J Oral Pathol Med (2014) 43: 8190
doi: 10.1111/jop.12135
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 muco-
sitis as published in the Journal of Oral Pathology and
Medicine 20082013 are specifically highlighted in this
context. 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 (oral
mucositis [OM]) is a common toxicity of antineoplastic
drugs and/or head and neck radiation in cancer patients (1).
OM can result in signicant 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, Nrre All
e 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
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop
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 signicant
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. Manage-
ment 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
Original research as well as review articles identied in
MEDLINE/PubMed was considered for inclusion. In addi-
tion, 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 sepa-
rated based on the aim of the intervention (prevention or
treatment of OM), type of treatment (radiotherapy, chemo-
therapy, chemoradiotherapy, or high-dose conditioning ther-
apy 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 aws as described
by Hadorn et al. (5). Level of evidence was then assigned for
each intervention based on criteria published by Somereld
et al. (6). The resultant clinical guidelines were thus based on
the strength of the overall level of evidence for each
intervention and were classied into three types: recommen-
dation, suggestion, or no guideline possible.
Pathobiology
The current modeling of OM pathobiology is primarily
based on in vitro and animal models that have collectively
identied a cascade of events in epithelial and submucosal
tissue compartments. As described below, the body of
knowledge denes a complex, multifactorial paradigm of
mucosal injury and repair (720). Selected outcomes of this
preclinical modeling have been translated into clinical trials
Figure 1 The ve-phase model of oral mucositis pathobiology divided into the following: initiation, the primary damage response (messaging and
signaling), amplication, ulceration, and healing. Reprinted with permission from Sonis ST. J Support Oncol 2007; 5(Suppl. 4):311.
J Oral Pathol Med
with varying degrees of success, as described later in this
section.
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 on
new scientic discoveries that have emerged in recent years
(Fig. 1). The contemporary model denes a complex
pathobiology including microvascular injury, up-regulation
of pro-inammatory cytokines including Tumor Necrosis
Factor-a, Interleukin (IL)-1b and IL-6, extracellular matrix
reactions and hostmicrobiome 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 dysre-
gulation 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 prole
varies in type, intensity and duration depending upon the
type and mechanism of action of the cancer treatment
regimen as well as upon patient-specic 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 compli-
cations 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 hypo-
function (objectively decreased saliva secretion)/xerostomia
(subjective feeling of dry mouth), fungal infection (27) or

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 be
exacerbated by colonizing oral microora 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 eld that warrant
pursuit. For example, the molecular and sensory compo-
nents 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 specic 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 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 tissue
response to cancer treatment (7, 8, 3639). In this context,
novel systems biology approaches as utilized in non-
mucositis 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
clinicians ability to deliver personalized cancer medicine in
the future (17). These and related recent scientic 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
Oral mucosal injury caused by cancer therapies
Jensen et al.
83
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 oppor-
tunity 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 eld 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
scientic and translational advances in recent years. Barriers
yet to be overcome include the following: (i) the need to
further rene the state-of-the-science molecular model, (ii)
competing corporate priorities for mucositis vs. non-muco-
sitis 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.
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 chemo-
therapy 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 consid-
erable 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,
4353). Findings the studies were integrated into recommen-
dations or suggestions at three levels: (i) in favor of
interventions for OM, (ii) against interventions for OM, or
(iii) no guideline possible due to insufcient or conicting
evidence. Given the state-of-the-science this last category was
the most prevalent conclusion by the MASCC/ISOO
reviewers.
J Oral Pathol Med
 Table 1 Journal of Oral Pathology and Medicine publications from 20082013 in the context of oral mucosal injury and other oral complications caused by cancer therapies
J Oral Pathol Med
Year published in
Journal of Oral
Pathology & Medicine First author Title of publication
2013 (29) M. Baharvand Taste alteration and impact on quality
of life after head and neck radiotherapy
2012 (32) S. Elad 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
2012 (33) C. Forster A non-invasive oral rinse assay predicts
bone marrow engraftment and 6 months
prognosis following allogeneic
hematopoietic stem cell transplantation
2012 (31) D. Olczak-Kowalczyk Bacteria and Candida yeasts in inammation
of the oral mucosa in children with
secondary immunodeciency
2011 (27) S. Schelenz Epidemiology of oral yeast colonization
and infection in patients with hematological
malignancies, head neck and solid tumors
2010 (30) M. Yamazaki Reduction of type II taste cells correlates
with taste dysfunction after X-ray
irradiation in mice
2009 (28) M. Djuric Prevalence of oral herpes simplex virus
reactivation in cancer patients: a
comparison of different techniques
of viral detection
84
Selected key ndings
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. Signicant 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 2128 days in patients having myeloablative chemotherapy) signicantly 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, rst 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 nding enabled conrmation 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
Jensen et al.
Oral mucosal injury caused by cancer therapies
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 identied 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 820,
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 immunouorescence 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 signicant difference in HSV positivity between patients with and without
oral mucosal lesions prior to and 14 days after initiation of a chemotherapeutic cycle
 Oral mucosal injury caused by cancer therapies
Jensen et al.

The MASCC/ISOO OM guidelines in favor of inter-
ventions 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 patient-
controlled analgesia with morphine/transdermal fentanyl/2%
morphine mouthwash/0.5% doxepin mouthwash to treat
OM pain. Additional details are presented in Table 2 (45,
4752). As noted in the Table, each recommendation and
suggestion is targeted to a specic cancer treatment
regimen (45, 4752).
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 prac-
tices. These approaches may also be inuenced by lack of
interdisciplinary sharing of knowledge and collaboration.
Interventions implemented out of tradition or customary
practice may not be efcient, and may actually prolong or
exacerbate the course of the oral complications. In
addition to safety and efcacy, cost-effectiveness of a
preventive or therapeutic intervention should be a priority
consideration. In this context, it is thus equally important
85
to address the evidence against interventions for OM, in
addition 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 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 inter-
ventions 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 insufcient or conicting evidence) (for details see references
(3, 4, 43, 4652) 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-inammatory agents
Natural agents
Antimicrobials, mucosal coating
agents, anesthetics, and analgesics
Level of
Guideline evidence References
Suggestion that oral care protocols be used to prevent OM in all III (45)
age groups and across all cancer treatment modalities
Recommendation that patients receiving bolus 5-FU CT undergo II (47)
30-min oral cryotherapy to prevent OM
Suggestion to use cryotherapy to prevent OM in patients receiving III
high-dose melphalan, +/- TBI as conditioning for HSCT
Recommendation for laser therapy (wavelength around 650 nm, II (48)
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 III
RT-induced OM without concomitant CT for H&N cancer
Recommendation for recombinant human keratinocyte growth factor-1 II (49)
(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 I (50)
patients receiving moderate dose RT (up to 50 Gy) without concomitant CT
Suggestion that systemic zinc supplements administered orally may be of III (51)
benet to prevent OM in oral cancer patients receiving RT or CT-RT
Recommendation for patient-controlled analgesia with morphine be used to II (52)
treat pain due to OM in patients undergoing HSCT
Suggestion that transdermal fentanyl may be effective to treat pain due to OM III
in patients receiving conventional CT and HD-CT, +/- TBI
Suggestion that 2% morphine mouthwash may effective to treat pain due III
to OM in H&N RT patients
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 cell
transplantation, 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 correlational
descriptive 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, V
evidence; 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.

J Oral Pathol Med

 Oral mucosal injury caused by cancer therapies
Jensen et al.
86
chlorhexidine mouthwash in head and neck radiation
cancer patients;
granulocytemacrophage 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 specic indication of either preven-
tion 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 insufcient or conicting
evidence. This outcome also applied to a number of other
interventions described above in context of other cancer
treatment settings than those dened 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-inammatory agents, natural agents, antimicro-
bials, mucosal coating agents, anesthetics and analgesics,
and other miscellaneous agents (45, 4753).
Oral mucosal toxicity of molecularly targeted cancer
therapies
The recent advent of molecularly targeted cancer therapies in
clinical oncology practice is redening treatment paradigms
for many types of cancers. These agents directed toward
blocking of specic molecular receptors or intracellular
pathways including vascular endothelial growth factor recep-
tor (VEGFR) inhibitors, multi-targeted tyrosine kinase
inhibitors (TKI), and mTOR inhibitors. Despite these molec-
ularly 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 inhibitor-
associated stomatitis (mIAS) (5559). mIAS may potentially
result in dose modications 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, 6062).
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 inammatory bowel
disease. A recent example of this new paradigm in fostering
novel research collaborations was the June 2013 rst-in-
kind Gordon Research Conference Mucosal Health &
Disease (63). This new conference brought together basic
and translational researchers from the international commu-
nity, with specic emphasis on dening 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 eld. Basic, translational, and clinical
research directed to these and related domains could likely
produce paradigm-shifting changes in fundamental scientic
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 specic research
domain (e.g., systems biology) directly applies to more than
one research direction and its potential impact in the eld.
Investigators from dental medicine, including oral med-
icine 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 specic pathobiologic and pharmacogenomic
targets for interventions need to be identied 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
 Table 3 New frontiers in research
Research domain
Molecular modeling
Mucosal homeostasis
Naturally occurring mucosal disease
Oral pain
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
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
J Oral Pathol Med
Key research direction
Study of privileged mucosal sites that do not typically develop clinical
mucosal injury caused by cancer treatment
Capitalizing upon research technology and research outcomes from studies
of naturally occurring mucosal disease, to inform new research strategies
for investigation of mucositis
Genetic and immunopathologic governance of oral pain in relation to
sensory pathways
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 signicantly contribute to mucosal injury
and repair
Development and application of non-invasive molecular imaging technol
ogies at the discovery and clinical level
Further delineation of the pathobiologic basis for mucositis, capitalizing
upon bioinformatics and other computational technologies in order to
dene central network hubs and pathways that drive mucosal
injury and repair
Potential impact on the eld
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
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
Enhanced customization of systematically administered pain
prevention
and treatment in cancer patients
Novel antimicrobials directed to mucositis prevention and treatment
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
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
Jensen et al.
sites
Strategic advances in creation of research and clinical models of
mucosal homeostasis as well as mucosal toxicity caused by
cancer therapeutics
Novel research outcomes relative to pathobiology as well as
enhanced capability to deliver personalized medicine to oncology
patients
Development of (i) a priori prediction of mucositis incidence and
Oral mucosal injury caused by cancer therapies
severity in a given oncology patient coupled with
(ii) customized therapeutic regimens for mucositis prevention
and treatment based upon that risk prediction
(continued)
87
 Oral mucosal injury caused by cancer therapies
Jensen et al.

88
science into clinical practice guidelines that produce effec-
tive, cost-effective outcomes could then transform the vision
of personalized medicine into a reality for cancer patients,

Reduced development time and costs for new therapeutics, including

their families, and their healthcare providers.

Enhanced quality of cancer care, with resultant improved rates of

Enhanced cancer patient care based on a continuously evolving

cancer cure and remission while reducing cost of that cancer

those being developed to prevent and/or treat oral mucositis
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Conflict of interest
The authors report no conicts of interest.