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R E V I E W

Pathobiology of Oral Mucositis:


Novel Insights and Opportunities
Stephen T. Sonis, DMD, DMSc

O
ral mucositis is one of the most frequent,
symptomatic, and troubling complications Abstract Oral mucositis is a common and debilitatingly painful side ef-
of cancer therapy. The incidence of oral fect of many forms of chemotherapy and radiation therapy. The erythem-
mucositis can be close to 100% in patients atous, atrophic, and ulcerative lesions that develop are a consequence
receiving certain conditioning regimens in antici- of epithelial damage and death mediated through a complex series of
pation of hematopoietic stem-cell transplant or ra- molecular and cellular events. The consequences of mucositis are far-
diation therapy, with or without chemotherapy, for reaching and include chemotherapy dose reductions, breaks in radiation
cancers of the mouth and oropharynx.1,2 Two-thirds treatment, cessation of cancer therapy, reliance on parenteral nutrition,
of patients being treated for cancers of the larynx administration of narcotics, hospitalization, and morbidity. In this review,
or hypopharynx suffer from mucositis. It is almost the underlying molecular and cellular pathobiology of oral mucositis is
ubiquitous in patients receiving induction therapy characterized in five phases: initiation, the primary damage response,
for leukemia, and oral mucositis affects between signaling and amplification, ulceration, and healing. The roles of reactive
25%–33% of patients who receive multicycle che- oxygen species, transduction and transcription pathways, signaling and
motherapy for the treatment of most common solid functional mediators, and bacteria on the development and resolution
tumors.1,2 As with many other toxicities, it is be- of mucositis are described as a dynamic process in which epithelial stem
coming increasingly clear that the incidence of oral cells are the targets. Insights into the mechanisms of oral mucositis are
mucositis is underreported. Although the clinical generating new approaches for effective, targeted treatment.
impact of oral mucositis might be underappreciated
by some healthcare professionals, that same regard
is certainly not held by the patients who report oral almost all cases, ulceration is seen by 30 Gy (the Dr. Sonis is Professor of
mucositis as one of the most difficult and debilitat- end of the third week of treatment). Chemother- Medicine, Department of
Oral Medicine, Harvard
ing complications of their cancer treatment. apy-induced mucositis typically begins 4 to 5 days Medical School; Senior
The severity of oral mucositis varies from mild following infusion and peaks about 5 days later.7 Surgeon, Oral and
erythema, which produces burning mucosal dis- The severe, intractable pain associated with mu- Maxillofacial Surgery
comfort, to large areas of deep, coalescing ulcers cositis is often of such severity that patients elect and Dentistry, Brigham
and Women’s Hospital;
that require high doses of opioids for effective to take treatment breaks from radiation therapy or and Chief, Division of
intervention (Figure 1). The presence of breaks need dose de-escalation in cycled chemotherapy. Oral Medicine, Dana-
in the mouth’s mucosa, an environment rich in In either case, the indirect consequence is that Farber Cancer Institute,
bacteria, fungi, and viruses, provides an important patients receive suboptimal cancer treatment. Boston, Massachusetts.
portal of entry for infectious organisms, especially Mucositis is not only an important driver of
in the neutropenic cancer patient. The impor- patients’ symptoms and infection risk, its pres-
tance of mucositis as a risk factor for bacteremia ence is also associated with a marked increase in
and sepsis is also well established.3–6 poor health outcomes, resource use, and costs.8
For patients receiving fractionated radiation For example, patients with oral mucositis have
or chemoradiation for cancers of the head and more pain and infection; have higher rates of par-
neck, adverse mucosal changes become apparent enteral or feeding tube use, emergency room and
at cumulative radiation doses as low as 10 Gy. In unplanned office visits, and hospitalizations; and
experience longer hospital stays than do patients
who do not develop the condition.
Correspondence to: Stephen T. Sonis, DMD, DMSc, Division
The existing therapeutic approach to mucositis
of Oral Medicine, Brigham and Women’s Hospital, 75 Francis
Street, Boston, MA 02115; telephone: (617) 732-6570; fax: has focused on palliation, which has been largely
(617) 232-8970; e-mail: ssonis@partners.org unsatisfactory. Fortunately, this situation is chang-
J Support Oncol 2007;5:3–11 © 2007 Elsevier Inc. All rights reserved. ing with the maturation of mechanistically based

VOLUME 5, NUMBER 9, SUPPLEMENT 4 ■ OCTOBER 2007 www.SupportiveOncology.net 3


Pathobiology of Oral Mucositis

A B

C D

Figure 1 Clinical Stages of Oral Mucositis


Although the cells and tissues of the submucosa and epithelium respond immediately and robustly to radiation and chemotherapy, the clinical appearance
of the mucosa is deceivingly normal during the primary damage phase (A). Early superficial changes in the mucosa may be seen during the signaling and
amplification phases, but the benign clinical appearance is in stark contrast to the biologic havoc that is taking place beneath the epithelium, which ulti-
mately results in basal cell injury, apoptosis, and death (B). The toll of direct and indirect basal cell injury and death is most dramatically manifest by frank
ulceration. This is the most symptomatic phase of mucositis and the one that is associated with the major significant adverse health and economic outcomes
associated with the condition (C). In the majority of cases, signaling from the submucosa to the epithelium results in spontaneous healing (D).

treatments that address the underlying pathogenesis of oral mu- occur. These ulcers were then unable to heal until the treat-
cositis.1 An updated appreciation of the complex molecular, cel- ment was reduced or stopped. Bacterial colonization and sec-
lular, and tissue-level changes involved in the development of ondary infection of the ulcers were viewed as contributing to
mucositis has led to new approaches to targeting these pathways. their development, duration, and healing. Consequently, at-
This review summarizes the current understanding of the patho- tempts were made to cure mucositis by approaching the con-
biology underlying oral mucositis and discusses the application dition as having an infectious etiology, but these approaches
of this model to novel, mechanistically based treatments. were of little or no benefit.10 Recent hypotheses suggest that
infection is neither causative of, nor central to, the develop-
Historic Pathobiologic View ment of oral mucositis.10,11
The historic paradigm explaining the mechanism of oral The simple linear model of damage, ulceration, and healing
mucositis was based on the assumption that cytotoxic treat- can no longer be considered complete. New evidence reveals
ments intended to kill rapidly dividing cancer cells would also a more complicated picture of events surrounding oral muco-
kill rapidly dividing normal cells, such as those found in renew- sitis and provides novel concepts for treatment.
ing epithelium. In the case of gastrointestinal mucosa like that
in the mouth, therapy-induced nonspecific DNA damage to New Evidence
the normal basal cells would cause clonogenic cell death, lead- EARLY TISSUE DAMAGE
ing to an imbalance in the equilibrium of epithelial loss and
replenishment.9 When sufficient atrophic damage occurred to Over the past 10 years, new evidence has expanded our
thin the epithelium to the point of breaking, ulceration would understanding of the pathogenesis of oral mucositis to include

4 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY


Sonis

initiating events in the cells and tissues of the submucosa that intensity of pro-inflammatory cytokine production, and inter-
begin almost immediately following radiation therapy or che- ference with cytokine production favorably modifies the course
motherapy. Morphologic evidence from histology and electron of experimental mucositis. Another cytokine, platelet-activat-
microscopy shows early damage to the submucosa before any ing factor, increases correspondingly with the severity of oral
clinical signs of erythema or ulceration are apparent. In these mucositis12; interventions that inhibited platelet aggregation
examinations, subepithelial tissue damage and apoptosis of fibro- have been demonstrated to reduce mucositis severity.19
blasts and microvascular endothelial cells are seen rather than
dying epithelium. Although the presence of microscopic damage APOPTOSIS
before macroscopic injury became visible was not surprising, it It appears that much of the tissue damage seen in mucositis
was revealing that this damage occurred in the submucosal en- is a consequence of apoptosis. Not only do apoptotic changes
dothelium, rather than the epithelium.12,13 These early histologic occur within the oral epithelium, they are seen as early indi-
signs of mucositis corresponded to patient-reported correlates of cators of radiation- or chemotherapy-induced damage within
mucositis, even in the absence of clinically visible lesions. the cells of the submucosa. In particular, apoptotic changes
In vitro studies of chemotherapeutic agents and radiation have been noted in both fibroblasts and endothelial cells, and
therapy support the hypothesis that cells in the submucosa in certain instances, interfering with apoptosis can prevent
play an important role in the pathogenesis of mucositis. Rapid mucositis. This process may be modified by both the ceramide
killing of cultured fibroblasts was observed after treatment pathway and genetic factors.
with chemotherapeutic agents, resulting in apoptosis, simi- Ceramide. The ceramide pathway is a relatively well-
lar to that seen in histologic studies of oral mucosa following understood mechanism leading to apoptosis. Many attenuators
administration of chemotherapy.14–16 Wearing and Sherratt17 of ceramide in the submucosa favorably affect the severity of mu-
developed a mathematical model of the paracrine interac- cosal injury. Paris et al13 found that mice deficient in the acidic
tions between the epithelial cells and endothelial cells dur- sphingomyelinase gene, a key part of the ceramide apoptosis
ing wound healing. These investigators studied keratinocyte pathway, had increased resistance to radiation-induced mucosi-
growth factor (KGF), a central molecule in the communica- tis of the gastrointestinal tract. This work was later extended by
tion between endothelial and epithelial cells. Endothelial cells Hwang et al20 who found that inhibition of different parts of the
produce KGF, which triggers epithelial cells to grow and dif- ceramide apoptosis pathway effectively attenuated the extent of
ferentiate. Simple diffusion of growth factors from the endo- radiation-induced oral mucositis in an animal model.
thelium determines the thickness of the overlying epithelium, Genetic conditions. Two genetic conditions, psoriasis and
suggesting that the loss of endothelial cells would remove the Addison’s disease, have shed light on the role of apoptosis in
pro-growth signaling normally provided to the epithelium. oral mucositis.18 Psoriasis is an inheritable disease in which
Using a murine model, Paris et al13 found that, following there is a lack of apoptosis, particularly in the skin. In patients
radiation therapy, endothelial injury led to epithelial injury, who underwent hematotoxic cancer therapy, psoriatic patients
demonstrating the importance of the endothelium in initiat- were 77% less likely to have oral mucositis than controls. In
ing radiation-induced mucosal damage. Importantly, Paris and Addison’s disease, there is an excess of apoptosis, and patients
co-workers were able to prevent endothelial apoptosis by the with Addison’s disease were seen to develop oral mucositis
addition of basic fibroblast growth factor (bFGF); such pro- 17% more often than controls. Thus, enhanced apoptosis ex-
tection of submucosal cells from radiation-induced apoptosis acerbates the risk of oral mucositis. These data support the
prevented epithelial stem-cell loss. idea that apoptosis and its regulation are critical factors in the
Although the ulceration of the epithelium occurs clinically development of oral mucositis.18
many days after treatment, microscopic damage takes place much
earlier—not in the epithelium but in the submucosal endothe- A Multiple Mechanism Model
lium. The submucosa acts as both the physical and biochemical Clearly, mucositis develops as a consequence of a sequence
foundation of the epithelium; when this foundation is lost, the of related and interacting biologic events, culminating in injury
epithelium collapses. In addition, signaling from damaged sub- and apoptosis of basal epithelial cells, which results in the loss
mucosal cells to the epithelium mediates epithelial injury. of epithelial renewal, atrophy, and ulceration. Since the events
that trigger the process occur almost immediately after the ad-
CYTOKINES ministration of radiation therapy or chemotherapy, inhibition of
Increases in pro-inflammatory cytokines are also associated the early molecular events can have a profound impact on the
with the development of mucositis and likely play important intensity of oral mucositis. Although the loss of epithelium re-
roles in mediating injury and in signaling pathways.18 Cytokines sults in the clinical manifestations of the condition, the events
are prevalent within the affected tissue and are also noted in taking place in the submucosa may provide the most powerful
peripheral blood. The levels of the pro-inflammatory cytokines targets for directed drug therapy. The following model describes
tumor necrosis factor (TNF), interleukin-6 (IL-6), and inter- the sequence of events that occur as mucosal injury progresses
leukin-1 beta (IL-1β) increase before tissue damage is apparent. from its initiation to a primary damage response, signal amplifi-
Furthermore, the severity of oral mucositis correlates with the cation, ulceration, and then healing (Figure 2; Table 1).

VOLUME 5, NUMBER 9, SUPPLEMENT 4 ■ OCTOBER 2007 www.SupportiveOncology.net 5


Pathobiology of Oral Mucositis

Normal Initiation (I) Primary damage response and signal amplification (II/III)
Radiation/
Chemotherapy
Epithelium

Basal
cell
Proliferating
basal cells

Basal
membrane
Submucosa

Blood
vessel

Macrophage
Fibroblast

Normal Initiation (I) Primary damage response and signal amplification (II/III)
Radiation Production of
DNA inside Pathway pro-inflammatory
mediator NFκB activated DNA damage,
Cytoplasm nucleus by ROS, injury and NFκB cytokines
Generation of ROS radiation death activates
ROS TNF
Production of
TNF, proteins
Macrophage
NFκB TNF

Lethal Nonlethal Pathway NFκB


Basal epithelium cell ROS induction IκB
DNA damage DNA damage
Fibroblast (Clonogenic TNF activates
cell death) more NFκB
Surface
receptors Tissue injury
Macrophage
Chemotherapy and cell death
Production of
Pathway ceramide synthase inducing
mediators apoptosis in submucosal cells

ROS
Blood vessel
Lethal DNA damage

Figure 2 A Multiple Mechanism Model of the Pathobiology of Mucositis

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Sonis

Ulceration (IV) Healing (V)

Reactive oxygen species (ROS)


Pro-inflammatory cytokines, proteins
Anti-inflammatory cytokines
Nuclear factor kappa-B (NFκB)
Tumor necrosis factor (TNF)
Pseudomembrane Interleukin (IL)-6, IL-1
(fibrin, dead cells, and
Ceramide synthase
bacteria)

Ulceration (IV) Healing (V)

Bacteria Pseudomembrane
Macrophage

Threshold
of cell death
results in ulcer

Macrophage Signals from the extracellular matrix


Production direct basal epithelial cells to migrate,
Macrophage proliferate, and differentiate
of cytokines
Bacteria present in
ulcer pseudomembrane
activate macrophages in
submucosa to produce
more cytokines resulting in
more inflammation

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Pathobiology of Oral Mucositis

Table 1
Five-Stage Model of Oral Mucositis
UPREGULATION AND MESSAGE SIGNALING AND
INITIATION GENERATION AMPLIFICATION ULCERATION HEALING
X-rays or chemotherapy The ceramide pathway NF-κB-activated COX-2 Submucosal cell death COX-2 activation promotes
cause direct DNA damage. signals cells to enter produces prostaglandins. removes epithelial trophic new angiogenesis.
apoptosis. factors such as KGF.
X-rays or chemotherapy Damaged cell membranes TNF-α activates NF-κB MMPs degrade the ECM. RM 2/3 macrophages
generate ROS. stimulate sphingo- and c-JUN. downregulate inflamma-
myelinases. tory responses.
ROS damage lipids, DNA, NF-κB modulates the Feedback loops re-initiate The ECM swells with fluid, Epithelial cells multiply
connective tissue, and pro-inflammatory the damage response weakening the attach- and migrate to close
other biomolecules. cytokines. pathways. ment between submucosa the ulcerative wound.
and epithelium.
Chemotherapy stimulates NRF2 transcription factor Damage responses are Clonogenic cell death, Submucosal cells
ceramide synthase. activates antioxidant- amplified in space and reduced epithelial regenerate.
related genes. intensity. regeneration, and apop-
tosis thin the epithelium.
X-rays stimulate nuclear NF-κB modulates TNF-α stimulates Opportunistic infections Healing produces a new
factor-kappaB (NF-κB). apoptosis genes in the apoptosis. release bacterial cell tissue that is not exactly
BCL family. wall components, which the same as the old tissue.
stimulate inflammatory
responses.
Abbreviation: NF-κB = nuclear factor kappa-B; COX-2 = cyclooxygenase-2; KGF = keratinocyte growth factor; ROS = reactive oxygen species; TNF-α = tumor
necrosis factor-alpha; MMPs = matrix metalloproteinases; ECM = extracellular matrix; NRF2 = nuclear factor erythroid-2 related factor 2

INITIATION
and the synthesis and release of biologically active mediators
Initiation occurs immediately following the administra- that impact the viability of the basal epithelium. Among the
tion of radiation therapy or chemotherapy and happens as most significant and well-studied transcription factors thought
a single event in time in patients receiving bolus therapy. to be important in the development of mucositis is NF-κB.
In other patients, such as those receiving fractionated dose NF-κB regulates the expression of approximately 200
radiation therapy, initiation events are chronically recurring; genes, many of which may play roles in the pathogenesis of
the chain of events leading to oral mucositis is triggered each mucositis.24 For example, NF-κB is an important regulator of
time the patient receives subsequent irradiation.21 Initial di- pro-inflammatory cytokines, such as TNF, IL-6, and IL-1β.
rect damage to DNA can lead to immediate cell death in These proteins are effective mediators of injury, and increased
basal epithelia and submucosal cells, but clonogenic cell levels in both tissue and peripheral blood correlate well with
death accounts only for a small number of injured cells and non-hematologic toxicities induced by radiation and chemo-
is not of sufficient magnitude to result in the extensive injury therapy. Importantly, effective pharmacologic attenuation of
that characterizes the clinical presentation of mucositis. Im- their production is associated with less frequent and severe
portantly, chemotherapeutics and ionizing radiation gener- mucositis in experimental models. In addition, NF-κB also
ate reactive oxygen species (ROS) that damage connective impacts genes of the BCL2 family, providing a mechanism
tissue, DNA, and cell membranes; stimulate macrophages; whereby induction of NF-κB can directly promote apoptosis.
and trigger a cascade of critical biologic mechanisms, mol- Both sphingomyelinase and ceramide synthase are acti-
ecules, and pathways such as the SP1-related retinoblastoma vated by neoplastic therapy to initiate apoptosis mediated by
control protein, p53, nuclear factor kappa-B (NF-κB), and the ceramide pathway. Also, direct radiation or chemotherapy
the ceramide pathway.22 damage to fibroblasts or indirect injury mediated by activating
protein 1 (AP1) stimulates the secretion of matrix metallopro-
PRIMARY DAMAGE RESPONSE teinase (MMP). This group of enzymes produces injury within
By activating a number of signaling pathways, chemothera- the tissues of the submucosa and disrupts the integrity of the
py, radiation, and ROS (directly) and damaged cells and their interface between the epithelium and submucosa at the base-
damaged DNA (indirectly) precipitate the start of the bio- ment membrane.
logic process that results in mucosal injury.23 Gene expression
changes in peripheral blood provide insight into the biologic SIGNAL AMPLIFICATION
mechanisms associated with regimen-related toxicities in pa- In the first two stages, multiple sources of damage lead to
tients being treated for cancers of the head and neck (Table 2). message generation that activates normal damage response
Activated transcription factors mediate both gene expression pathways on the cellular and molecular levels. Many of the pro-

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Sonis

teins produced during the primary damage response serve to


stimulate additional injury through positive feedback loops. Table 2
For example, the pro-inflammatory cytokine TNF is a po- Signaling Pathways Involved in the
tent activator of NF-κB,24 sphingomyelinase,25 and members Development of Mucositis
of the TNF receptor family. As a result, its presence can drive
the NF-κB and ceramide pathways to produce and acceler- Nitrogen metabolism
ate tissue injury and initiate mitogen-activated protein kinase Toll-like receptor signaling
(MAPK) signaling. MAPK signaling activates c-JUN amino- NF-κB signaling
terminal kinase,26 which plays a role in regulating the AP1 B-cell receptor signaling
transcription factor, which, in turn, is thought to affect MMP P13K/AKT signaling
Cell cycle: G2/M DNA damage checkpoint receptor
secretion.
p38 MAPK signaling
These feedback loops magnify the response of the initial
Wnt/B-catenin signaling
injury by amplifying and potentiating the original biologic sig-
Glutamate receptor signaling
nals. These feedback loops not only increase tissue injury but
Integrin signaling
also prolong damage by continuing to provide signals for days
VEGF signaling
after the original chemotherapeutic or irradiation insult. IL-6 signaling
ULCERATION Death receptor signaling
SAPK/JNK signaling
Clinically and symptomatically, the ulcerative phase is Reprinted with permission from Sonis et al23
the most significant. The ulcerations of mucositis are gener- Abbreviaions: NF-κB = nuclear factor kappa-B; MAPK = mitogen-activated protein kinase;
ally deep, broad, and painful. They are usually covered by a VEGF = vascular endothelial growth factor; IL-6 = interleukin-6

pseudomembrane composed of dead cells and fibrin, a desir-


able environment for secondary bacterial colonization. Both 2004, palifermin (KGF-1; Kepivance) became the first agent
gram-positive and gram-negative organisms thrive within to receive approval by the US Food and Drug Administra-
the psuedomembrane and may penetrate and invade the ves- tion for the prevention and treatment of mucositis induced
sels of the submucosa to produce bacteremias. In the case of by conditioning regimens for hematopoietic stem-cell trans-
granulocytopenic patients, microbial colonization creates a plant. Palifermin provides an example of how an agent that
significant risk of sepsis. In addition, bacterial cell wall prod- is biologically pleiotropic can effectively attenuate the devel-
ucts that find their way into the submucosa are excellent opment of mucositis.
stimulators of macrophage pro-inflammatory cytokine pro- Palifermin is a truncated version of human KGF and has
duction and the release of additional destructive MMPs. It is the same biologic properties as endogenous KGF but offers
during the ulceration phase that the inflammatory infiltrate increased stability. It is a member of the FGF superclass of
is most robust. growth factors. Endogenous KGF is produced by the submu-
cosal endothelial cells and T cells. It functions as a trophic
HEALING factor for maintenance of the overlying epithelium and as a
In most cases, the ulcers of mucositis resolve spontane- stimulant of wound repair during epithelial wound closure.
ously within two to three weeks following the completion of Its effect on wound healing prompted animal studies on the
treatment. Of all the stages of mucositis, the healing phase potential of KGF as an intervention for mucositis. Early pre-
is probably the least understood. Cyclooxygenase-2 (COX-2), clinical investigations observed thickening of the oral epithe-
expressed in fibroblasts and vascular endothelium, may play a lia after treatment with KGF.28 KGF normally stimulates basal
role in the rebuilding of the submucosa, as COX-2 potentiates cells to proliferate and keratinocytes to migrate and differenti-
angiogenesis, a hallmark of the end of the ulcerative phase.27 ate. The thickened epithelium was thought to be the cause of
The extracellular matrix provides signals to the epithelium increased resistance to mucositis by allowing the epithelium to
that impact its migration, proliferation, and differentiation. withstand more clonogenic cell death before ulcerating. How-
Even after the full replenishment of the epithelium, the struc- ever, closer evaluation suggested that KGF’s effect on mucosi-
ture of the reconstituted submucosa is not identical to its state tis has a broader mechanistic base.29
prior to mucotoxic damage.21 KGF impacts a number of the phases of mucositis develop-
ment. First, KGF may upregulate certain detoxifying enzymes,
Opportunities for Prevention and Treatment which are naturally occurring antioxidants, by the activation
Despite its frequency, symptomatic impact, and health of the transcription factor NRF2 during the initiation stage
and economic costs, there has been no effective intervention of mucositis.30 Second, during the primary damage response,
until recently for the prevention or treatment of mucositis. KGF may effectively modulate both direct and indirect clono-
However, with increased mechanistic understanding has genic cell death by inhibiting both DNA strand breaks and ep-
come the opportunity for effective interventions that rely on ithelial cell apoptosis. Through its ability to alter the cytokine
interference with the biologic drivers of the condition. In profile from T helper cells toward a Th2 balance, KGF may

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Pathobiology of Oral Mucositis

modulate the mix of cytotoxic pro-inflammatory cytokines (ie, Conclusion


TNF) and anti-inflammatory cytokines (ie, IL-4 and IL-13) to
lessen the effects of the signal amplification phase. Its direct Elucidation of the complex biology of mucositis has resulted
effect on the epithelium and the interaction between the con- in the identification of numerous potential therapeutic targets.
nective tissue and the epithelium impact the ulceration and In addition to palifermin, other mechanistically based therapies
healing phases. are being evaluated for treatment of oral mucositis, including
The observation that KGF’s efficacy relative to mucositis growth factor and non-growth factors such as FGF-20 (velafer-
was dependent on its schedule of administration around mu- min), gastric peptide antrum mucosal protein, NAC, amifostine
cotoxic therapy suggests the complexity of the biologic events (Ethyol), and trefoil factors. These treatments may affect differ-
leading to ulceration. Although pre- and post-mucotoxic ent aspects of each stage of the pathogenesis pathway.
treatment was effective for KGF in both animal models and As with all interventions for complications or side effects
humans,28,31–33 its administration simultaneous with mucotox- of antineoplastic therapy, the challenge is to ensure that the
ic therapy actually worsened the outcome.29 treatment confers specific cytoprotection to normal cells while
Other agents in clinical development are also illustrative avoiding the protection of tumor cells. Fortunately, it appears
of the efficiency of a mechanistically based approach to inter- that fundamental differences between normal and malignant
vention. For example, the results of a recent phase II trial of cells do permit selective protection in many instances. None-
N-acetylcysteine (NAC) suggests it may be efficacious in the theless, this dichotomy continues to be studied carefully, and
prevention/treatment of mucositis associated with radiation other growth factors or therapies for mucositis may be contra-
therapy.34 Although there have not yet been direct studies of indicated in certain patients.
NAC with respect to mucositis, other data indicate that it can Further advances in the understanding of the pathobiol-
inhibit transcription factors and pro-inflammatory cytokines ogy of mucositis and the complex set of interactions occurring
and block sphingomyelinase.35–37 Likewise, IL-11, which was among multiple molecules and pathways will improve the ef-
shown to be efficacious in preclinical studies of mucositis,12 fective use of such targeted therapies. Continued research on
modulates pro-inflammatory cytokines. See the article in how factors such as tumor type and genetic background of the
this supplement by Drs. Posner and Haddad for an expanded patient will help physicians tailor appropriate treatment regi-
discussion of novel therapies for mucositis (J Support Oncol mens for effective prophylaxis and treatment of oral mucositis
2007;5(suppl 4):33–39). associated with cancer therapy.

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