those conducted to examine primary mechanisms and toxicities. Complementary studies of a strong predictor in preclinical studies can also be followed-up in phase I/II studies as exploratory analyses. Challenges and Opportunities for Mucositis Research These collective strategies may contribute to identification of potential preventive and therapeutic options. Most importantly, these approaches demand integrated research and interactions between disciplines to form new research teams with complementary expertise to capitalize on opportunities created by major research endeavors such as the human genome project and its “–omic” outgrowths, stem cell research, and powerful new methodologic approaches to complex data analysis (85). Innovation is imperative, not only for discovery, but also for garnering research funding. First and foremost, mucosal injury research must be re-envisioned in the context of current disease epidemiology as well as research assets. Mucosal injury research has suffered from a lack of public and private funding due to the misperception that it relates to orphan diseases that have little public health impact or market share. This view does not incorporate the key fact that an aging population is increasingly being treated for cancer, with therapy-limiting mucosal toxicity affecting a growing proportion of the population. Significantly, advances in research methodologies, new technologies, and creative partnering relationships enhance the feasibility of these proposed strategies through efficiency in conduct as well as economy. Joint funding of proposals with National Cancer Institute, National Institute of Dental and Craniofacial Research, and other institutes with overlapping missions has been considered an approach to leveraging funds. Other examples of recent facilitation of larger scientific endeavors include a growing NIH investment in clinical research networks such as Patient Based Research Networks; the linking of Clinical and Translational Study Award-supported academic sites; and complementary electronic resources, such as Clinical Research Networks. The latter is designed to promote and expand clinical research networks that can rapidly conduct high-quality clinical studies that address multiple research questions across multiple research sites. Collaboration across sites through these mechanisms makes it feasible to increase sample size and generalizability, facilitates standardized data collection methods, and has the potential to promote scientific exchange across programs and study sites. Clinical research networks can be further developed into data repositories to permit modeling of variable interactions such as pharmacogenomics and pharmacoproteomics, gene expression or proteomic changes in human specimens, and patient-reported outcomes, linked to clinical phenotypes. This will ultimately move the field towards population-based rather than clinic-specific research while encouraging standardization of data measures. Such networks are exemplified by NIH initiatives using public-private partnering mechanisms to provide publicly available resources such as PhenX (the Phenotyping and Exposures toolkit: https://www.phenxtoolkit.org) and PROMIS (Patient Reported Outcomes Measurement Information System: http://www.nihpromis.org). An important recent source of funding for oral mucositis research has been industry. There are a number of mechanistically based agents in clinical trials for oral mucositis, mostly in the head and neck cancer population. This increased activity speaks to the market need and provides optimism that effective interventions might be on the way. Lastly, there is scant evidence for many of the available approaches used for prevention, palliation, and therapy (86). Of the studies conducted, many exhibit design flaws such as lack of power or comparison groups and use of a validated and standardized set of instruments for data collection, which, among others, limit the interpretation and application of the results. Thus, rigorous clinical trials of approaches currently in use, as well as those being newly developed, should be conducted to take advantage of the variety of approaches discussed in this section. Taken together, these approaches have the potential to maximize scientific efficiency and cost-effectiveness of the research investment and thus improve the scope and impact of mucosal injury research. Key Points  1. Oral mucositis is a common side-effect of chemotherapy and or/radiation therapy, resulting in pain, difficulty swallowing, and interruptions of cancer therapy. 2. The pathobiology of mucositis is complex and multifactorial. Our understanding of the contributions of the various components to mucosal injury is still incomplete. 3. The clinical management of oral mucositis is largely palliative, although several preventive and therapeutic strategies have been studied. 4. A number of key research areas provide fertile ground for future studies. 5. New approaches must be considered to promote and support research in this area. Notes Affiliations of authors: Section of Oral Medicine, University of Connecticut Health, Farmington, CT (RVL); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Foundational Sciences, East Carolina University School of Dental Medicine, Greenville, NC (SMG); Division of Oral Medicine, Dana-Farber Cancer Institute, Boston, MA (STS); Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX (DIR); Faculty of Health Sciences, University of Adelaide, Adelaide, Australia (DMK). None of the authors reported any conflicts related to this manuscript. 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Journal

JNCI MonographsOxford University Press

Published: Aug 1, 2019

References