J Oral Pathol Med (2014) 43: 81–90 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

doi: 10.1111/jop.12135

wileyonlinelibrary.com/journal/jop

REVIEW ARTICLE

Oral mucosal injury caused by cancer therapies: current management and new frontiers in research Siri B. Jensen1, Douglas E. Peterson2 1

Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine and Program in Head & Neck Cancer and Oral Oncology, Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT, USA

ABSTRACT This invited update is designed to provide a summary of the state-of-the-science regarding oral mucosal injury (oral mucositis) caused by conventional and emerging cancer therapies. Current modeling of oral mucositis pathobiology as well as evidence-based clinical practice guidelines for prevention and treatment of oral mucositis are presented. In addition, studies addressing oral mucositis as published in the Journal of Oral Pathology and Medicine 2008–2013 are specifically highlighted in this context. Key research directions in basic and translational science associated with mucosal toxicity caused by cancer therapies are also delineated as a basis for identifying pathobiologic and pharmacogenomic targets for interventions. This collective portfolio of research and its ongoing incorporation into clinical practice is setting the stage for the clinician in the future to predict mucosal toxicity risk and tailor therapeutic interventions to the individual oncology patient accordingly. J Oral Pathol Med (2014) 43: 81–90 Keywords: cancer therapy; oral prevention; research; treatment

mucositis;

pathobiology;

also negatively affect diet, nutrition, oral hygiene, and quality of life. In immunosuppressed patients, secondary infection of oral mucositis lesions can lead to bacteremia, fungemia, and sepsis. In selected patients, the significant morbidity associated with OM may result in dose reductions, delays, and/or treatment interruptions in cancer therapy which in turn can negatively impact patient survivorship. Management of OM has for several decades and continues to be directed to supportive care including basic oral care, oral pain control, prevention and treatment of infection, and nutritional support. The lesion continues to represent an important unmet medical need in oncology practice. Depending on type and mechanism of action, the cancer treatment regimens can also impact other mucosal sites of the alimentary tract including the esophagus, stomach, and small and large intestine. Oral and gastrointestinal mucositis can cause hospital admission and is thus also associated with increased use of healthcare resources (2). This invited update provides a summary of oral mucosal injury induced by cancer therapies, including recent advances in pathobiology, evidence for prevention and treatment, and emerging frontiers in research.

Methods Introduction Oral mucosal injury caused by cancer therapies (oral mucositis [OM]) is a common toxicity of antineoplastic drugs and/or head and neck radiation in cancer patients (1). OM can result in significant pain and the patient often requires systemic narcotics for pain relief. The lesion can Correspondence: Siri Beier Jensen, DDS, PhD, Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, Department of Odontology, Faculty of Health & Medical Sciences, University of Copenhagen, Nørre All
e 20, DK-2200 N Copenhagen, Denmark. Tel: +45 35 32 65 52, Fax: +45 35 32 67 22, E-mail: [email protected] This work was funded in part by NIH/NIDCR 1R01 DE021578. Accepted for publication October 14, 2013

Original research as well as review articles identified in MEDLINE/PubMed was considered for inclusion. In addition, the article database of the Journal of Oral Pathology and Medicine was searched for articles addressing various aspects of oral mucosal injury and related oral complications of cancer therapies published in the period between 2008 and 2013. Key word terms for both searches included the following: oral, mucositis, stomatitis, mucous membrane, mucosa, cancer therapies, chemotherapy, antineoplastic agents, radiation therapy, chemoradiation, head and neck cancer, leukemia, lymphoma, hematopoietic stem cell transplantation, tumor, neoplasm. The OM clinical guidelines from the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/

Oral mucosal injury caused by cancer therapies Jensen et al.

82

ISOO) are also included in this review. Methods utilized by the MASCC/ISOO Study Group to produce the guidelines are described in detail in Bowen et al. (3) and Elad et al. (4). In brief, methodology included a literature search for all relevant papers indexed in Medline until 31st December 2010. In addition, reference lists of previous guidelines papers as well as Cochrane reviews were searched in order to identify potential additional studies. Clinical guidelines were separated based on the aim of the intervention (prevention or treatment of OM), type of treatment (radiotherapy, chemotherapy, chemoradiotherapy, or high-dose conditioning therapy for hematopoietic stem cell transplantation (HSCT)), and route of administration of the OM intervention. Studies were evaluated based on a list of major and minor flaws as described by Hadorn et al. (5). Level of evidence was then assigned for each intervention based on criteria published by Somerfield et al. (6). The resultant clinical guidelines were thus based on the strength of the overall level of evidence for each intervention and were classified into three types: recommendation, suggestion, or no guideline possible.

Pathobiology The current modeling of OM pathobiology is primarily based on in vitro and animal models that have collectively identified a cascade of events in epithelial and submucosal tissue compartments. As described below, the body of knowledge defines a complex, multifactorial paradigm of mucosal injury and repair (7–20). Selected outcomes of this preclinical modeling have been translated into clinical trials

with varying degrees of success, as described later in this section. A key advance in OM research occurred when Sonis published a five-phase model of OM pathobiology in 1998 (21). This model has been subsequently modified based on new scientific discoveries that have emerged in recent years (Fig. 1). The contemporary model defines a complex pathobiology including microvascular injury, up-regulation of pro-inflammatory cytokines including Tumor Necrosis Factor-a, Interleukin (IL)-1b and IL-6, extracellular matrix reactions and host–microbiome interactions (7, 10, 20, 22– 26). It is important to recognize that while selected biologic events may occur sequentially, the collective injury to the epithelium and submucosa can be concurrent. This adversely synergistic interaction results in profound dysregulation of mucosal homeostasis and repair. In addition to this oral mucosal dysregulation, other oral complications in addition to OM often appear concurrently in patients. The pattern of this collective toxicity profile varies in type, intensity and duration depending upon the type and mechanism of action of the cancer treatment regimen as well as upon patient-specific factors. As delineated in Journal of Oral Pathology and Medicine publications over the past 5 years the knowledge base regarding mechanisms and interactions among oral complications in oncology patients continues to increase (Table 1). In addition to OM, for example, oral complications may include pain caused by oral cancer, salivary gland hypofunction (objectively decreased saliva secretion)/xerostomia (subjective feeling of dry mouth), fungal infection (27) or

Figure 1 The five-phase model of oral mucositis pathobiology divided into the following: initiation, the primary damage response (messaging and signaling), amplification, ulceration, and healing. Reprinted with permission from Sonis ST. J Support Oncol 2007; 5(Suppl. 4):3–11. J Oral Pathol Med

Oral mucosal injury caused by cancer therapies Jensen et al.

viral infection (28), taste disturbances (dysgeusia) (29, 30), and muscular fibrosis (head and neck radiation patient) (Table 1). As noted in three publications, OM can be exacerbated by colonizing oral microflora when local and systemic immune function is compromised (Table 1) (27, 31, 32). An additional example of these complex and unique oral interactions and their relationship to systemic status is well illustrated in one of the Journal of Oral Pathology and Medicine publications. In this study, neutrophils in oral tissues (oral engraftment) occur earlier in time status/post stem cell transplantation as compared to the time of appearance of neutrophils in the peripheral circulation (blood engraftment) (Table 1) (33). Investigations such as those published in Journal of Oral Pathology and Medicine continue to contribute to identifying new directions in science as well as their potential impact on clinical practice in the future. In addition to these well-documented toxicities, there are important new directions in the research field that warrant pursuit. For example, the molecular and sensory components associated with oral pain in the OM modeling represent a relatively unexplored frontier. Even though moderate/severe oral pain has long been a clinical hallmark of OM, the specific molecular modeling associated with the symptom has not been systematically studied in detail. Literature developed in non-mucositis cancer pain models (34, 35) could provide powerful information to advance this aspect of the etiopathogenesis in relation to clinical impact. It is important to note that, in the clinical setting, it is often the oral pain and not necessarily the extent of erythema and/ or ulceration that is the principal reason that patients require hospitalization as well as expensive supportive care interventions when the mucosal injury develops. It is also clear in recent years that the patient’s genomic profile can be a key contributor to the cellular and tissue response to cancer treatment (7, 8, 36–39). In this context, novel systems biology approaches as utilized in nonmucositis modeling (40, 41) are increasingly being utilized to systematically delineate key network hubs and pathways that collectively contribute to the OM trajectory (24). Investigative strategies that then link with applied genomics are setting the stage for exciting new advances relative to genome-wide risk prediction that will likely enhance the clinician’s ability to deliver personalized cancer medicine in the future (17). These and related recent scientific advances thus continue to enhance the opportunity to delineate the complex pathobiology such that key molecular pathways can be targeted for mucositis therapeutics in the years to come. These technologies and ‘lessons learned’ from molecular studies of OM caused by conventional cancer treatments such as high-dose chemotherapy or head and neck radiation will likely also have high value in the study of the unique expression of oral mucosal injury recently being described in cancer patients receiving molecularly targeted biologics. These treatments are directed, for example, to inhibitors of angiogenesis or the mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), or multikinase Abl pathways (42). They are increasingly being documented as causing oral mucosal injury that is distinctly different

in incidence, clinical appearance and response to therapy as contrasted with mucositis caused by chemotherapy and/ or head and neck radiation. Given the relative recent emergence of the mucositis associated with molecularly targeted cancer agents, there is important need and opportunity for new research regarding causation as well as optimal clinical management strategies. The research agenda described in this section provides an excellent opportunity for investigators representing the oral pathology and oral medicine sciences to continue at leadership and collaborative levels in the future. The summary of future research directions (‘New frontiers in research’) presented later in this review further delineates these and other opportunities for discovery and clinical translation. Despite these exciting new directions in the field a word of caution is appropriate at this stage in the discussion. Without question selected aspects of this knowledge base have been effectively translated into clinical drug and device development in recent years, as described above. However, the actual impact on cancer patient care clinically has only been partially successful to date, despite the impressive scientific and translational advances in recent years. Barriers yet to be overcome include the following: (i) the need to further refine the state-of-the-science molecular model, (ii) competing corporate priorities for mucositis vs. non-mucositis therapeutics, and (iii) varying degrees of incorporation of mucositis management technologies across the extensive clinical oncology practice cohort worldwide. Until these rate-limiting issues can be more fully addressed, the future of OM prevention and treatment will be negatively impacted. It is thus essential to incorporate these additional components into the research and clinical planning so as to optimize research and clinical outcomes.

83

The evidence-base for management of oral mucositis Oral mucosal toxicity caused by chemotherapy or head and neck radiation A number of agents and interventions have been studied for prevention and treatment of OM in patients receiving conventional cancer therapies such as high-dose chemotherapy or head and neck radiation. They encompass a wide range of biologic rationales and potential mechanisms relative to the pathogenesis of OM. Having said this and with few exceptions, however, there is in general considerable variability across results. As noted earlier the evidence-base for various preventive and treatment interventions has been reviewed by the MASCC/ISOO Mucositis Study Group. This has resulted in publication of clinical practice guidelines for OM as recently as 2013, with a goal of enhancing evidence-based oncology care and improving overall cancer treatment outcomes (3, 4, 43–53). Findings the studies were integrated into recommendations or suggestions at three levels: (i) in favor of interventions for OM, (ii) against interventions for OM, or (iii) no guideline possible due to insufficient or conflicting evidence. Given the state-of-the-science this last category was the most prevalent conclusion by the MASCC/ISOO reviewers. J Oral Pathol Med

J Oral Pathol Med

M. Baharvand

S. Elad

C. Forster

D. Olczak-Kowalczyk

S. Schelenz

M. Yamazaki

M. Djuric

2012 (32)

2012 (33)

2012 (31)

2011 (27)

2010 (30)

2009 (28)

First author

Prevalence of oral herpes simplex virus reactivation in cancer patients: a comparison of different techniques of viral detection

Reduction of type II taste cells correlates with taste dysfunction after X-ray irradiation in mice

Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors

Bacteria and Candida yeasts in inflammation of the oral mucosa in children with secondary immunodeficiency

A non-invasive oral rinse assay predicts bone marrow engraftment and 6 months prognosis following allogeneic hematopoietic stem cell transplantation

The antimicrobial effect of Iseganan HCL oral solution in patients receiving stomatotoxic chemotherapy: analysis from a multicenter, double-blind, placebo-controlled, randomized, phase III clinical trial

Taste alteration and impact on quality of life after head and neck radiotherapy

Title of publication

Oral tissues with high turnover rates such as taste buds can be damaged by radiation therapy All head and neck cancer patients had dysgeusia after radiation therapy and 72.2% had total aste loss. Significant changes were observed in concentrations and intensities of perceived taste modalities, mainly salt and bitter followed by sour and sweet. Dysgeusia negatively impacted quality of life Oral infections frequently affect immunosuppressed cancer patients and are associated with systemic infections. Topical Iseganan hydrochloride (administered as swish and swallow, six times daily for 21–28 days in patients having myeloablative chemotherapy) significantly reduced the oral total load of aerobic bacteria, streptococci (mainly viridans streptococci and non-hemolytic streptococci), and yeasts Topical Iseganan has potential as an oral antimicrobial agent in the prevention of infection. A non-invasive oral rinse was used in a hematopoietic stem cell transplant population to monitor oral neutrophil counts On average, first appearance of neutrophils in oral tissues (oral engraftment) following hematopoietic stem cell transplantation were detected 8.4 days earlier than neutrophils appearing in the blood circulation (peripheral blood engraftment). This finding enabled confirmation of engraftment one week earlier than when using peripheral blood neutrophil counts alone Oral engraftment marked the beginning of oral mucositis recovery phase The time span between oral engraftment and peripheral blood engraftment was a predictor of treatment outcome at 6 months following hematopoietic stem cell transplantation. A time span of less than 6 days resulted in 100% of patients having a negative outcome Oral mucosal damage in immunocompromised patients may increase risk of bacteremia and fungemia A correlation was found between prevalence of stomatitis/oral mucositis and presence of coagulase-negative Staphylococci, Enterococcus spp., and Candida spp. in an immunocompromised pediatric population (organ transplant recipients on immunosuppressive medications and central nervous system tumor patients having chemotherapy) 56.8% of the cancer patient study population were colonized with oral yeasts The incidence of oral candidiasis in yeast colonized patients was 29.2% in head and neck cancer, 17% in solid tumors, and 20.5% in hematological malignancies. The majority of infections were caused by Candida albicans; however, one third of patients harbored non-C. albicans species such as C. glabrata which were more resistant to anti-fungal agents. Overall resistance to azoles was 28.2%. No resistance was found for amphotericin B or nystatin Age and dentures were identified as independent risk factors associated with yeast carriage Histopathologic examination of circumvallate papillae in mice exposed to a single radiation dose of 15 Gy to the head and neck region showed disappearance of basal cells by day 4 after irradiation followed by a decrease in the number of taste cells by day 8–20, particularly type II taste cells, with recovery by day 24 Preference for sweet taste was decreased in parallel with taste cell number Before chemotherapy, 91.7% of cancer patients were herpes simplex virus 1 (HSV-1) seropositive Polymerase chain reaction was HSV-1 positive in 71.7% of cancer patients before chemotherapy and 85% after chemotherapy, direct immunofluorescence was HSV-1 positive in 3.3% before and 11.7% after chemotherapy, and cell cultures were positive in 33.3% and 40%, respectively. HSV-2 was not detected There was no significant difference in HSV positivity between patients with and without oral mucosal lesions prior to and 14 days after initiation of a chemotherapeutic cycle

Selected key findings

84

2013 (29)

Year published in Journal of Oral Pathology & Medicine

Table 1 Journal of Oral Pathology and Medicine publications from 2008–2013 in the context of oral mucosal injury and other oral complications caused by cancer therapies

Oral mucosal injury caused by cancer therapies Jensen et al.

Oral mucosal injury caused by cancer therapies Jensen et al.

The MASCC/ISOO OM guidelines in favor of interventions to prevent or treat OM include oral care protocols, oral cryotherapy, laser therapy, recombinant human keratinocyte growth factor-1 (palifermin), benzydamine hydrochloride, systemic zinc supplements, and patientcontrolled analgesia with morphine/transdermal fentanyl/2% morphine mouthwash/0.5% doxepin mouthwash to treat OM pain. Additional details are presented in Table 2 (45, 47–52). As noted in the Table, each recommendation and suggestion is targeted to a specific cancer treatment regimen (45, 47–52). Management approaches to oral complications in the out-patient and hospital setting may to some extent rely on tradition or subjective approaches in some clinical practices. These approaches may also be influenced by lack of interdisciplinary sharing of knowledge and collaboration. Interventions implemented out of tradition or customary practice may not be efficient, and may actually prolong or exacerbate the course of the oral complications. In addition to safety and efficacy, cost-effectiveness of a preventive or therapeutic intervention should be a priority consideration. In this context, it is thus equally important

to address the evidence against interventions for OM, in addition to addressing the evidence in favor of interventions for OM. The MASCC/ISOO OM guidelines recommend avoiding the following for prevention of OM:

85

• use of intravenous glutamine in patients receiving highdose chemotherapy for HSCT; • sucralfate mouthwash in head and neck radiation cancer • •

patients/concomitant chemoradiation or chemotherapy. In addition, sucralfate is not recommended for treatment of OM in head and neck radiation cancer patients nor in chemotherapy patients; iseganan mouthwash in high-dose chemotherapy for HSCT, or in head and neck radiation cancer patients/ concomitant chemoradiation; polymyxin/tobramycin/amphotericin B lozenges/paste and bacitracin/clotrimazole/gentamicin lozenges in head and neck radiation cancer patients (51, 52).

MASCC/ISOO clinical guideline suggestions of interventions not to be used to prevent OM include the following:

Table 2 The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Evidence-Based Clinical Practice Guidelines in favor of interventions for oral mucositis secondary to cancer therapy (Not included in the table: Recommendations/suggestions against an intervention for oral mucositis and interventions where no guidelines were possible due to insufficient or conflicting evidence) (for details see references (3, 4, 43, 46–52) and http://www.mascc.org/mucositis-guidelines (54)

Prevention/treatment approach Oral care protocol Oral cryotherapy

Laser and other light therapy

Cytokines and growth factors

Anti-inflammatory agents Natural agents Antimicrobials, mucosal coating agents, anesthetics, and analgesics

Guideline Suggestion that oral care protocols be used to prevent OM in all age groups and across all cancer treatment modalities Recommendation that patients receiving bolus 5-FU CT undergo 30-min oral cryotherapy to prevent OM Suggestion to use cryotherapy to prevent OM in patients receiving high-dose melphalan, +/- TBI as conditioning for HSCT Recommendation for laser therapy (wavelength around 650 nm, intensity 40 mW, tissue energy dose of 2 J/cm2) to prevent OM in HSCT Suggestion for laser therapy (wavelength of 632 nm) to prevent RT-induced OM without concomitant CT for H&N cancer Recommendation for recombinant human keratinocyte growth factor-1 (palifermin), 60 lg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplantation to prevent OM in HD-CT with TBI followed by auto-HSCT Recommendation for benzydamine mouthwash to prevent OM in H&N cancer patients receiving moderate dose RT (up to 50 Gy) without concomitant CT Suggestion that systemic zinc supplements administered orally may be of benefit to prevent OM in oral cancer patients receiving RT or CT-RT Recommendation for patient-controlled analgesia with morphine be used to treat pain due to OM in patients undergoing HSCT Suggestion that transdermal fentanyl may be effective to treat pain due to OM in patients receiving conventional CT and HD-CT, +/- TBI Suggestion that 2% morphine mouthwash may effective to treat pain due to OM in H&N RT patients Suggestion that 0.5% doxepin mouthwash may be effective to treat pain due to OM

Level of evidence

References

III

(45)

II

(47)

III II

(48)

III II

(49)

I

(50)

III

(51)

II

(52)

III III IV

OM Oral mucositis, 5-FU 5-fluorouracil, HD high-dose, CT chemotherapy, +/- with or without, TBI Total body irradiation, HSCT Hematopoietic stem cell transplantation, auto-HSCT autologous hematopoietic stem cell transplantation, RT Radiation therapy, H&N Head and neck. Quality of recommendations based on Hadorn and Somerfield criteria (5, 6): Level of evidence; I, Meta-analysis of multiple well-designed studies. Highpowered randomized trials; II, At least one well-designed experimental trial. Low-powered randomized trials; III, Well-designed, quasi-experimental studies (e.g., non-randomized, controlled, single-group, pre–post, cohort); IV, Well-designed, non-experimental studies (e.g., comparative and correlational descriptive and case studies); V, Case reports and clinical examples. Guideline classification: Recommendation, This is reserved for guidelines based on levels I or II evidence; Suggestion, Guideline based on levels III, IV, V evidence; implies panel consensus on the interpretation of the evidence; No guideline possible, Used with insufficient evidence to base a guideline because (i) little or no evidence on the practice in question or (ii) the panel lacks consensus on the interpretation of existing evidence. J Oral Pathol Med

Oral mucosal injury caused by cancer therapies Jensen et al.

86

• chlorhexidine mouthwash in head and neck radiation cancer patients; • granulocyte–macrophage colony-stimulating growth fac• • •

tor (GM-CSF) mouthwash in patients receiving high-dose chemotherapy for HSCT; misoprostol mouthwash in head and neck radiation cancer patients; systemic pentoxifylline in patients undergoing HSCT; systemic pilocarpine in head and neck radiation cancer patients or high-dose chemotherapy for HSCT (45, 49, 50, 53).

Consideration of the specific indication of either prevention or treatment of OM is important when interpreting and implementing the collective guidelines. For example, it has been suggested not to use chlorhexidine mouthwash for the prevention of OM in head and neck cancer patients receiving radiation therapy. However, it may be used on other indication, for example, reduction of oral microbial load (45, 54). For other OM interventions [e.g., amifostine (46)], no guidelines were possible due to insufficient or conflicting evidence. This outcome also applied to a number of other interventions described above in context of other cancer treatment settings than those defined in the ‘MASCCISOO’ clinical practice guidelines in favor of the interventions. Examples of this disparity include oral cryotherapy, laser therapy and other light therapy, cytokines and growth factors, anti-inflammatory agents, natural agents, antimicrobials, mucosal coating agents, anesthetics and analgesics, and other miscellaneous agents (45, 47–53). Oral mucosal toxicity of molecularly targeted cancer therapies The recent advent of molecularly targeted cancer therapies in clinical oncology practice is redefining treatment paradigms for many types of cancers. These agents directed toward blocking of specific molecular receptors or intracellular pathways including vascular endothelial growth factor receptor (VEGFR) inhibitors, multi-targeted tyrosine kinase inhibitors (TKI), and mTOR inhibitors. Despite these molecularly precise mechanisms of action, however, a novel expression of oral mucosal injury distinct from the classic chemotherapy- and radiation-induced OM has also emerged clinically. For example, painful oral ulcerations are a common complication of mTOR inhibitors and resemble aphthous stomatitis, hence have been referred to as mTOR inhibitorassociated stomatitis (mIAS) (55–59). mIAS may potentially result in dose modifications or delay, or discontinuation of the cancer therapy. Further study of this lesion is needed at both the basic science as well as clinical trial level. Until results of such studies become available, high quality systematic evidence is not available for development of evidence-based clinical practice guidelines. In the interim, the clinical management strategy of mIAS is empirically based on drugs that have been used for the prevention and treatment of aphthous stomatitis and includes topical, intralesional, or systemic corticosteroid therapy dependent on severity of the oral lesions (42, 60–62).

J Oral Pathol Med

New frontiers in research Based on laboratory and clinical progress highlighted in this review, the next decade of research promises to bring strategic new advances in pathobiologic modeling that in turn can drive development of new mucositis therapeutics and guidelines for use in clinical practice. In addition to studies of mucosal toxicity, novel research collaborations are being fostered in settings in which the basic and translational science associated treatment-induced mucosal toxicity is compared and contrasted with the science of mucosal health and homeostasis as well as naturally occurring mucosal disease such as inflammatory bowel disease. A recent example of this new paradigm in fostering novel research collaborations was the June 2013 first-inkind Gordon Research Conference Mucosal Health & Disease (63). This new conference brought together basic and translational researchers from the international community, with specific emphasis on defining new research opportunities for emerging investigators. Table 3 delineates several of important research domains in relation to key research directions and their potential impact on the field. Basic, translational, and clinical research directed to these and related domains could likely produce paradigm-shifting changes in fundamental scientific discovery associated with mucosal homeostasis, injury and repair. In addition, the future research could contribute to development of novel clinical interventions that could strategically enhance cancer patient care while reducing cost of that care. In selected cases, a specific research domain (e.g., systems biology) directly applies to more than one research direction and its potential impact in the field. Investigators from dental medicine, including oral medicine and oral pathology, continue to collaborate with other basic and clinical scientists as well as oncology clinicians to further create and pursue these opportunities.

Conclusion The scope and depth of research and its translation to clinical practice for management of OM in oncology patients has strategically escalated over the past 15 years. In addition to delineating new insights into pathobiology of OM, these advances include development of high quality evidence-based guidelines for prevention and management of the lesion in clinical practice. Despite these advances, however, OM continues to represent an important unmet medical need in many cancer patients receiving mucotoxic cancer treatments. Precise delineation of specific pathobiologic and pharmacogenomic targets for interventions need to be identified in order to enhance quality of cancer care while reducing cost of that cancer treatment. In addition, further development of novel drugs, biologics, and devices is essential to optimizing clinical management of this biologically complex toxicity. New research directions such as those highlighted in this review will likely in turn position clinicians to predict toxicity risk and tailor therapeutic interventions to the individual patient. This translation of discovery-level

Interfacing high throughput sequencing technology with systems biology in order to discern the biodiversity of microbial communities associated with mucositis causation and progression Analysis of the role of patient-based factors, including genomics and proteomics, in contributing to clinical development of oral mucositis

Integrating the etiopathogenic models of mucosal and dermal injury to identify potential shared or unique causative factors

Incorporation of computational biology technology to delineate molecular and network pathways hubs that significantly contribute to mucosal injury and repair Development and application of non-invasive molecular imaging technol ogies at the discovery and clinical level

Oral mucosa and the oral microbiome

Molecular basis for cancer patient-based variation in incidence and severity of oral mucosal injury

Shared vs. unique molecular pathobiology: mucosa and skin

Systems biology, also see below, Molecular imaging

Molecular imaging

Further delineation of the pathobiologic basis for mucositis, capitalizing upon bioinformatics and other computational technologies in order to define central network hubs and pathways that drive mucosal injury and repair

Genetic and immunopathologic governance of oral pain in relation to sensory pathways

Oral pain

Development of molecularly targeted drugs, biologics, and devices Systems biology to more comprehensively delineate key molecular and network pathway targets for perturbation and resultant mucositis prevention and/or treatment

Capitalizing upon research technology and research outcomes from studies of naturally occurring mucosal disease, to inform new research strategies for investigation of mucositis

Study of ‘privileged’ mucosal sites that do not typically develop clinical mucosal injury caused by cancer treatment

Key research direction

Naturally occurring mucosal disease

Molecular modeling Mucosal homeostasis

Research domain

Table 3 New frontiers in research

(continued)

Development of (i) a priori prediction of mucositis incidence and severity in a given oncology patient coupled with (ii) customized therapeutic regimens for mucositis prevention and treatment based upon that risk prediction

Novel research outcomes relative to pathobiology as well as enhanced capability to deliver personalized medicine to oncology patients

Strategic advances in creation of research and clinical models of mucosal homeostasis as well as mucosal toxicity caused by cancer therapeutics

Advances in discovery-level knowledge of mucosal and dermal wound injury and repair & development of therapeutics that could mitigate cancer treatment injury at mucosal as well as dermal sites

Creation of a priori predictive models for development of oral mucositis, particularly in (i) solid tumor patients receiving multi-cycle chemotherapeutic regimens, or (ii) patients receiving molecularly targeted cancer treatment biologics

Enhanced customization of systematically administered pain prevention and treatment in cancer patients Novel antimicrobials directed to mucositis prevention and treatment

Determination of the degree to which the pathobiology of naturally occurring mucosal diseases is concordant or discordant with the pathobiology of mucositis caused by cancer treatment regimens

Discovery of genetic-, molecular-, and cellular-unique characteristics that either provide a protective role at these sites and/or the absence of which increase risk for mucosal injury

Potential impact on the field

Oral mucosal injury caused by cancer therapies Jensen et al.

87

J Oral Pathol Med

Oral mucosal injury caused by cancer therapies Jensen et al.

J Oral Pathol Med

Enhanced quality of cancer care, with resultant improved rates of cancer cure and remission while reducing cost of that cancer treatment Capitalizing on clinical practice network technology to assess impact of mucositis guidelines in clinical oncology practice relative to (i) improved cancer treatment efficacy with (ii) reduced toxicity profile Interprofessional research directed to assessment of clinical and economic impact when state-of-the-science clinical guidelines are incorporated into cancer patient care

Enhanced cancer patient care based on a continuously evolving contemporary evidence base Measurement of impact of software technology upon enhanced use of (i) mucositis guidelines as well as (ii) updated guideline versions as they emerge over time Clinical practice Enhanced dissemination of high quality mucositis guidelines via software-based technology (e.g., podcasts, smartphones, tablets)

Reduced development time and costs for new therapeutics, including those being developed to prevent and/or treat oral mucositis Creating novel pre-clinical and clinical models that address patient-specific responses rather than an overall averaging of efficacy and toxicity profiles across patients Incorporation of patient-based risk profiling into clinical trial design for development of novel drugs, biologics, and devices

Research domain

Table 3 (continued)

Key research direction

Potential impact on the field

88

science into clinical practice guidelines that produce effective, cost-effective outcomes could then transform the vision of personalized medicine into a reality for cancer patients, their families, and their healthcare providers.

References 1. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004; 100: 1995–2025. 2. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003; 98: 1531–9. 3. Bowen JM, Elad S, Hutchins RD, Lalla RV. Methodology for the MASCC/ISOO Mucositis Clinical Practice Guidelines Update. Support Care Cancer 2013; 21: 303–8. 4. Elad S, Bowen J, Zadik Y, Lalla RV. Development of the MASCC/ISOO Clinical Practice Guidelines for Mucositis: considerations underlying the process. Support Care Cancer 2013; 21: 309–12. 5. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996; 49: 749–54. 6. Somerfield MR, Einhaus K, Hagerty KL, Brouwers MC, Seidenfeld J, Lyman GH. American Society of Clinical Oncology clinical practice guidelines: opportunities and challenges. J Clin Oncol 2008; 26: 4022–6. 7. Al-Dasooqi N, Sonis ST, Bowen JM, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer 2013; 21: 2075–83. 8. Mougeot JL, Bahrani-Mougeot FK, Lockhart PB, Brennan MT. Microarray analyses of oral punch biopsies from acute myeloid leukemia (AML) patients treated with chemotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011; 112: 446–52. 9. Bowen JM, Gibson RJ, Keefe DM. Animal models of mucositis: implications for therapy. J Support Oncol 2011; 9: 161–8. 10. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol 2009; 63: 239–51. 11. Yasuda M, Kato S, Yamanaka N, et al. 5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. Br J Pharmacol 2013; 168: 1388–400. 12. Logan RM, Gibson RJ, Sonis ST, Keefe DM. Nuclear factorkappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Oral Oncol 2007; 43: 395–401. 13. Chen P, Lingen M, Sonis ST, Walsh-Reitz MM, Toback FG. Role of AMP-18 in oral mucositis. Oral Oncol 2011; 47: 831–9. 14. Sonis ST. Oral mucositis. Anticancer Drugs 2011; 22: 607–12. 15. Sonis ST. New thoughts on the initiation of mucositis. Oral Dis 2010; 16: 597–600. 16. Sonis ST. Mucositis: the impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol 2009; 45: 1015–20. 17. Peterson DE, Keefe DM, Sonis ST. New frontiers in mucositis. In: Govindan R, ed. ASCO Educational Book. Alexandria,VA, USA: American Society of Clinical Oncology, 2012; 545–51.

Oral mucosal injury caused by cancer therapies Jensen et al.

18. Sonis ST, Tracey C, Shklar G, Jenson J, Florine D. An animal model for mucositis induced by cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1990; 69: 437–43. 19. Sonis ST, Scherer J, Phelan S, et al. The gene expression sequence of radiated mucosa in an animal mucositis model. Cell Prolif 2002; 35(Suppl 1): 93–102. 20. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004; 4: 277–84. 21. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998; 34: 39–43. 22. Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293: 293–7. 23. Al-Dasooqi N, Bowen JM, Gibson RJ, Logan RM, Stringer AM, Keefe DM. Irinotecan-induced alterations in intestinal cell kinetics and extracellular matrix component expression in the dark agouti rat. Int J Exp Pathol 2011; 92: 357–65. 24. Sonis S, Antin J, Tedaldi M, Alterovitz G. SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Oral Dis 2013; doi:10. 1111/odi.12146. 25. Stringer AM. Interaction between host cells and microbes in chemotherapy-induced mucositis. Nutrients 2013; 5: 1488–99. 26. Ye Y, Carlsson G, Agholme MB, et al. Oral bacterial community dynamics in pediatric patients with malignancies in relation to chemotherapy-related oral mucositis: a prospective study. Clin Microbiol Infect 2013; doi:10.1111/ 1469-0691.12287. 27. Schelenz S, Abdallah S, Gray G, et al. Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors. J Oral Pathol Med 2011; 40: 83–9. 28. Djuric M, Jankovic L, Jovanovic T, et al. Prevalence of oral herpes simplex virus reactivation in cancer patients: a comparison of different techniques of viral detection. J Oral Pathol Med 2009; 38: 167–73. 29. Baharvand M, ShoalehSaadi N, Barakian R, Moghaddam EJ. Taste alteration and impact on quality of life after head and neck radiotherapy. J Oral Pathol Med 2013; 42: 106–12. 30. Yamazaki M, Fujii S, Ochiai A. Reduction of type II taste cells correlates with taste dysfunction after X-ray irradiation in mice. J Oral Pathol Med 2010; 39: 212–8. 31. Olczak-Kowalczyk D, Daszkiewicz M, Krasuska S, et al. Bacteria and Candida yeasts in inflammations of the oral mucosa in children with secondary immunodeficiency. J Oral Pathol Med 2012; 41: 568–76. 32. Elad S, Epstein JB, Raber-Durlacher J, Donnelly P, Strahilevitz J. The antimicrobial effect of Iseganan HCl oral solution in patients receiving stomatotoxic chemotherapy: analysis from a multicenter, double-blind, placebo-controlled, randomized, phase III clinical trial. J Oral Pathol Med 2012; 41: 229–34. 33. Forster C, Aboodi G, Lipton J, Glogauer M. A non-invasive oral rinse assay predicts bone marrow engraftment and 6 months prognosis following allogeneic hematopoietic stem cell transplantation. J Oral Pathol Med 2012; 41: 165–70. 34. Lam DK, Dang D, Zhang J, Dolan JC, Schmidt BL. Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2. J Neurosci 2012; 32: 14178–83. 35. Viet CT, Schmidt BL. Biologic mechanisms of oral cancer pain and implications for clinical therapy. J Dent Res 2012; 91: 447–53. 36. Al-Dasooqi N, Bowen JM, Gibson RJ, Logan RM, Stringer AM, Keefe DM. Selection of housekeeping genes for gene

37.

38.

39.

40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

50.

51. 52.

53. 54.

expression studies in a rat model of irinotecan-induced mucositis. Chemotherapy 2011; 57: 43–53. Mougeot JL, Mougeot FK, Peterson DE, Padilla RJ, Brennan MT, Lockhart PB. Use of archived biopsy specimens to study gene expression in oral mucosa from chemotherapy-treated cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 115: 630–7. Hahn T, Zhelnova E, Sucheston L, et al. A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant 2010; 16: 801–8. Sonis S, Haddad R, Posner M, et al. Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers. Oral Oncol 2007; 43: 289–300. Michelson S, Sehgal A, Friedrich C. In silico prediction of clinical efficacy. Curr Opin Biotechnol 2006; 17: 666–70. Molina F, Dehmer M, Perco P, et al. Systems biology: opening new avenues in clinical research. Nephrol Dial Transplant 2010; 25: 1015–8. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin 2013; 63: 249–79. Lalla RV. The MASCC/ISOO Mucositis Guidelines Update: introduction to the first set of articles. Support Care Cancer 2013; 21: 301–2. Gibson RJ, Keefe DM, Lalla RV, et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer 2013; 21: 313–26. McGuire DB, Fulton JS, Park J, et al. Systematic review of basic oral care for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 3165–77. Nicolatou-Galitis O, Sarri T, Bowen J, et al. Systematic review of amifostine for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 357–64. Peterson DE, Ohrn K, Bowen J, et al. Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer 2013; 21: 327–32. Migliorati C, Hewson I, Lalla RV, et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 333–41. Raber-Durlacher JE, von B€ ultzingsl€ owen I, Logan RM, et al. Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 343–55. Nicolatou-Galitis O, Sarri T, Bowen J, et al. Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 3179–89. Yarom N, Ariyawardana A, Hovan A, et al. Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 3209–21. Saunders DP, Epstein JB, Elad S, et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 3191–207. Jensen SB, Jarvis V, Zadik Y, et al. Systematic review of miscellaneous agents for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 3223–32. Mucositis Study Group Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Evidence-based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy, 2013. Available at: http://www.mascc.org/mucositis-guidelines (accessed on 11 November 2013).

89

J Oral Pathol Med

Oral mucosal injury caused by cancer therapies Jensen et al.

90

55. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 2010; 116: 210–5. 56. Ferte C, Paci A, Zizi M, et al. Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur J Cancer 2011; 47: 2249–55. 57. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 2012; 17: 135–44. 58. Martins F, de Oliveira MA, Wang Q, et al. A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 2013; 49: 293–8. 59. Elting LS, Chang YC, Parelkar P, et al. Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis. Support Care Cancer 2013; 21: 3243–54.

J Oral Pathol Med

60. Chuang P, Langone AJ. Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus. Am J Transplant 2007; 7: 714–7. 61. de Oliveira MA, Martins EM, Wang Q, et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 2011; 47: 998–1003. 62. Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 2011; 15: E83–E9. 63. Gordon Research Conference Mucosal Health & Disease. 2013. Available at: http://www.grc.org/programs.aspx?year= 2013&program=mucosal (accessed on 11 November 2013).

Conflict of interest The authors report no conflicts of interest.