REVIEW ARTICLE

Oral mucosal injury caused by cancer therapies: currentmanagement and new frontiers in research

Siri B. Jensen1, Douglas E. Peterson2

1Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, Department of Odontology, Faculty of Health andMedical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Section of Oral Medicine, Department of Oral Health & DiagnosticSciences, 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 muco-

sitis as published in the Journal of Oral Pathology and

Medicine 20082013 are specifically highlighted in thiscontext. Key research directions in basic and transla-

tional 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: 8190

Keywords: cancer therapy; oral mucositis; pathobiology;

prevention; research; treatment

Introduction

Oral mucosal injury caused by cancer therapies (oralmucositis [OM]) is a common toxicity of antineoplasticdrugs and/or head and neck radiation in cancer patients (1).OM can result in signicant pain and the patient oftenrequires systemic narcotics for pain relief. The lesion can

also negatively affect diet, nutrition, oral hygiene, andquality of life. In immunosuppressed patients, secondaryinfection of oral mucositis lesions can lead to bacteremia,fungemia, and sepsis. In selected patients, the signicantmorbidity associated with OM may result in dose reductions,delays, and/or treatment interruptions in cancer therapywhichin turn can negatively impact patient survivorship. Manage-ment of OM has for several decades and continues to bedirected to supportive care including basic oral care, oral paincontrol, prevention and treatment of infection, and nutritionalsupport. The lesion continues to represent an important unmetmedical need in oncology practice.Depending on type and mechanism of action, the cancer

treatment regimens can also impact other mucosal sites ofthe alimentary tract including the esophagus, stomach, andsmall and large intestine. Oral and gastrointestinal mucositiscan cause hospital admission and is thus also associatedwith increased use of healthcare resources (2).This invited update provides a summary of oral mucosal

injury induced by cancer therapies, including recentadvances in pathobiology, evidence for prevention andtreatment, and emerging frontiers in research.

Methods

Original research as well as review articles identied inMEDLINE/PubMed was considered for inclusion. In addi-tion, the article database of the Journal of Oral Pathologyand Medicine was searched for articles addressing variousaspects of oral mucosal injury and related oral complicationsof cancer therapies published in the period between 2008and 2013. Key word terms for both searches included thefollowing: oral, mucositis, stomatitis, mucous membrane,mucosa, cancer therapies, chemotherapy, antineoplasticagents, radiation therapy, chemoradiation, head and neckcancer, leukemia, lymphoma, hematopoietic stem celltransplantation, tumor, neoplasm.The OM clinical guidelines from the Mucositis Study

Group of theMultinational Association of Supportive Care inCancer/International Society of Oral Oncology (MASCC/

Correspondence: Siri Beier Jensen, DDS, PhD, Section of Oral Medicine,Clinical Oral Physiology, Oral Pathology & Anatomy, Department ofOdontology, Faculty of Health & Medical Sciences, University ofCopenhagen, Nrre Alle 20, DK-2200 N Copenhagen, Denmark. Tel:+45 35 32 65 52, Fax: +45 35 32 67 22, E-mail: sirib@sund.ku.dk

This work was funded in part by NIH/NIDCR 1R01 DE021578.Accepted for publication October 14, 2013

doi: 10.1111/jop.12135

J Oral Pathol Med (2014) 43: 8190

2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

wileyonlinelibrary.com/journal/jop

ISOO) are also included in this review.Methodsutilizedby theMASCC/ISOO Study Group to produce the guidelines aredescribed in detail in Bowen et al. (3) and Elad et al. (4). Inbrief, methodology included a literature search for all relevantpapers indexed in Medline until 31st December 2010. Inaddition, reference lists of previous guidelines papers as wellas Cochrane reviews were searched in order to identifypotential additional studies. Clinical guidelines were sepa-rated based on the aim of the intervention (prevention ortreatment of OM), type of treatment (radiotherapy, chemo-therapy, chemoradiotherapy, or high-dose conditioning ther-apy for hematopoietic stem cell transplantation (HSCT)), androute of administration of the OM intervention. Studies wereevaluated based on a list ofmajor andminoraws as describedby Hadorn et al. (5). Level of evidence was then assigned foreach intervention based on criteria published by Somereldet al. (6). The resultant clinical guidelines were thus based onthe strength of the overall level of evidence for eachintervention and were classied into three types: recommen-dation, suggestion, or no guideline possible.

Pathobiology

The current modeling of OM pathobiology is primarilybased on in vitro and animal models that have collectivelyidentied a cascade of events in epithelial and submucosaltissue compartments. As described below, the body ofknowledge denes a complex, multifactorial paradigm ofmucosal injury and repair (720). Selected outcomes of thispreclinical modeling have been translated into clinical trials

with varying degrees of success, as described later in thissection.A key advance in OM research occurred when Sonis

published a ve-phase model of OM pathobiology in 1998(21). This model has been subsequently modied based onnew scientic discoveries that have emerged in recent years(Fig. 1). The contemporary model denes a complexpathobiology including microvascular injury, up-regulationof pro-inammatory cytokines including Tumor NecrosisFactor-a, Interleukin (IL)-1b and IL-6, extracellular matrixreactions and hostmicrobiome interactions (7, 10, 20, 2226). It is important to recognize that while selected biologicevents may occur sequentially, the collective injury to theepithelium and submucosa can be concurrent. Thisadversely synergistic interaction results in profound dysre-gulation of mucosal homeostasis and repair.In addition to this oral mucosal dysregulation, other oral

complications in addition to OM often appear concurrentlyin patients. The pattern of this collective toxicity prolevaries in type, intensity and duration depending upon thetype and mechanism of action of the cancer treatmentregimen as well as upon patient-specic factors.As delineated in Journal of Oral Pathology and Medicine

publications over the past 5 years the knowledge baseregarding mechanisms and interactions among oral compli-cations in oncology patients continues to increase (Table 1).In addition to OM, for example, oral complications mayinclude pain caused by oral cancer, salivary gland hypo-function (objectively decreased saliva secretion)/xerostomia(subjective feeling of dry mouth), fungal infection (27) or

Figure 1 The ve-phase model of oral mucositis pathobiology divided into the following: initiation, the primary damage response (messaging andsignaling), amplication, ulceration, and healing. Reprinted with permission from Sonis ST. J Support Oncol 2007; 5(Suppl. 4):311.

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viral infection (28), taste disturbances (dysgeusia) (29, 30),and muscular brosis (head and neck radiation patient)(Table 1). As noted in three publications, OM can beexacerbated by colonizing oral microora when local andsystemic immune function is compromised (Table 1) (27,31, 32). An additional example of these complex and uniqueoral interactions and their relationship to systemic status iswell illustrated in one of the Journal of Oral Pathology andMedicine publications. In this study, neutrophils in oraltissues (oral engraftment) occur earlier in time status/poststem cell transplantation as compared to the time ofappearance of neutrophils in the peripheral circulation(blood engraftment) (Table 1) (33). Investigations such asthose published in Journal of Oral Pathology and Medicinecontinue to contribute to identifying new directions inscience as well as their potential impact on clinical practicein the future.In addition to these well-documented toxicities, there are

important new directions in the research eld that warrantpursuit. For example, the molecular and sensory compo-nents associated with oral pain in the OM modelingrepresent a relatively unexplored frontier. Even thoughmoderate/severe oral pain has long been a clinical hallmarkof OM, the specic molecular modeling associated with thesymptom has not been systematically studied in detail.Literature developed in non-mucositis cancer pain models(34, 35) could provide powerful information to advance thisaspect of the etiopathogenesis in relation to clinical impact.It is important to note that, in the clinical setting, it is oftenthe oral pain and not necessarily the extent of erythema and/or ulceration that is the principal reason that patients requirehospitalization as well as expensive supportive care inter-ventions when the mucosal injury develops.It is also clear in recent years that the patients genomic

prole can be a key contributor to the cellular and tissueresponse to cancer treatment (7, 8, 3639). In this context,novel systems biology approaches as utilized in non-mucositis modeling (40, 41) are increasingly being utilizedto systematically delineate key network hubs and pathwaysthat collectively contribute to the OM trajectory (24).Investigative strategies that then link with applied genomicsare setting the stage for exciting new advances relative togenome-wide risk prediction that will likely enhance theclinicians ability to deliver personalized cancer medicine inthe future (17). These and related recent scientic advancesthus continue to enhance the opportunity to delineate thecomplex pathobiology such that key molecular pathwayscan be targeted for mucositis therapeutics in the years tocome.These technologies and lessons learned from molecular

studies of OM caused by conventional cancer treatmentssuch as high-dose chemotherapy or head and neck radiationwill likely also have high value in the study of the uniqueexpression of oral mucosal injury recently being describedin cancer patients receiving molecularly targeted biologics.These treatments are directed, for example, to inhibitors ofangiogenesis or the mammalian target of rapamycin(mTOR), epidermal growth factor receptor (EGFR), humanepidermal growth factor receptor 2 (HER2), or multikinaseAbl pathways (42). They are increasingly being documentedas causing oral mucosal injury that is distinctly different

in incidence, clinical appearance and response to therapyas contrasted with mucositis caused by chemotherapy and/or head and neck radiation. Given the relative recentemergence of the mucositis associated with molecularlytargeted cancer agents, there is important need and oppor-tunity for new research regarding causation as well asoptimal clinical management strategies.The research agenda described in this section provides an

excellent opportunity for investigators representing the oralpathology and oral medicine sciences to continue atleadership and collaborative levels in the future. Thesummary of future research directions (New frontiers inresearch) presented later in this review further delineatesthese and other opportunities for discovery and clinicaltranslation.Despite these exciting new directions in the eld a word

of caution is appropriate at this stage in the discussion.Without question selected aspects of this knowledge basehave been effectively translated into clinical drug and devicedevelopment in recent years, as described above. However,the actual impact on cancer patient care clinically has onlybeen partially successful to date, despite the impressivescientic and translational advances in recent years. Barriersyet to be overcome include the following: (i) the need tofurther rene the state-of-the-science molecular model, (ii)competing corporate priorities for mucositis vs. non-muco-sitis therapeutics, and (iii) varying degrees of incorporationof mucositis management technologies across the extensiveclinical oncology practice cohort worldwide. Until theserate-limiting issues can be more fully addressed, the futureof OM prevention and treatment will be negativelyimpacted. It is thus essential to incorporate these additionalcomponents into the research and clinical planning so as tooptimize research and clinical outcomes.

The evidence-base for management of oralmucositisOral mucosal toxicity caused by chemotherapy or head andneck radiationA number of agents and interventions have been studied forprevention and treatment of OM in patients receivingconventional cancer therapies such as high-dose chemo-therapy or head and neck radiation. They encompass a widerange of biologic rationales and potential mechanismsrelative to the pathogenesis of OM. Having said this andwith few exceptions, however, there is in general consid-erable variability across results.As noted earlier the evidence-base for various preventive

and treatment interventions has been reviewed by theMASCC/ISOO Mucositis Study Group. This has resulted inpublication of clinical practice guidelines for OM as recentlyas 2013, with a goal of enhancing evidence-based oncologycare and improving overall cancer treatment outcomes (3, 4,4353). Findings the studies were integrated into recommen-dations or suggestions at three levels: (i) in favor ofinterventions for OM, (ii) against interventions for OM, or(iii) no guideline possible due to insufcient or conictingevidence. Given the state-of-the-science this last categorywasthe most prevalent conclusion by the MASCC/ISOOreviewers.

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Tab

le1

Journalof

OralPathology

andMedicinepublications

from

2008

2013in

thecontextof

oralmucosalinjury

andotheroralcomplications

caused

bycancer

therapies

Year

publishedin

Journalof

Oral

Pathology

&Medicine

Firstauthor

Title

ofpublication

Selected

keyndings

2013

(29)

M.Baharvand

Tastealterationandimpacton

quality

oflifeafterhead

andneck

radiotherapy

Oraltissues

with

high

turnover

ratessuch

astastebuds

canbe

damaged

byradiationtherapy

Allhead

andneck

cancer

patientshaddysgeusiaafterradiationtherapyand72.2%

hadtotal

asteloss.Signicant

changeswereobserved

inconcentrations

andintensities

ofperceivedtastemodalities,mainlysaltandbitterfollowed

bysour

andsw

eet.Dysgeusianegativelyimpacted

quality

oflife

2012

(32)

S.Elad

The

antim

icrobialeffectof

Iseganan

HCL

oralsolutionin

patientsreceiving

stom

atotoxicchem

otherapy:analysisfrom

amulticenter,double-blind,

placebo-controlled,

random

ized,

phaseIIIclinicaltrial

Oralinfections

frequently

affectimmunosuppressedcancer

patientsandareassociated

with

system

icinfections.

TopicalIseganan

hydrochloride(adm

inisteredas

swishandsw

allow,sixtim

esdaily

for21

28days

inpatientshaving

myeloablativechem

otherapy)signicantly

reducedthe

oraltotalload

ofaerobicbacteria,streptococci(m

ainlyviridans

streptococciand

non-hemolyticstreptococci),andyeasts

TopicalIseganan

haspotentialas

anoralantim

icrobialagentin

thepreventionof

infection.

2012

(33)

C.Fo

rster

Anon-invasive

oralrinseassaypredicts

bone

marrow

engraftmentand6months

prognosisfollowingallogeneic

hematopoieticstem

celltransplantation

Anon-invasive

oralrinsewas

used

inahematopoieticstem

celltransplant

populationto

monitororalneutrophilcounts

Onaverage,rstappearance

ofneutrophils

inoraltissues

(oralengraftment)followinghematopoietic

stem

celltransplantationweredetected

8.4days

earlierthan

neutrophils

appearingin

theblood

circulation(peripheralbloodengraftment).Thisndingenabledconrm

ationof

engraftmentone

weekearlierthan

whenusingperipheralbloodneutrophilcountsalone

Oralengraftmentmarkedthebeginningof

oralmucositisrecovery

phase

The

timespan

betweenoralengraftmentandperipheralbloodengraftmentwas

apredictor

oftreatmentoutcom

eat6monthsfollowinghematopoieticstem

celltransplantation.

Atim

espan

ofless

than

6days

resultedin

100%

ofpatientshaving

anegativeoutcom

e2012

(31)

D.Olczak-Kow

alczyk

BacteriaandCandida

yeastsin

inam

mation

oftheoralmucosain

childrenwith

secondaryimmunodeciency

Oralmucosaldamagein

immunocom

prom

ised

patientsmay

increase

risk

ofbacterem

iaandfungem

iaAcorrelationwas

foundbetweenprevalence

ofstom

atitis/oralmucositisandpresence

ofcoagulase-negativeStaphylococci,Enterococcusspp.,andCandida

spp.

inan

immunocom

prom

ised

pediatricpopulation(organ

transplant

recipientson

immunosuppressive

medications

andcentralnervoussystem

tumor

patientshaving

chem

otherapy)

2011

(27)

S.Schelenz

Epidemiology

oforalyeastcolonization

andinfectionin

patientswith

hematological

malignancies,head

neck

andsolid

tumors

56.8%

ofthecancer

patient

studypopulationwerecolonizedwith

oralyeasts

The

incidenceof

oralcandidiasisin

yeastcolonizedpatientswas

29.2%

inhead

andneck

cancer,17%

insolid

tumors,and20.5%

inhematologicalmalignancies.

The

majority

ofinfections

werecaused

byCandida

albicans;however,onethirdof

patientsharbored

non-C.albicans

speciessuch

asC.glabrata

which

weremore

resistantto

anti-fungalagents.

Overallresistance

toazoles

was

28.2%.Noresistance

was

foundforam

photericin

Bor

nystatin

Age

anddentures

wereidenti

edas

independentrisk

factorsassociated

with

yeastcarriage

2010

(30)

M.Yam

azaki

Reductionof

type

IItastecells

correlates

with

tastedysfunctionafterX-ray

irradiationin

mice

Histopathologicexam

inationof

circum

vallatepapillaein

miceexposedto

asingleradiation

dose

of15

Gyto

thehead

andneck

region

show

eddisappearanceof

basalcells

byday4

afterirradiationfollowed

byadecrease

inthenumberof

tastecells

byday820,

particularly

type

IItastecells,with

recovery

byday24

Preference

forsw

eettastewas

decreasedin

parallelwith

tastecellnumber

2009

(28)

M.Djuric

Prevalence

oforalherpes

simplex

virus

reactivationin

cancer

patients:a

comparisonof

differenttechniques

ofviraldetection

Beforechem

otherapy,91.7%

ofcancer

patientswereherpes

simplex

virus1(HSV

-1)seropositive

Polymerasechainreactionwas

HSV

-1positivein

71.7%

ofcancer

patientsbefore

chem

otherapy

and85%

afterchem

otherapy,directimmunouorescence

was

HSV

-1positivein

3.3%

before

and11.7%

afterchem

otherapy,andcellcultures

werepositivein

33.3%

and40%,respectively.

HSV

-2was

notdetected

There

was

nosignicant

difference

inHSV

positivity

betweenpatientswith

andwithout

oralmucosallesionspriorto

and14

days

afterinitiationof

achem

otherapeuticcycle

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The MASCC/ISOO OM guidelines in favor of inter-ventions to prevent or treat OM include oral care protocols,oral cryotherapy, laser therapy, recombinant humankeratinocyte growth factor-1 (palifermin), benzydaminehydrochloride, systemic zinc supplements, and patient-controlled analgesia with morphine/transdermal fentanyl/2%morphine mouthwash/0.5% doxepin mouthwash to treatOM pain. Additional details are presented in Table 2 (45,4752). As noted in the Table, each recommendation andsuggestion is targeted to a specic cancer treatmentregimen (45, 4752).Management approaches to oral complications in the

out-patient and hospital setting may to some extent rely ontradition or subjective approaches in some clinical prac-tices. These approaches may also be inuenced by lack ofinterdisciplinary sharing of knowledge and collaboration.Interventions implemented out of tradition or customarypractice may not be efcient, and may actually prolong orexacerbate the course of the oral complications. Inaddition to safety and efcacy, cost-effectiveness of apreventive or therapeutic intervention should be a priorityconsideration. In this context, it is thus equally important

to address the evidence against interventions for OM, inaddition to addressing the evidence in favor of interven-tions for OM.The MASCC/ISOO OM guidelines recommend avoiding

the following for prevention of OM:

use of intravenous glutamine in patients receiving high-dose chemotherapy for HSCT;

sucralfate mouthwash in head and neck radiation cancerpatients/concomitant chemoradiation or chemotherapy. Inaddition, sucralfate is not recommended for treatment ofOM in head and neck radiation cancer patients nor inchemotherapy patients;

iseganan mouthwash in high-dose chemotherapy forHSCT, or in head and neck radiation cancer patients/concomitant chemoradiation;

polymyxin/tobramycin/amphotericin B lozenges/pasteand bacitracin/clotrimazole/gentamicin lozenges in headand neck radiation cancer patients (51, 52).

MASCC/ISOO clinical guideline suggestions of inter-ventions not to be used to prevent OM include thefollowing:

Table 2 The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Evidence-Based ClinicalPractice Guidelines in favor of interventions for oral mucositis secondary to cancer therapy (Not included in the table: Recommendations/suggestions againstan intervention for oral mucositis and interventions where no guidelines were possible due to insufcient or conicting evidence) (for details see references(3, 4, 43, 4652) and http://www.mascc.org/mucositis-guidelines (54)

Prevention/treatment approach GuidelineLevel ofevidence References

Oral care protocol Suggestion that oral care protocols be used to prevent OM in allage groups and across all cancer treatment modalities

III (45)

Oral cryotherapy Recommendation that patients receiving bolus 5-FU CT undergo30-min oral cryotherapy to prevent OM

II (47)

Suggestion to use cryotherapy to prevent OM in patients receivinghigh-dose melphalan, +/- TBI as conditioning for HSCT

III

Laser and other light therapy Recommendation for laser therapy (wavelength around 650 nm,intensity 40 mW, tissue energy dose of 2 J/cm2) to prevent OM in HSCT

II (48)

Suggestion for laser therapy (wavelength of 632 nm) to preventRT-induced OM without concomitant CT for H&N cancer

III

Cytokines and growth factors Recommendation for recombinant human keratinocyte growth factor-1(palifermin), 60 lg/kg per day for 3 days prior to conditioning treatmentand for 3 days post-transplantation to prevent OM in HD-CT with TBIfollowed by auto-HSCT

II (49)

Anti-inammatory agents Recommendation for benzydamine mouthwash to prevent OM in H&N cancerpatients receiving moderate dose RT (up to 50 Gy) without concomitant CT

I (50)

Natural agents Suggestion that systemic zinc supplements administered orally may be ofbenet to prevent OM in oral cancer patients receiving RT or CT-RT

III (51)

Antimicrobials, mucosal coatingagents, anesthetics, and analgesics

Recommendation for patient-controlled analgesia with morphine be used totreat pain due to OM in patients undergoing HSCT

II (52)

Suggestion that transdermal fentanyl may be effective to treat pain due to OMin patients receiving conventional CT and HD-CT, +/- TBI

III

Suggestion that 2% morphine mouthwash may effective to treat pain dueto OM in H&N RT patients

III

Suggestion that 0.5% doxepin mouthwash may be effective to treat pain due to OM IV

OM Oral mucositis, 5-FU 5-uorouracil, HD high-dose, CT chemotherapy, +/- with or without, TBI Total body irradiation, HSCT Hematopoietic stem celltransplantation, auto-HSCT autologous hematopoietic stem cell transplantation, RT Radiation therapy, H&N Head and neck.Quality of recommendations based on Hadorn and Somereld criteria (5, 6): Level of evidence; I, Meta-analysis of multiple well-designed studies. High-powered 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, prepost, cohort); IV, Well-designed, non-experimental studies (e.g., comparative and correlationaldescriptive and case studies); V, Case reports and clinical examples.Guideline classication: Recommendation, This is reserved for guidelines based on levels I or II evidence; Suggestion, Guideline based on levels III, IV, Vevidence; implies panel consensus on the interpretation of the evidence; No guideline possible, Used with insufcient 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.

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chlorhexidine mouthwash in head and neck radiationcancer patients;

granulocytemacrophage colony-stimulating growth fac-tor (GM-CSF) mouthwash in patients receiving high-dosechemotherapy for HSCT;

misoprostol mouthwash in head and neck radiation cancerpatients;

systemic pentoxifylline in patients undergoing HSCT; systemic pilocarpine in head and neck radiation cancerpatients or high-dose chemotherapy for HSCT (45, 49,50, 53).

Consideration of the specic indication of either preven-tion or treatment of OM is important when interpreting andimplementing the collective guidelines. For example, it hasbeen suggested not to use chlorhexidine mouthwash for theprevention of OM in head and neck cancer patientsreceiving radiation therapy. However, it may be used onother indication, for example, reduction of oral microbialload (45, 54).For other OM interventions [e.g., amifostine (46)], no

guidelines were possible due to insufcient or conictingevidence. This outcome also applied to a number of otherinterventions described above in context of other cancertreatment settings than those dened in the MASCCISOOclinical practice guidelines in favor of the interventions.Examples of this disparity include oral cryotherapy, lasertherapy and other light therapy, cytokines and growthfactors, anti-inammatory agents, natural agents, antimicro-bials, mucosal coating agents, anesthetics and analgesics,and other miscellaneous agents (45, 4753).

Oral mucosal toxicity of molecularly targeted cancertherapiesThe recent advent of molecularly targeted cancer therapies inclinical oncology practice is redening treatment paradigmsfor many types of cancers. These agents directed towardblocking of specic molecular receptors or intracellularpathways including vascular endothelial growth factor recep-tor (VEGFR) inhibitors, multi-targeted tyrosine kinaseinhibitors (TKI), and mTOR inhibitors. Despite these molec-ularly precise mechanisms of action, however, a novelexpression of oral mucosal injury distinct from the classicchemotherapy- and radiation-induced OM has also emergedclinically. For example, painful oral ulcerations are a commoncomplication of mTOR inhibitors and resemble aphthousstomatitis, hence have been referred to as mTOR inhibitor-associated stomatitis (mIAS) (5559). mIAS may potentiallyresult in dose modications or delay, or discontinuation of thecancer therapy. Further study of this lesion is needed at boththe basic science as well as clinical trial level. Until results ofsuch studies become available, high quality systematicevidence is not available for development of evidence-basedclinical practice guidelines. In the interim, the clinicalmanagement strategy of mIAS is empirically based on drugsthat have been used for the prevention and treatment ofaphthous stomatitis and includes topical, intralesional, orsystemic corticosteroid therapy dependent on severity of theoral lesions (42, 6062).

New frontiers in research

Based on laboratory and clinical progress highlighted in thisreview, the next decade of research promises to bringstrategic new advances in pathobiologic modeling that inturn can drive development of new mucositis therapeuticsand guidelines for use in clinical practice. In addition tostudies of mucosal toxicity, novel research collaborationsare being fostered in settings in which the basic andtranslational science associated treatment-induced mucosaltoxicity is compared and contrasted with the science ofmucosal health and homeostasis as well as naturallyoccurring mucosal disease such as inammatory boweldisease. A recent example of this new paradigm in fosteringnovel research collaborations was the June 2013 rst-in-kind Gordon Research Conference Mucosal Health &Disease (63). This new conference brought together basicand translational researchers from the international commu-nity, with specic emphasis on dening new researchopportunities for emerging investigators.Table 3 delineates several of important research domains

in relation to key research directions and their potentialimpact on the eld. Basic, translational, and clinicalresearch directed to these and related domains could likelyproduce paradigm-shifting changes in fundamental scienticdiscovery associated with mucosal homeostasis, injury andrepair. In addition, the future research could contribute todevelopment of novel clinical interventions that couldstrategically enhance cancer patient care while reducingcost of that care. In selected cases, a specic researchdomain (e.g., systems biology) directly applies to more thanone research direction and its potential impact in the eld.Investigators from dental medicine, including oral med-

icine and oral pathology, continue to collaborate with otherbasic and clinical scientists as well as oncology clinicians tofurther create and pursue these opportunities.

Conclusion

The scope and depth of research and its translation toclinical practice for management of OM in oncologypatients has strategically escalated over the past 15 years.In addition to delineating new insights into pathobiology ofOM, these advances include development of high qualityevidence-based guidelines for prevention and managementof the lesion in clinical practice.Despite these advances, however, OM continues to

represent an important unmet medical need in many cancerpatients receiving mucotoxic cancer treatments. Precisedelineation of specic pathobiologic and pharmacogenomictargets for interventions need to be identied in order toenhance quality of cancer care while reducing cost of thatcancer treatment. In addition, further development of noveldrugs, biologics, and devices is essential to optimizingclinical management of this biologically complex toxicity.New research directions such as those highlighted in this

review will likely in turn position clinicians to predicttoxicity risk and tailor therapeutic interventions to theindividual patient. This translation of discovery-level

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Tab

le3

New

frontiersin

research

Researchdomain

Key

research

direction

Potentia

limpact

ontheeld

Molecular

modeling

Mucosal

homeostasis

Studyof

privileged

mucosal

sitesthatdo

nottypically

developclinical

mucosal

injury

caused

bycancer

treatment

Discovery

ofgenetic-,molecular-,andcellular-unique

characteristics

thateither

provideaprotectiveroleatthesesitesand/or

theabsence

ofwhich

increase

risk

formucosal

injury

Naturally

occurringmucosal

disease

Capitalizingupon

research

technology

andresearch

outcom

esfrom

studies

ofnaturally

occurringmucosal

disease,to

inform

new

research

strategies

forinvestigationof

mucositis

Determinationof

thedegree

towhich

thepathobiology

ofnaturally

occurringmucosal

diseases

isconcordant

ordiscordant

with

thepathobiology

ofmucositiscaused

bycancer

treatmentregimens

Oralpain

Genetic

andimmunopathologicgovernance

oforalpain

inrelationto

sensorypathways

Enhancedcustom

izationof

system

atically

administeredpain

prevention

andtreatmentin

cancer

patients

Oralmucosaandtheoralmicrobiom

eInterfacinghigh

throughput

sequencing

technology

with

system

sbiologyin

orderto

discernthebiodiversity

ofmicrobial

communities

associated

with

mucositiscausationandprogression

Novelantim

icrobialsdirected

tomucositispreventionandtreatment

Molecular

basisforcancer

patient-based

variationin

incidenceandseverity

oforal

mucosal

injury

Analysisof

theroleof

patient-based

factors,includinggenomicsand

proteomics,in

contributingto

clinicaldevelopm

entof

oralmucositis

Creationof

aprioripredictivemodelsfordevelopm

entof

oral

mucositis,particularly

in(i)solid

tumor

patientsreceiving

multi-cyclechem

otherapeutic

regimens,or

(ii)patientsreceiving

molecularly

targeted

cancer

treatmentbiologics

Shared

vs.unique

molecular

pathobiology:

mucosaandskin

Integratingtheetiopathogenic

modelsof

mucosal

andderm

alinjury

toidentifypotentialshared

orunique

causativefactors

Advancesin

discovery-levelknow

ledgeof

mucosal

andderm

alwound

injury

andrepair&

developm

entof

therapeuticsthat

couldmitigate

cancer

treatmentinjury

atmucosal

aswellas

derm

alsites

System

sbiology,

also

seebelow,

Molecular

imaging

Incorporationof

computationalbiologytechnology

todelineate

molecular

andnetworkpathwayshubs

thatsignicantly

contribute

tomucosal

injury

andrepair

Strategicadvances

increationof

research

andclinical

modelsof

mucosal

homeostasisas

wellas

mucosal

toxicity

caused

bycancer

therapeutics

Molecular

imaging

Developmentandapplicationof

non-invasive

molecular

imagingtechnol

ogiesatthediscoveryandclinicallevel

Novelresearch

outcom

esrelativeto

pathobiology

aswellas

enhanced

capabilityto

deliver

personalized

medicineto

oncology

patients

Developmentof

molecularly

targeted

drugs,

biologics,anddevices

System

sbiologyto

morecomprehensively

delineatekeymolecular

andnetworkpathway

targetsforperturbationandresultant

mucositis

preventionand/or

treatment

Furtherdelineationof

thepathobiologicbasisformucositis,capitalizing

upon

bioinformaticsandothercomputationaltechnologies

inorderto

dene

centralnetworkhubs

andpathwaysthatdrivemucosal

injury

andrepair

Developmentof

(i)aprioripredictionof

mucositisincidenceand

severity

inagivenoncology

patient

coupledwith

(ii)custom

ized

therapeutic

regimensformucositisprevention

andtreatmentbasedupon

thatrisk

prediction

(continued)

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87

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

References

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9. Bowen JM, Gibson RJ, Keefe DM. Animal models ofmucositis: implications for therapy. J Support Oncol 2011;9: 1618.

10. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST,Keefe DM. Is the pathobiology of chemotherapy-inducedalimentary tract mucositis inuenced by the type of mucotoxicdrug administered? Cancer Chemother Pharmacol 2009; 63:23951.

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Tab

le3

(continued)

Researchdomain

Key

research

direction

Potentia

limpact

ontheeld

Incorporationof

patient-based

risk

pro

ling

into

clinical

trialdesign

fordevelopm

entof

noveldrugs,biologics,anddevices

Creatingnovelpre-clinical

andclinical

modelsthataddresspatient-specic

responsesrather

than

anoverallaveragingof

efcacy

andtoxicity

pro

les

across

patients

Reduced

developm

enttim

eandcostsfornew

therapeutics,including

thosebeingdevelopedto

preventand/or

treatoralmucositis

Clinical

practice

Enhanceddissem

inationof

high

quality

mucositisguidelines

viasoftware-basedtechnology

(e.g.,podcasts,sm

artphones,tablets)

Measurementof

impact

ofsoftwaretechnology

upon

enhanced

useof

(i)

mucositisguidelines

aswellas

(ii)updatedguidelineversions

asthey

emerge

over

time

Enhancedcancer

patient

care

basedon

acontinuously

evolving

contem

porary

evidence

base

Interprofessionalresearch

directed

toassessment

ofclinical

andeconom

icimpact

when

state-of-the-science

clinicalguidelines

are

incorporated

into

cancer

patient

care

Capitalizingon

clinicalpracticenetworktechnology

toassess

impact

ofmucositisguidelines

inclinicaloncology

practicerelativeto

(i)improved

cancer

treatmentefcacy

with

(ii)reducedtoxicity

pro

le

Enhancedquality

ofcancer

care,with

resultant

improved

ratesof

cancer

cure

andremission

whilereducing

costof

thatcancer

treatment

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Conflict of interest

The authors report no conicts of interest.

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