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Mucositis: Perspectives and Clinical Practice GuidelinesSupplement to Cancer
Perspectives on Cancer Therapy-InducedMucosal InjuryPathogenesis, Measurement, Epidemiology, and Consequences for Patients
Stephen T. Sonis, D.M.D., D.M.Sc.1
Linda S. Elting, Dr.P.H.2
Dorothy Keefe, M.D.3
Douglas E. Peterson, D.M.D., Ph.D.4
Mark Schubert, D.D.S., M.S.D.
5
Martin Hauer-Jensen, M.D., Ph.D.6
B. Nebiyou Bekele, Ph.D.2
Judith Raber-Durlacher, D.D.S.7
J. Peter Donnelly, Ph.D.8
Edward B. Rubenstein, M.D.9
for the Mucositis Study Section of theMultinational Association of Support-ive Care in Cancer and the Interna-tional Society for Oral Oncology.
1 Division of Oral Medicine, Brigham & Women’s
Hospital, Boston, Massachusetts.
2 Department of Biostatistics and Applied Mathe-matics, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas.
3 Department of Medical Oncology, Royal Adelaide
Hospital, Adelaide, South Australia, Australia.
4 Department of Oral Diagnosis, University of Con-
necticut Health Center, Farmington, Connecticut.
5 Department of Oral Medicine, Fred Hutchinson
Cancer Research Center, Seattle, Washington.
6 Arkansas Cancer Research Center, University of
Arkansas for Medical Sciences, Little Rock, Arkansas.
7 Department of Clinical Oncology, Leiden Univer-
sity Medical Center, Leiden, The Netherlands.
8 Department of Hematology, Nijmegen University
Hospital, Nijmegen, The Netherlands.
9 Department of Palliative Care and Rehabilitation
Medicine, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas.
Supported by unrestricted educational grants to
the Mucositis Study Section of the Multinational
Association of Supportive Care in Cancer (MASCC)
and the International Society for Oral Oncology
(ISOO). Corporate sponsors include Amgen
(Thousand Oaks, CA), GelTex Pharmaceuticals
(Waltham, MA), Helsinn Healthcare SA (Pazzallo,
Switzerland), Human Genome Sciences (Rockville,
MD), McNeil Consumer and Specialty Pharmaceu-
ticals (Fort Washington, PA), MGI Pharma (Bloom-
ington, MN), MedImmune (Gaithersburg, MD), Ora-
Pharma (Warminster, PA), and RxKinetix
(Louisville, CO).
The MASCC and ISOO Mucositis Study Section
thank medical librarian Ronald D. Hutchins andmedical editor Beth W. Allen.
Edward B. Rubenstein’s current address: MGI
Pharma, Bloomington, Minnesota.
Address for reprints: Stephen T. Sonis, Division of
Oral Medicine, Brigham & Women’s Hospital, 25
Francis Street, Boston, MA 02115; Fax: (617) 232-
8970; E-mail: [email protected]
Dr. Sonis has served as a consultant for Biomodels
and Affiliates, LLC (Wellesley, MA).
Dr. Elting has received speaker’s honoraria from
McNeill Pharmaceuticals and Endo Pharmaceuti-
cals (Chadds Ford, PA).
Dr. Keefe has received research funding and
speaker’s honoraria from Amgen.
Dr. Peterson has served as a paid consultant for
Aesgen, Inc. (Princeton, NJ).
Dr. Schubert is a member of the Advisory Boards
for Endo Pharmaceuticals, OSI Pharmaceuticals,
and McNeill Pharmaceuticals and has receivedconsulting fees per meeting plus expenses.
Dr. Rubenstein has received research funding from
and is a member of the speakers program and
advisory board at Merck (Whitehouse Station, NJ);
he owns common stock in and is a member of the
advisory board at MGI Pharma; and he is a mem-
ber of the advisory boards at Endo Pharmaceuti-
cals, McNeil Consumer and Specialty Pharmaceu-
ticals, and OSI Pharmaceuticals.
Received December 19, 2003; accepted January
22, 2004.
BACKGROUND. A frequent complication of anticancer treatment, oral and gastro-
intestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to
dose reductions, increases healthcare costs, and impairs patients’ quality of life.
The Multinational Association of Supportive Care in Cancer and the International
Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and
treatment of mucositis.
METHODS. The panelists examined medical literature published from January 1966
through May 2002, presented their findings at two separate conferences, and then
created a writing committee that produced two articles: the current study and
another that codifies the clinical implications of the panel’s findings in practice
guidelines.
RESULTS. New evidence supports the view that oral mucositis is a complex process
involving all the tissues and cellular elements of the mucosa. Other findings
suggest that some aspects of mucositis risk may be determined genetically. GI
1995
© 2004 American Cancer Society
DOI 10.1002/cncr.20162Published online in Wiley InterScience (www.interscience.wiley.com).
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proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps
explaining differences in the frequency with which mucositis occurs at different
sites. Studies of mucositis incidence in clinical trials by quality and using meta-
analysis techniques produced estimates of incidence that are presented herein for
what to our knowledge may be a broader range of cancers than ever presented
before.
CONCLUSIONS. Understanding the pathobiology of mucositis, its incidence, and
scoring are essential for progress in research and care directed at this common
side-effect of anticancer therapies. Cancer 2004;100(9 Suppl):1995–2025.
© 2004 American Cancer Society.
KEYWORDS: stomatitis, oral mucositis, gastrointestinal mucositis, mucosal barrier
injury, mucositis clinical assessment scales, mucositis etiopathogenesis.
Oral mucositis is a frequent complication of cytore-ductive cancer chemotherapy and radiotherapy.In many patients, it is associated with considerable
pain and, thus, can significantly impair quality of life;
in neutropenic patients with cancer, mucositis repre-
sents a clinically significant risk factor for sepsis.1 Fur-
thermore, in some patients, it becomes a dose-limit-
ing toxicity, slowing or preventing continuation of
selected cancer therapies, including accelerated frac-
tionation and hyperfractionation in radiotherapy and
interventions that combine chemotherapy and radio-
therapy.
Gastrointestinal (GI) mucositis, which represents
injury of the rest of the alimentary tract, also is be-
coming recognized increasingly as a toxicity associ-
ated with many standard-dose chemotherapy regi-
mens commonly used in the treatment of cancer and
with radiation to any part of the GI tract. After che-motherapy, GI mucositis is most prominent in the
small intestine, but it also occurs in the esophagus,
stomach, and large intestine. Radiation esophagitis
and radiation proctitis are also manifestations of GI
mucositis.
Over the past 5 years, investigators have devel-
oped insight into the basic molecular mechanisms of
mucosal barrier injury, prompting new strategies for
prevention and treatment. Equally significant are re-
cent studies that have defined the epidemiologic as-
pects of mucositis further, because they form the basis
for any analysis in which the potential efficacy of anintervention is evaluated.1 Furthermore, because in-
terpreting the epidemiologic data depends on under-
standing the scoring systems used to measure and
objectively classify mucositis, the strengths and limi-
tations of the scoring systems are reviewed before the
epidemiologic data are presented. Therefore, in this
article, we describe the most current view of mucositis
pathobiology, the scoring systems, the current epide-
miology, and the economic and clinical consequences
of mucositis for patients. The epidemiologic data are
drawn from a comprehensive, evidence-based litera-
ture review that was conducted by the Mucositis Sec-
tion of the Multinational Association of Supportive
Care in Cancer and the International Society for Oral
Oncology, as part of the effort to create clinical prac-
tice guidelines (see the accompanying article in this
issue2).
BIOLOGIC BASIS AND PATHOGENESISOral Mucositis
The biologic complexities underlying mucosal barrier
injury and, in particular, oral mucositis have been
appreciated only recently. In fact, our understanding
of the molecular, cellular, and tissue events that lead
to this common and often dose-limiting toxicity con-
tinue to evolve. Historically, mucositis was viewed
solely as an epithelium-mediated event that was the
result of the nonspecific toxic effects of radiation or
chemotherapy on dividing epithelial stem cells.3 It was
believed that direct damage by chemotherapy or radi-
ation therapy to the basal epithelial cell layer led to
loss of the renewal capacity of the epithelium, result-
ing in clonogenic cell death, atrophy, and consequent
ulceration. This direct, somewhat linear process failed
to account for several more recent findings about the
role of other cells and the extracellular matrix in the
submucosal region. These observations outlined be-
low indicate that the mechanisms that result in mu-
cositis are not so direct or simple.4
Microvascular injury (e.g., injury mediated by en-dothelial apoptosis) may play a significant role in the
development of radiation-induced intestinal injury.5
Morphologic evidence provided by electron micros-
copy demonstrates that endothelial and connective
tissue damage precedes epithelial changes in irradi-
ated oral mucosa,4 suggesting that endothelial injury
is an early event in the development of radiation-
induced mucosal injury. Whether endothelial injury
has a sustaining role is unclear, however, inasmuch as
morphologic evidence of vascular damage was not
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observed in human material obtained from patients
who had received cumulative radiation doses of 30
grays, despite increased expression of adhesion mol-
ecules.6 The finding that the inhibition of platelet ag-
gregation is associated with reduced mucosal toxicity
also suggests a possible role for vascular endotheliumand platelets in the pathogenesis of mucositis.7
Further evidence suggesting that mucositis is not
just an epithelial process comes from examining the
relation between proinflammatory cytokines and mu-
cosal toxicity in animal and human studies. Increased
peripheral blood levels of tumor necrosis factor-alpha
(TNF-) and interleukins 1 and 6 (IL-1 and IL-6) cor-
relate with the extent of nonhematologic toxicities in
patients following chemotherapy.8 Similarly, mucosal
levels of IL-1 and gene expression of TNF- are as-
sociated with the development of mucositis in animal
models.4 Agents known to attenuate the expression of
both cytokines have demonstrated efficacy in the pre-vention of both experimental4 and clinical9 mucositis.
For example, in a radiation-injury mucositis model,
IL-11, a pleotrophic cytokine, can decrease TNF- lev-
els, an event associated with a reduction in mucositis
scores. Furthermore, it has been noted recently that
tissue apoptotic rates that vary in different disease
states (in psoriasis, antiapoptotic; in Addison disease,
proapoptotic) are associated with opposing risks for
mucositis compared with controls without either con-
dition (Chen E, unpublished data).
Increasing direct and indirect experimental evi-
dence supports the concept that virtually all the cells
and tissues of the oral mucosa, including the extracel-
lular matrix, contribute to barrier injury. The sequence
of cell and tissue changes further implies that nothing
occurs within the mucosa as a biologically isolated
event. Rather, it appears that interactions among the
various mucosal components, including those influ-
enced by the oral environment, collectively lead to
mucositis.
For illustrative purposes, mucosal barrier injury
can be viewed as having five phases: initiation, up-
regulation with generation of messengers, signaling
and amplification, ulceration with inflammation, and,
finally, healing. This model of injury is demonstratedbest in the oral mucosa but also may take place in the
rest of the alimentary canal. Although the model as
described seems linear, injury occurs very quickly and
simultaneously in all tissues.
Initiation
Whatever the target tissue, generation of oxidative
stress and reactive oxygen species (ROS) by chemo-
therapeutic agents or radiation appears to be a pri-
mary event in most pathways leading to mucositis.
The consistent reports of ROS generation after expo-
sure to stomatotoxic agents10 and the results of studies
that demonstrate successful attenuation of mucosal
injury by agents that effectively block or scavenge
oxygen-free radicals11 suggest a significant role for
ROS in injury induction. Whether they are generatedby chemotherapy or radiation exposure, ROS directly
damage cells, tissues, and blood vessels. The activa-
tion of ROS and their subsequent ability to stimulate a
number of transcription factors seem to characterize
the acute tissue response to a stomatotoxic challenge
and are considered the hallmark of the initiation
phase of mucositis leading to other biologic events.
Up-regulation and generation of messenger signals
During the second phase, multiple events occur si-
multaneously. ROS cause DNA damage and subse-
quent clonogenic cell death in the epithelial layer.
Importantly, direct clonogenic death of basal epithe-lial cell death is insufficient to account for the extent
of mucositis observed. Given the observed sequence
of cellular and tissue events, the search for a pivotal
biologic event that drives mucositis is compelling. Of
the transcription factors that may be significant, nu-
clear factor-B (NF-B) has many of the characteris-
tics that suggest that it may be a key element in the
genesis of mucositis: It is activated by either radiother-
apy or chemotherapy, the 26S proteasome is detect-
able in stressed mucosa, it has the capacity to up-
regulate a large panel of genes with the potential to
elicit a broad range of tissue responses, and it can re-
spond differently to varying challenges. Once activated,
NF-B leads to the up-regulation of many genes, includ-
ing those that result in the production of the proinflam-
matory cytokines TNF-, IL-1, and IL-6. This leads to
tissue injury and apoptosis. Upregulation of other genes
causes the expression of adhesion molecules, subse-
quent activation of the cyclooxgenase-2 pathway, and
consequent angiogenesis (Fig. 1).
It would be naı̈ve to suggest that NF-B is the sole
pathway leading to chemotherapy-induced or radio-
therapy-induced normal tissue apoptosis. For exam-
ple, ROS can activate sphyngomyelinase, chemother-
apy can activate ceramide synthase directly, and theceramide pathway may work in parallel or sequen-
tially to induce primary apoptosis.12 Fibronectin
break-up also occurs during the up-regulation and
message-generating phase of mucositis. Macrophages
are activated subsequently, leading matrix metallo-
proteinases to then cause tissue injury directly or lead-
ing to more production of TNF-. The end result of the
up-regulation and message-generation phase of mu-
cositis is one of simultaneous events in all involved
tissues at all levels (see Fig. 2).
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FIGURE 1. Chemotherapy (CT) or radiotherapy (RT) may initiate mucositis directly by causing DNA strand breaks, through the generation of reactive oxygen species
(ROS), or through enzymatic or transcription factor activation in multiple cellular elements within the mucosa. ROS may damage other cells and tissues directly and
also stimulate secondary mediators of injury, including such transcription factors as nuclear factor-B (NF-B). When messenger signals are up-regulated and
generated, multiple events occur simultaneously. ROS cause DNA damage leading to clonogenic cell death. Activation of transcription factors in response to ROS,
RT, or CT results in gene up-regulation, including the genes tumor necrosis factor- (TNF-) and the interleukins (IL-1) and IL-6, leading to tissue injury and
apoptosis of cells within the submucosa and primary injury of cells within the basal epithelium. Other genes also are up-regulated, leading to the expression of
adhesion molecules, cyclooxygenase-2 (COX-2), and subsequent angiogenesis.
FIGURE 2. During up-regulation and
generation of messenger signals, en-
zymes (sphingomyelinase and ceramide
synthase) that catalyze ceramide syn-
thesis are activated directly by radio-
therapy (RT) or chemotherapy (CT) or
indirectly by reactive oxygen species
(ROS) and tumor necrosis factor (TNF-
). The ceramide pathway provides an
alternative conduit for apoptosis of both
submucosal and basal epithelial cells. Inaddition, fibronectin breakdown leads to
macrophage activation and subsequent
tissue injury mediated by matrix metal-
loproteinase (MMP) and production of
additional TNF-.
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Signaling and amplification
It seems likely that, in addition to exerting a direct
damaging effect on mucosal target cells, proinflam-
matory cytokines also play an indirect role in ampli-
fying mucosal injury initiated by radiation and che-
motherapy. For example, TNF- is a very capable
activator of a number of pathways that can lead to
tissue injury, including the ceramide and caspase
pathways and the transcription pathway mediated by
NF-B. These signals lead to further production of the
proinflammatory cytokines TNF-, IL-1, and IL-6. In
addition, activation of the ceramide pathway by
TNF- may provide an effector mechanism for sec-
ondary TNF--mediated tissue damage. The ultimate
consequence of this phase is that the tissue is altered
biologically, even though it may appear normal (Fig. 3).
Ulceration
Mucositis, especially that induced by radiation, fre-
quently is referred to as an inflammatory process;
however, the phrase may misrepresent the signifi-
cance of inflammation in mucosal barrier injury. An
acute inflammatory infiltrate is not identifiable histo-
logically during the early stages of radiation-induced
mucositis. Furthermore, stomatotoxicity occurs dur-
ing periods of maximum myeloablation in patients
treated with chemotherapy. Despite the lack of a ro-
bust neutrophil infiltrate during the development of
mucositis, a round cell infiltrate, comprised largely of
reparative RM3/1 positive macrophages, has been re-
ported in response to increasing doses of radiation.13
This infiltrate most likely is the consequence of a
sequence of events triggered by oxidative stress, me-
diated by activated T cells, and preceded by the pro-
duction of adhesion molecules. It has been suggested
that the presence of these cells represents an interme-
diate, antiinflammatory response.13 Mast cells have
been observed in irradiated rat intestinal mucosa, and
investigators have speculated that these cells have a
protective role.14 Not unexpectedly, the ulcerative
phase of mucositis is characterized by a robust inflam-
matory infiltrate comprised of both polymorphonu-clear and round inflammatory cells.
During the ulcerative phase of mucositis, bacterial
colonization occurs with gram-positive, gram-nega-
tive, and anaerobic organisms. The role of such oral
environmental factors as bacteria and their products is
unclear. Cell wall products from bacteria can activate
tissue macrophages, leading to more production of
the proinflammatory cytokines TNF-, IL-1, and
IL-6. Although bacterial cell wall products have the
ability to amplify and accelerate local tissue damage
FIGURE 3. During the signaling andamplification phase, one consequence
of the flood of mediators released in
response to the initial insult is a series of
positive feedback loops that serve to
amplify and prolong tissue injury
through their effects on transcription
factors and on the ceramide and
caspase pathways (not shown). Conse-
quently, gene up-regulation occurs with
resultant increases in injurious cytokine
production. Because the damaging
events are focused in the submucosa
and basal epithelium, the clinical ap-
pearance of the mucosal surface re-
mains deceptively normal. CT: chemo-
therapy; IL: interleukin; MMP: matrix
metalloproteinase; NF-B: nuclear fac-
tor-B; ROS: reactive oxygen species;
RT: radiotherapy; TNF-, tumor necrosis
factor-.
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markedly by stimulating a variety of pathways, the
effect of directly reducing the bacterial load on the
course of mucositis has been erratic. Similarly,
changes in the composition and amount of saliva pre-
sumably may influence the susceptibility of tissue to
cytotoxic agents and the tissue’s ability to heal. None-
theless, to our knowledge, outcomes of mucositis
studies in which salivary function is targeted are un-
clear. Ultimately, the consequences of ulceration are
further cytokine amplification, inflammation, and
pain, and the patient is at increased risk for bactere-
mia and sepsis (Fig. 4).
Healing
A review of the physiology of wound healing is far
beyond the scope of this report; however, the healing
phase of oral mucositis starts with a signal from the
extracellular matrix. This leads to a renewal of epithe-
lial proliferation and differentiation and reestablish-
ment of the local microbial flora. Depending on the
clinical setting, other associated clinical events simul-
taneously return to normal. For example, in hemato-
poietic stem cell transplantation (HSCT), the healing
phase also is marked by leukocyte recovery. After the
healing phase, the oral mucosa appears normal; how-
ever, despite its normal appearance, the mucosal en-
vironment has been altered significantly. There is re-
sidual angiogenesis, and the patient is now at
increased risk of future episodes of oral mucositis andits complications with subsequent anticancer therapy.
Genetic risk and modulation of mucositis
All of the tissue changes described above may occur in
the context of tissue that either is primed genetically
or is resistant to regimen-related toxicities. Mounting
evidence suggests that some aspects of mucositis risk
may be determined genetically. Three lines of evi-
dence support this hypothesis. Differences in individ-
ual susceptibility to chemotherapy-induced and ra-
diotherapy-induced toxicities have been noted for
years. Recently reported studies have concluded that
murine strains vary in their mucosal response to radi-ation.15 Single nucleotide polymorphisms have been
identified that are associated with the metabolism of a
number of chemotherapeutic agents. Individuals who
express phenotypes that result in deficiencies of en-
zymes needed for metabolism of specific chemother-
apy drugs are at increased risk for toxicity. For exam-
ple, polymorphisms that predispose to methotrexate-
related toxicities have been noted in bone marrow
transplantation recipients with increased levels of mu-
cositis.16 These findings, as well as results suggesting
that the risk of toxicity is determined in part by gender
or ethnicity, undoubtedly will be topics for additional
investigation.
The effect of NF-B on apoptosis is paradoxical.
There are numerous reports demonstrating that acti-
vation of NF-B is antiapoptotic and, therefore, that
regimen-related toxicity may lead to the conclusion
that chemotherapy-induced or radiotherapy-induced
NF-B activation in normal cells is not only not cyto-
protective but also proapoptotic. This concept sug-
gests that there are differences in the way in which
normal cells and tumor cells respond to cytotoxic
challenges and potentially presents a huge opportu-
nity for targeted mucositis interventions that do not
jeopardize therapy-induced tumor kill.17
Conse-quently, the role of NF-B, and other transcription
factors in the pathogenesis of mucositis is of great
potential interest.
Although to our knowledge much of the mecha-
nistic basis for regimen-related mucosal injury has yet
to be determined, based on the data available, it is
evident that mucositis is much more than just an
epithelial event. This five-phase model helps to pro-
vide a mechanistic understanding of the complex bi-
ology of mucositis. It also serves as a basis for under-
FIGURE 4. The ulcerative phase is the phase associated most consistently
with mucositis. The injury and death of the basal epithelial stem cells resulting
from the prior phases result in atrophic changes that culminate in true
deterioration and breakdown of the mucosa. This phase generally is markedly
symptomatic. The ulcer serves as a focus for bacterial colonization, particularly
in an environment so rich in microorganisms. Secondary infection is common.
What is significant is that cell wall products from bacteria penetrate the
submucosa and further exacerbate the condition by stimulating infiltrating
macrophages to produce and release additional proinflammatory cytokines. In
neutropenic patients, whole bacteria may invade submucosal vessels to cause
bacteremia or sepsis. IL: interleukin; TNF-: tumor necrosis factor-.
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standing the rationale for therapeutic interventions as
single agents or combination therapies.
GI Mucositis
In contrast to earlier thinking, there is no reason to
assume that the pathobiology of intestinal mucositis isany less complex than the pathobiology suggested for
oral mucositis. The common embryologic develop-
ment of the entire GI tract makes it likely that the basic
pathogenesis of mucositis is similar, with local differ-
ences due to the specialized differentiation in each
area. In fact, it is likely that the initiating events in
both tissue types are similar. However, in addition to
the obvious morphologic differences observed be-
tween the most proximal and distal elements of the GI
tract and its intestinal elements, specific functional
components also make each section distinctive.
Teleologically, it might be assumed that chemo-
therapy-derived or radiotherapy-derived, cell-damag-ing or cell-destroying mechanisms must share a cer-
tain degree of commonality. It could be argued that
the damage that occurs in the intestine is similar to
the damage that occurs in the basal epithelium of
stratified mucosa but acts at a much faster rate. In
addition, the functional and symptomatic outcomes
of gut toxicity are very different from the outcomes
noted secondary to oral, esophageal, or rectal injury.
Similar to oral mucositis, in GI mucositis, it was
believed historically that radiation caused direct cyto-
cidal injury (clonogenic and apoptotic cell death), di-
rect functional injury, and a number of reactive (indi-
rect) changes. Although, to a large extent, acute
toxicity is a result of crypt cell death, resulting in the
breakdown of the mucosal barrier and in mucosal
inflammation, controversy exists regarding whether
this effect, in fact, is direct or is mediated through a
series of intermediate steps. Paris et al.,5 as noted
earlier, argued that crypt cell death is actually an in-
direct consequence of endothelial cell apoptosis and
that endothelial cell apoptosis, therefore, is the pri-
mary lesion responsible for the intestinal radiation
syndrome. Although these findings are not accepted
universally, they provide strong evidence that intesti-
nal injury may be the consequence, at least in part, of intermediate events mediated by nonepithelial tis-
sues. This hypothesis may be supported by the finding
that during fractionated radiation therapy, a number
of compensatory changes also occur. For example,
during pelvic radiation therapy, intestinal permeabil-
ity and histologic injury actually are maximal in the
middle of the radiation course and then improve to-
ward the end, despite continued daily irradiation and
increasing symptoms of intestinal toxicity.18,19 This
suggests that mechanisms other than histologically
detectable changes in the mucosa are responsible for
bowel symptoms (nausea, emesis, diarrhea,and pain)
in patients during fractionated radiation therapy.
Although aspects of GI radiation-induced injury
have been studied in all segments of the alimentary
tract (esophagus, stomach, duodenum, small intes-tine, colon, and rectum) and have been reviewed re-
cently by Fajardo et al.20 and Hauer-Jensen et al.,21 to
our knowledge, investigations of chemotherapy-in-
duced GI mucositis have been focused mainly on the
small intestine.
Many cytotoxic chemotherapeutic agents kill rap-
idly dividing cells, making the GI tract particularly
vulnerable. In the small intestine, cytotoxic agents act
at different levels of the crypt cell hierarchy, leading to
crypt hypoplasia followed by regeneration.22,23 The
first abnormality noted in the human small intestine is
an increase in apoptosis on Day 1 after chemotherapy;
this is followed by reductions in crypt length, villusarea, and mitotic index, which reach their nadir on
Day 3. Rebound hyperplasia follows on Day 5, prior to
normalization.24 This has now been modeled in rats,
in which it follows a similar pattern over a shorter time
course.25–27 However, Pritchard et al.28 have shown
that an increase in apoptosis does not necessarily
correlate with the severity of overt mucositis, suggest-
ing a contribution from p53 and p21. Gibson et al.29
confirmed this in the DA rat model. Further research
has shown30 that the ratio of proapoptotic genes to
antiapoptotic genes of the bcl -2 family changes along
the GI tract. There is a higher ratio of proapoptotic to
antiapoptotic genes in the small intestine than in the
large intestine, which may help explain the differences
in mucositis that occur. The different ratio of pro-
apoptotic to antiapoptotic genes found at the different
levels of the GI tract most likely relates to the differ-
ences in function, with the small intestine receiving a
large volume of potential toxins, most of which have
been neutralized prior to arrival in the colon. It also
may help to explain the rarity of small intestinal ma-
lignancy compared with colonic malignancy. Because
chemotherapy acts on tumors partly through apopto-
sis, antiapoptotic strategies to prevent mucositis
would need to be very specific to the GI tract ratherthan tumor. Gibson et al. have shown that the small
intestine damage caused by irinotecan (CPT-11) is the
same as that caused by drugs such as methotrexate,
but that there is more colonic crypt goblet cell hyper-
plasia.31
The esophagus is lined by nonkeratinized epithe-
lium with a lamina propria and muscularis mucosa.
Chemotherapy damages the dividing and differentiat-
ing cells, leading to a thin and ulcerated epithelium.32
Chemotherapy also alters the proliferative rate of con-
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nective tissue cells within the lamina propria, which
results in increased vascular permeability and an in-
flammatory infiltrate. Fibrosis and tissue ischemia en-
sue. There is little information in the literature regard-
ing esophageal mucositis because most symptoms
localized to the esophagus usually are attributed togastroesophageal reflux disease or to either viral or
fungal infections, which can coexist with any direct
chemotherapy-induced toxicity.
Likewise, little data exist concerning mucositis of
the stomach. Sartori et al. described gastric erosions
after chemotherapy with combined cyclophospha-
mide, methotrexate, and 5-fluorouracil (5-FU) or with
5-FU alone.33,34 The colon is not considered an area
that is particularly susceptible to chemotherapy-in-
duced mucositis. Gibson et al.26 reported crypt dam-
age in the colon after methotrexate and CPT-11 ther-
apy, but the damage observed was less than that noted
in the small intestine. Typhlitis, or postchemotherapy enterocolitis (usually involving the cecum), has been
reported in several articles,35–39 but to our knowledge
no histopathologic studies have been performed. It
appears to be increasing in incidence with the advent
of newer chemotherapeutic agents, such as the tax-
anes.
Whatever the initiating event, it is likely that mu-
cosal barrier injury in the GI tract and the oral mucosa
share similar mechanisms. Although more molecular
events have been elucidated in the pathogenesis of
oral mucositis relative to its GI counterpart, future
research is likely to demonstrate that the oral cavity
and the GI tract have sufficient homology that differ-
ences between them will be due to local differences in
specialized cell differentiation.
CLINICAL MUCOSITIS ASSESSMENT SCALESFrom routine patient care to sophisticated clinical re-
search settings, the importance of being able to de-
scribe precisely, classify objectively, and measure re-
producibly the severity of mucosal damage cannot be
overestimated. Ideally, a mucositis scoring system
should be objective, validated, and reproducible
across all clinical situations and applications. The
scale should be sufficiently sensitive to measure ap-propriate parameters of the mucositis experience con-
sistently across different treatment modalities, including
cancer chemotherapy, radiotherapy, and chemoradio-
therapy. It also should precisely measure elements
associated with mucositis consistently (i.e., content
validity). Minimal training should be necessary to pro-
duce systematic, accurate results, and the scale should
be characterized by intrarater and interrater reliabil-
ity. No scale established to date meets all these criteria
or is accepted universally.
Because the need for mucositis measurement in-
struments has become more acute, a number of dif-
ferent scoring systems have been developed (Table
1).40–54 A few scales measure GI mucositis, but the
majority of the scales measure oral mucositis. Oral
mucositis scales range considerably in their complex-ity and have undergone varying degrees of validation.
Scoring of Oral Mucositis
The mucositis scales used most commonly were de-
signed to define in global terms stomatotoxicity result-
ing from different cancer treatments. These tools are
comprised of four-point or five-point scales that rate
the overall status of the mouth relative to the clinically
observed mucosal appearance, severity of patient
pain, and, in some instances, the patient’s functional
capabilities relative to his or her oral status (e.g., the
ability to eat). Historically, many of these simple, com-
bined, variable toxicity scales have been based on ascale developed by the World Health Organization
(WHO) for the clinical assessment of patients receiv-
ing cancer therapy. A number of similar scales have
been developed and promoted as part of the National
Cancer Institute-Common Toxicity Criteria (NCI-CTC)
scales, which are used frequently by cooperative on-
cology groups and oncology researchers (Table 1).
A second group of scales has evolved out of these
simpler scales, and developed as nursing management
and clinical research tools. These can be characterized
as utilizing a combination of objective, functional, and
symptomatic variables. Like the simpler toxicity
scales, the oral mucositis scales combining objective,
functional, and symptomatic descriptors apply them
to specific anatomic areas, adding greater specificity
with various aspects of oral function and subjective
patient responses. A third series of scales, the detailed
objective scoring scales, were designed for clinical re-
search trials and tend to focus on directed, separately
scored, objective and subjective end points (for a de-
scription of these scales, see Table 2).
The most relevant scales for clinical management
appear to be those based on NCI or WHO design. As
noted earlier, symptoms, signs, and functional distur-
bances are assessed, and a global score is achievedreadily. Analysis of approximately 400 trials, as a com-
ponent of the evidence-based review for the clinical
practice guidelines, determined that most of the stud-
ies utilized the NCI (43%) or WHO (38%) scales. Ten
percent of studies employed a study-specific scale,
and 5% used a cooperative group scale, such as scales
used by the Radiation Therapy Oncology Group or the
Eastern Cooperative Oncology Group (ECOG). Re-
maining scales, including the Stanford and Herzig
scales, were used by 0.5% of studies each.
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TABLE 1Measurement of Oral Mucositis
Scale (use) Source Elements measured Advantages Disadvantages
Simple, combined-variable mucositisscoring scales
NCI-CTC (clinical and research) Trotti et al., 200040 (see alsohttp://ctep.cancer.gov/forms/CTCv20 4-30-992.pdf 41)
Combined elements: symptom(pain), signs (erythema,ulceration); function; type of dietary intake
Used widely in research and clinical caresettings; specific scales for mucositisin patients undergoing head/neck radiation, chemotherapy, or HSCT
Research assessment potentially confounded by combinationof symptoms, signs, andfunctional changes
WHO (clinical and research) WHO, 197942 Combined elements: symptom(pain), signs (erythema,ulceration); function: type of dietary intake
Used widely in research and clinical caresettings; specific scales for mucositisin patients undergoing head/neck radiation, chemotherapy, or HSCT
Research assessment potentially confounded by combinationof symptoms, signs, andfunctional changes
RTOG (clinical and research) RTOG (seehttp://www.rtog.org/members/toxicity/acute.htm43)
Combined elements: symptom(pain), signs (unspecified);function: unspecified
Used widely in research and clinical caresettings
Research assessment potentially confounded by combinationof symptoms, signs, andfunctional changes
Detailed, objective mucositis scoringscales
OMI for HSCT (research) Schubert et al., 199244 Thirty-four mucosal changes: signs(atrophy, erythema, ulceration/pseudomembrane, edema, andselected sites); pain scores
(separate VAS)
Specific to 11 oral anatomic sites, thereby permitting subanalyses of changesacross the oral mucosa; eliminatesconfounders of symptoms and
functional disturbances; coresconsistent with NCI and WHO scores
Requires more examinerexperience and time thanNCI-CTC and WHO scales;only tested in patients
undergoing HSCT
Twenty-item OMI for HSCT(research)
McGuire et al., 200245 Twenty mucosal changes: signs(atrophy, erythema, ulceration/pseudomembrane edema, andselected sites)
Specific to nine oral anatomic sites;clinical objective changes scored as infull OMI
Requires less expertise thanOMI
OMAS for chemotherapy, radiation,and HSCT (research)
Sonis et al., 199946 Signs (erythema, ulceration) Same advantages as OMI with fewer oralanatomic sites scored
Requires more examinerexperience and time thanNCI-CTC and WHO scalesbut less time than OMI
Spijkervet Radiation Mucositis Scale(research)
Spijkervet, 198947 White discoloration, erythema,pseudomembrane ulceration
Permits objective measure of tissue injury of tissue injury
Detailed mathematicalcalculation required;requires further validation inmulticenter setting
Combined objective/functional/symptom scales
Oral Assessment Guide (clinical) Eilers et al. (1988)47 Signs (erythema), symptoms (pain,salivary changes), functional
disturbances (swallowing,voice)
Global scale that can reflect clinicalstatus/outcomes; suitable for nursing
care decision making
Not all variables necessarily link with clinical status; some
variables not continuous
Western Consortium for CancerNursing Scale (clinical)
Western Consortium for Cancer Nursing Research,199149
Lesions, color, bleeding, subjectivevariables
Global scale that can reflect clinicalstatus/outcomes; refined in 1998,based on elimination of five measuresother than lesions, color, or bleeding
Mixed objective, subjective, andfunctional variables; difficultto score precisely
Walsh Quantitative Scoring Systemfor Oral Mucositis (clinical andresearch)
Walsh et al., 199950 Mucosal changes, functionalchanges, salivary function, pain
Conceptual elements of NCI or WHOscale applied to specific anatomicsites; moderate training
Not validated; only tested inHSCT patients
Tardieu Quantitative Scale of OralMucositis for HSCT (research)
Tardieu et al., 199651 Mucosal changes, salivary function, function (voice,swallow), pain
Includes four anatomic sites, range of severity
Not validated (pilot study only);only tested in HSCTpatients; detailed, requiresmoderate to significanttraining
Daily Mucositis Scale for HSCT(research and clinical)
Donnelly et al., 199252 Erythema, oral edema, pain,dysphagia
Global scale that can reflect clinicalstatus/outcomes; less detailed thanmost
Validation in multicenter study needed
MacDibbs Mouth Assessment(research and clinical)
Dibble et al., 199653 Patient symptoms, ulcerations,erythema/hyperkeratosis,sputum smear/herpes simplex virus culture
Ease of administration generalizedassessment (not oral site-specific)
Only reported for radiationmucositis; not validated(pilot study only)
In vitro measurement
Epithelial Viability Scale (research) Wymenga et al., 199754 Trypan blue-based exclusion,based on oral epithelial smears
Easily administered; in vitro objectivemeasure; studied with bothchemotherapy-induced and radiation-induced mucositis
Early in development; requiresadditional validation
NCI-CTC: National Cancer Institute Common Toxicity Criteria; HSCT: hematopoietic stem cell transplantation; WHO: World Health Organization; RTOG: Radiation Therapy Oncology Group; VAS: visual analog scale;
OMI: Oral Mucositis Scale; OMAS: Oral Mucositis Assessment Scale.
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Regardless of the scale used, increasing evidence
confirms the importance of training and standardiza-
tion to improving the accuracy and consistency of
mucositis assessment. It is interesting to note that the
clinical qualifications of the evaluator (M.D., D.M.D.,
R.N. degrees) appear to be less important, ultimately,
than training and experience with using the scale.55
The frequency with which mucosal health needs
to be assessed is a function of the objective of the
examination. Whereas daily evaluations are of value
for a nursing care plan, an intense, twice-weekly ex-
amination may be effective for an interventional
study. In contrast, the success of a study in which
mucositis duration is a primary endpoint may require
daily evaluations.
Similar to other aspects of physical examination,
sensitivity and accuracy are often a function of the
conditions under which the examination takes place.Examination conditions are an issue of practicality—if
the examiner cannot conduct an adequate visual in-
spection of the area to be examined, then results will
be compromised. Adequate illumination of oral tis-
sues is critical for an accurate assessment.
Halogen light sources can provide consistent in-
tensity and color. In contrast, flashlights can vary sig-
nificantly in intensity and may cast patterns based on
the quality and type of light bulb, reflector, and lens.
In addition, depending on bulb type (e.g., element and
gas parameters), the color of light emitted from the
flashlight can distort the color of the oral tissues and
produce variable light intensity.
The convenience and comfort of both the exam-
iner and the patient during the examination can in-
fluence the quality of the overall examination results.
For example, whether the patient is being evaluated in
a hospital bed, on a medical examination table, or in a
dental chair may influence access and inspection of
oral tissues.
Visualization of the oral cavity becomes compro-
mised and, along with it, accuracy and reproducibility
as a patient’s medical condition deteriorates and/or as
mucositis worsens. Oral debris, pseudomembranous
candidiasis, and topical oral care therapies can ob-
scure tissue conditions. If a patient requires orotra-
cheal intubation, it becomes all but impossible to
examine the entire oral cavity unless arrangements aremade to examine the patient when tube care and
retaping occur. At times, oral hemorrhage can com-
promise observation of oral tissues significantly.
Many scoring systems have not compensated for
instances in which a patient cannot be examined be-
cause of these and other compromising situations—
bleeding, pain, nausea, or emesis. Although, in some
instances, the clinical situation may be a direct exten-
sion of the severity of the oral mucositis, whereas at
other times it may be unrelated. Consideration must
TABLE 2Comparison of Toxicity Grading of Oral Mucositis According to World Health Organization Criteria, National Cancer Institute—CommonToxicity Criteria, and Radiation Therapy Oncology Group Scales and Subscales
Scale Side effect(s) Grade 0 (none) Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Grade 4 (life-threatening) Grade 5 (death)
WHO Oral mucositis
(stomatitis)
None Oral soreness, erythema Oral erythema, ulcers,
solid diet tolerated
Oral ulcers, liquid diet only Oral alimentation impossible —
NCI-CTC Chemotherapy-inducedstomatitis/pharyngitis(oral/pharyngealmucositis)
None P ainl ess u lc ers , e ry thema ,or mild soreness inthe absence of lesions
Painful erythema, edema,or ulcers but eating oror swallowing possible
Painful erythema, edema, orulcers requiring IV hydration
Severe ulceration or requiringparenteral or enteralnutritional support orprophylactic intubation
Death related totoxicity
NCI-CTC Associated with HSCT(stomatitis/pharyngitis,oral/pharyngealmucositis)
None P ainl ess u lc ers , e ry thema ,or mild soreness inthe absence of lesions
Painful erythema, edema,or ulcers butswallowing possible
Painful erythema, edema, orulcers preventingswallowing or requiringhydration or parenteral (orenteral) nutritionalsupport
Severe ulceration requiringprophylactic intubation orresulting in documentedaspiration pneumonia
Death related totoxicity
NCI-CTC Mucositis due toradiation
Non e Erythema of the mucos a Patchy,pseudomembranousreaction (patchesgenerally 1.5 cm ingreatest dimensionand noncontiguous)
Pseudo-membranous reaction(contiguous patchesgenerally 1.5 cm ingreatest dimension)
Ulceration and occasionalbleeding not induced by minor trauma or abrasion
Death related totoxicity
RTOG Acute oral mucous
membrane toxicity caused by radiation
No change over
baseline
Injection, may experience
mild pain notrequiring analgesic
Patchy mucositis that may
produce inflammatory serosanguinitisdischarge; may experience moderatepain requiringanalgesia
Confluent, fibrinous
mucositis, may includesevere pain requiringnarcotic
Ulceration, hemorrhage, or
necrosis
—
WHO: World Health Organization; NCI-CTC: National Cancer Institute Common Toxicity Criteria; IV: intravenous; HSCT: hematopoietic stem cell transplantation; RTOG: Radiation Therapy Oncology Group.
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be given to these clinical parameters, especially if the
scale is administered for research purposes and the
assessment accuracy is paramount.
There is clear utility in separately scoring objec-
tive measures of mucosal damage and other variables
related to oral mucositis (e.g., subjective variablessuch as pain and dryness and functional variables
such as talking, swallowing, or ability to eat). Investi-
gators have demonstrated that detailed oral mucositis
scores, such as the Oral Mucositis Index and the Oral
Mucositis Assessment Scale, correlate closely with oral
mucositis pain scores.44,56 Conversely, scoring of func-
tional variables may not be correlated directly with
oral mucosal events. For example, oral mucositis as-
sessed with a scale such as the NCI-CTC scale may be
rated Grade 4, which describes the patient as requiring
“parenteral or enteral nutrition or support.” However,
in the HSCT setting, many patients are placed on total
parenteral nutrition because of intestinal toxicity; oth-erwise, they very well could continue with oral nutri-
tional intake. Similar problems exist for the NCI-CTC
Grade 3 oral toxicity category, in which the patient
requires intravenous hydration. Consideration of how
best to integrate these issues with the specific out-
comes of the study should be determined during pro-
tocol design.
Scoring of GI Mucositis
Most of the available information regarding the inci-
dence of GI toxicity relates to symptoms and func-
tional changes. Making accurate evaluation of damage
impossible are the problems of obtaining sequential
biopsy before, during, and after treatment; the speci-
mens’ typically superficial nature; and the inaccessi-
bility of important segments of the GI tract. With
chemotherapy, 40–100% of patients experience GI
mucositis, depending on the dose and type of chemo-
therapy.57 It is difficult to identify when the problem is
based solely on symptoms: pain and diarrhea are uni-
versal and cannot be traced easily to the section of the
GI tract that is affected (for a comparison of scoring
systems used to assess GI tract mucositis, see Table 3).
EPIDEMIOLOGY AND OUTCOMESMost data supporting the computation of incidence of
mucositis are derived from clinical trials of chemo-
therapy and radiotherapy regimens in which the re-
porting of mucositis is a secondary objective. Not un-
expectedly, in the current review, we found that
virtually all trials were underpowered and unable to
produce stable estimates of rarely occurring events,
such as toxicities, and most studies included only lim-
ited discussion of methods for analyzing toxicity data.
The quality of articles was graded on three parame-
ters: adequate definition of mucositis, blinded or in-
dependent assessment of mucositis, and sample size.
Articles that provided either a definition of mucositis
or named a standard grading system, such as the
systems of the NCI, the ECOG, or the National Cancer
Institute of Canada, were assigned 1 quality point. Articles with a blinded or independent assessment of
mucositis were assigned 1 quality point. The quality
score was obtained by summing the quality points and
adding the sum to 1 (the quality score for the lowest
quality article). Therefore, all articles were scored on a
scale of 1 to 3. Sample size and the quality scores were
incorporated in the computation of the average inci-
dence of mucositis as follows: We defined the overall
quality-adjusted mucositis rate, p overall , as:
P overall
j
1
J qs j n j p j
i 1
J
qs i n i
,
in which qs j is the quality score for the j th study, nj is
the sample size for the j th study, and p j is the mucosi-
tis rate observed in the j th study. This method is a
modification of that of Berard and Bravo.58 Because
some of the study sample sizes were small, it was
believed that the Gaussian approximation to the bino-
mial distribution was not applicable (because the
Gaussian approximation is a large-sample result).
Therefore, an estimate of the 95% confidence interval
for the overall quality-adjusted mucositis rate was ob-
tained using the bootstrap method described by
Efron.59
One thousand bootstrap samples were generated
for a given treatment regimen using the SAS/IML sta-
tistical software package (SAS Inc., Cary, NC). For each
of the bootstrap samples, the overall mucositis rate
was calculated. These bootstrap mucositis rates then
were ordered from smallest to largest. The 2.5th per-
centile and 97.5th percentile bootstrap mucositis rates
then were used to report the 95% bootstrap confi-
dence interval for the treatment regimen.
To our knowledge, Grades 1 and 2 mucositis are
not reported uniformly in clinical trials of chemother-apy; therefore, for estimates of incidence, only Grade 3
and 4 mucositis, which were combined across all scor-
ing systems (Grade 3– 4), are reported. For the few
reports that used study-specific scoring systems,
scores that corresponded with ulceration or that were
considered severe have included.
Risk of Grade 3–4 Oral or GI Mucositis
The incidence of oral and GI mucositis varied signifi-
cantly among different treatment regimens and mo-
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dalities (Table 4).60–398 Most anthracycline-based reg-
imens were associated with rates of oral mucositis in
the 1–10% range, except when regimens included
5-FU. Included among these are the standard regi-
mens for adjuvant therapy in patients with breast can-
cer (5-FU, doxorubicin, and cyclophosphamide; doxo-
rubicin and cyclophosphamide; or 5-FU, epirubicin,
and cyclophosphamide) as well as regimens for pa-
tients with non-Hodgkin lymphomas, including cyclo-
phosphamide, doxorubicin, vincristine, and pred-
TABLE 3Grading Systems in Gastrointestinal Mucositis
Organ, tract, and symptoms Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
RTOG: Acute radiationmorbidity scoring criteria
Pharynx and esophagus No change overbaseline
Mild dysphagia orodynophagia; may require topicalanesthetic ornonnarcotic analgesis;may require soft diet
Moderate dysphagia or odynophadga;may require narcotic analgesics;may requi re purée or liquid diet
Severe dysphagia orodynophagia withdehydration or weight loss( 15% from pretreatmentbaseline) requiring NG tubefeeing and IV fluids orhyperalimentation
Complete obstruction,ulceration, perforation,fistula
Larynx No change overbaseline
Mild or intermittenthoarseness/though notrequiring antitussive/erythema of mucosis
Persistent hoarseness but able tovocalize; referred ear pain, sorethroat, patchy fibrinous exudatesor mild arytenoid edema notrequiring narcotics/coughrequiring antitussive
Whispered speech, throat painor referred ear pain requiringnarcotic, confluent fibrinousexudate, marked arytenoidedema
Marked dyspnea, stridor, orhemoptysis withtracheostomy or intubationnecessary
Upper GI tract No change Anorexia with 5% weight loss frompretreatment baseline,nausea not requiringantiemetics, abdominaldiscomfort notrequiringparasympatholytisdrugs or analgesics
Anorexia with 15% weight lossfrom pretreatment baseline,nausea and/or emesis requiringantemetics, abdominal painrequiring analgesics
Anorexia with 15% weight lossfrom pretreatment baselineor requiring NG tube orparenteral support; nauseaand/or emesis requiring tubeor parenteral support;abdominal pain severedespite medication;hematemesis or melena;abdominal distention (flat-plate radiographdemonstrates distendedbowel loops)
Ileus, subacute or acuteobstruction, perforation. GIbleeding requiringtransfusion, abdominalpain requiring tubedecompression or boweldiversion
Lower GI tract, includingpelvis
No change Increased frequency orchange in quality of bowel habits notrequiring medication,rectal discomfort notrequiring analgesics
Diarrhea requiring parasympatholyticdrugs (e.g., Lomotil[diphenoxylate atropine]); mucousdischarge not necessitatingsanitary pads; rectal or abdominalpain requiring analgesics
Diarrhea requiring parenteralsupport, severe mucous orblood discharge necessitatingsanitary pads, abdominaldistention (flat-plateradiograph demonstratesdistended bowel loops)
Acute or subacute obstruction,fistula or perforation, GIbleeding requiringtransfusion; abdominalpain or tenesmus requiringtube decompression orbowel diversion
RTOG chronic toxicity: GItract
Nausea None Able to eat, reasonableintake
Intake significantly decreased, butpatient can eat
No significant intake —
Emesis None One episode in 24 hrs Two to 5 episodes in 24 hrs Six to 10 episodes in 24 hrs Greater than 10 episodes in 24hrs or requiring parenteralsupport
Diarrhea None Increase of 2 to 3 stoolsper day overpretreatment level
Increase of 4 to 6 stools per day,nocturnal stools, or moderatecramping
Increase of 7 to 9 stools per day or incontinence or severecramping
Increase of 10 stools per day or macroscopically bloody diarrhea, or need forparenteral support
RTOG-EORTC: Late radiationmorbidity scoring system
Esophagus None Mild fibrosis, slightdifficulty in swallowingsolids, no pain onswallowing
Unable to take solid food normally,swallowing semisolid food,dilatation may be indicated
Severe fibrosis, able to swallow only liquids, may have painon swallowing, dilatationrequired
Necrosis, perforation, fistula
Small/large in te stine None Mild diarrhea, mildcramping, bowelmovement 5 timesdaily, slight rectaldischarge or bleeding
Moderate diarrhea and colic, bowelmovement 5 times daily,excessive rectal mucus orintermittent bleeding
Obstruction or bleedingrequiring surgery
Necrosis, perforation, fistula
NCI-CTC — Mild Moderate Severe Life-threatening
Emesis episodes/24 hr — 1 2–5 6–10 10 or parenteral supportDiarrhea (increased
frequency over normal)— 2–3 4–6 or nocturnal 7–9 or incontinence or severe
cramping 9, macroscopic blood,
enteral support
RTOG: Radiation Therapy Oncology Group; NG: nasogastric; IV: intravenous; GI: gastrointestinal; EORTC: European Organization for Research and Treatment of Cancer.
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TABLE 4Relation between Antineoplastic Therapy and Risk of Grade 3–4 Oral and Gastrointestinal Mucositis a
Regimen No. of studies No. of patients
Risk of Grade 3–4oral mucositis
Risk of Grade 3–4GI mucositis
% 95% CI % 95% CI
Anthracycline s 19 1139 10 9–12 3 1–4 Cyclophosphamide 4 872 9 7–10 NR NR 5-FU/cyclophosphamide (FAC, FEC) 8 1382 3 2–4 1 1–1 5-FU/platinum 3 130 8 3–12 3 1–6 Paclitaxel 10 790 11 9–13 1 1–1 Docetaxel 17 845 11 5–18 14 11–18 Docetaxel/cyclophosphamide 2 105 11 5–18 1 1–42Docetaxel/5-FU 2 108 66 58–74 73 63–82 Paclitaxel/platinum 2 107 5 3–10 5 2–9 Docetaxel/platinum 2 53 12 2–25 NR NR
TaxanesDocetaxel alone 16 1697 13 11–15 7 5–10Paclitaxel alone 3 167 3 1–6 2 1–4Docetaxel XRT 1 21 98 90–98 NR NRPaclitaxel XRT 7 117 48 39–56 6 6–15Docetaxel/5-FU 3 303 46 41–50 5 2–8Paclitaxel/5-FU 1 16 6 3–19 6 3–19Paclitaxel/5-FU XRT 2 113 75 67–83 1 1–2Docetaxel/platinum 4 311 2 1–3 2 1–4Paclitaxel/platinum 4 296 1 1–3 8 3–17Docetaxel/platinum XRT 1 15 20 3–40 NR NRPaclitaxel/platinum XRT 10 346 60 56–64 2 2–8Docetaxel/platinum/5-FU 2 115 43 34–52 6 3–9Paclitaxel/platinum/5-FU 3 225 27 23–31 18 12–23Docetaxel/gemcitabine 10 347 7 5–10 3 2–5Paclitaxel/gemcitabine 1 45 2 1–7 1 1–4Docetaxel/vinorelbine 5 625 7 5–10 NR NRDocetaxel and others 3 77 18 9–27 13 4–23Paclitaxel and others 6 257 13 9–17 4 3–6
Platinum 3 55 3 3–8 2 2–8Platinum XRT 6 309 11 8–14 11 7–16Oxaliplatin XRT 1 29 31 17–48 NR NRPlatinum/gemcitabine 3 237 3 2–6 7 3–11Platinum/gemcitabine/taxane 1 36 3 1–8 14 2–25Platinum/gemcitabine/5-FU 3 168 4 2–6 3 1–6Platinum and any taxane 10 671 2 1–3 3 2–5Platinum/taxane XRT 12 329 64 59–69 2 2–8Platinum/taxane/irinotecan 1 21 5 2–14 10 2–24Platinum/methotrexate/leucovorin 3 73 18 10–27 NR NRPlatinum/UFT 1 46 1 1–4 NR NR
5-FU 5 1615 2 1–3 5 1–115-FU CI 3 146 14 10–18 1 1–45-FU/leucovorin 21 3177 14 12–15 11 10–125-FU CI XRT 1 84 6 1–12 12 6–195-FU/cyclophosphamide/methotrexate 5 810 3 2–4 2 1–45-FU/platinum 12 508 18 15–21 14 10–185-FU/leucovorin/platinum 16 763 5 4–7 8 6–105-FU/platinum XRT 12 687 38 35–41 14 10–175-FU/LPALM 1 687 7 5–9 NR NR5-FU/other misc drugs 5 543 6 4–8 5 4–85-FU CI/other misc drugs 7 213 12 8–17 6 3–135-FU/other misc drugs XRT 1 9 11 6–33 NR NR5-FU/leucovorin/other misc drugs 8 338 4 2–6 4 3–75-FU/leucovorin/other misc drugs XRT 1 43 7 1–16 7 1–165-FU/leucovorin/taxane 4 145 41 34–49 6 2–105-FU/leucovorin/mitomycin C 3 161 15 9–20 10 5–16
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nisolone (CHOP). To our knowledge, it has not been
demonstrated that the addition of rituximab to CHOP
increases the risk of oral or GI mucositis. Other new
agents, such as imatinib, are associated with a very
low incidence of oral and GI mucositis. Similar rates
are reported with taxane-based and platinum-based
regimens, again except for regimens containing 5-FU.
However, radiation therapy to the head and neck or to
the pelvis or abdomen was associated with increasedincidence of Grade 3–4 oral or GI mucositis, respec-
tively, often exceeding 50% of patients.
In contrast, the administration of 5-FU often was
associated with rates of Grade 3–4 oral mucositis
15%, whereas CPT-11 was associated with similarly
high rates of GI mucositis. The addition of radiation
therapy to 5-FU-based and CPT-11-based regimens
may increase the risk of Grade 3–4 oral and GI mu-
cositis to 30%. Because these agents form the basis
of most regimens for patients with GI malignancies,
the severe mucositis resulting from these agents is of
particular clinical importance.
Patients who underwent HSCT, particularly those
who received total body irradiation, experienced high
rates of mucositis. The highest rates were observed
when total body irradiation was used, with the rate of
Grade 3–4 mucositis exceeding 60% in most reports.
However, incidence rates approached 30–50% without
total body irradiation. Slightly lower rates were notedamong some of those patients, depending on the che-
motherapy regimen received. Children who under-
went HSCT also experienced a high incidence of oral
mucositis, particularly when total body irradiation was
used for conditioning. Rates with other chemotherapy
regimens varied from very low (1–2%) with single-
agent therapy with topotecan or etoposide to very
high ( 20%) with combination regimens, including
high doses of ifosfamide or anthracyclines.
Because they frequently receive radiation therapy,
TABLE 4(continued )
Regimen No. of studies No. of patients
Risk of Grade 3–4oral mucositis
Risk of Grade 3–4GI mucositis
% 95% CI % 95% CI
Irinotecan 4 409 2 1–4 30 25–35Irinotecan/5-FU 3 524 3 1–4 6 4–8Irinotecan/5-FU XRT 2 36 36 22–47 71 50–93Irinotecan/5-FU CI XRT 1 22 NR NR 18 5–36Irinotecan/5-FU/platinum 1 70 9 3–16 NR NRIrinotecan/5-FU/leucovorin 5 318 5 3–8 25 20–30Irinotecan/5-FU/leucovorin/platinum 3 130 6 2–11 38 30–47Irinotecan/taxane 3 57 3 3–9 22 11–33Irinotecan/UFT/leucovorin 1 24 4 2–13 29 13–50
Adult BM T With TBI 8 611 64 61–68 7 3–16Busulfan conditioning regimen (no TBI) 10 360 52 47–55 10 7–14Other conditioning regimens (no TBI) 3 439 31 27–35 15 11–19Stem cells: Myeloma 5 139 36 30–43 14 8–23Stem cells: Solid tumors 9 266 27 24–31 6 4–9
Pediatric BMT With TBI 7 320 42 37–47 33 12–62 With busu lfan/etoposide/cyclophosphamide co nditioning (no TBI) 3 36 27 13–42 NR NR With melpha lan/carboplatin/etoposide conditioning (no TBI) 4 59 31 25–40 14 3–36
Other pediatric regimens Ara-C, idarubicin, fludarabine 4 192 20 10–33 13 7–21Methotrexate 3 132 23 16–30 NR NRDoxorubicin/L-asparaginase 1 36 27 13–42 NR NRDoxorubicin/5-FU/cyclophosphamide 1 12 0 0–17 NR NRMitoxantrone 1 66 12 5–21 — —Thiotepa/cyclophosphamide 1 51 6 1–14 NR NRTopotecan 1 49 0 0–4 2 1–48Ifosfamide/etoposide 1 60 20 12–30 NR NR
GI: gastrointestinal; 95% CI: 95% confidence interval; 5-FU: 5-fluorouracil; FAC: doxorubicin and cyclophosphamide; FEC: 5-FU, epirubicin, and cyclophosphamide; NR: not reported (no mention of toxicity in the
reports); XRT: radiotherapy; UFT: tegafur–uracil; CI: continuous infusion; misc: miscellaneous; BMT: bone marrow transplantation; TBI: total body irradiation; ara-C: cytosine arabinoside.a Source: Risk measures based on reports of clinical antineoplastic therapy.58–396
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5-FU, or CPT-11, patients with GI or gynecologic ma-
lignancies experience Grade 3–4 GI mucositis at sig-
nificantly higher rates than their counterparts with
other malignancies (Table 5).60–398 Patients with can-
cers of the head and neck, esophagus, or upper GI
tract were found to be at high risk of Grade 3–4 oral
mucositis for the same reasons. Acute damage to theGI mucosa is a consequence of radiotherapy in 85% of
patients symptomatically and in 100% of patients his-
tologically.
These data are supported by recent reports of the
incidence of mucositis among patients with solid tu-
mors receiving myelosuppressive chemotherapy. Elt-
ing et al. observed oral mucositis in 22% of cycles of
myelosuppressive chemotherapy, GI mucositis in 7%
of cycles, and both oral and GI mucositis in 8% of
cycles.1
Outcomes and Cost of Oral and GI Mucositis
Even rates of 5–15% for Grade 3–4 oral or GI mucositis
are significant clinically because of the serious clinical
outcomes that result from this condition. In approxi-
mately 35% of patients with Grade 3–4 mucositis, the
subsequent cycle of chemotherapy is delayed. The
doses of chemotherapy are reduced in approximately 60% of patients (range, 15–100%), and the regimen is
discontinued in approximately 30% of patients (range,
8 –100%). Among patients receiving standard-dose
chemotherapy regimens, 70% of patients with Grade
3–4 oral mucositis require feeding tubes to maintain
adequate nutrition, approximately 60% of patients
have fever, and 62% of patients require hospitaliza-
tion. Among adult HSCT recipients and patients re-
ceiving high-dose chemotherapy with HSCT support,
87% require feeding tubes. Opioid analgesics are re-
TABLE 5Relation between Cancer Diagnosis and Risk of Grade 3–4 Oral and Gastrointestinal Mucositis a
Diagnosis No. of studies No. of patients
Risk of Grade 3–4 oralmucositis
Risk of Grade 3–4gastrointestinalmucositis
% 95% CI % 95% CI
Acute myelogenous leukemia 11 262 12 10–16 6 5–11 Acute lymphoblastic leukemia 3 64 34 25–44 NR NRChronic myelogenous leukemia 2 36 7 3–17 3 3–12Non-Hodgkin lymphoma 4 83 15 9–24 NR NRLymphomas—various 2 96 23 15–32 5 1–11Breast cancer 96 10,530 8 8–9 6 5–6Colorectal cancer 65 8412 6 6–7 12 11–12Rectal cancer 2 106 8 3–12 13 7–20Prostate cancer 5 122 14 9–21 4 2–8Small cell lung cancer 9 753 9 8–12 3 2–5Nonsmall cell lung cancer 15 622 6 4–8 5 3–8Mesothelioma 3 53 20 12–30 3 3–13Head and neck cancer 58 2206 42 40–44 6 5–8Esophageal cancer 3 194 46 40–53 10 6–15Gastric cancer 11 637 8 6–10 4 3–6Pancreatic cancer 13 477 14 11–16 7 5–9Gastrointestinal tumors—various 4 136 53 47–58 39 27–49Cervical cancer 6 724 1 1–2 15 13–18Uterine cancer 1 39 1 1–5 1 1–5Ovarian cancer 11 516 7 5–10 3 2–5Gynecologic cancers—various 1 125 1 1–2 NR NRBladder cancer 1 22 2 2–9 9 2–23Renal cell cancer 1 24 8 2–21 NR NRTesticular cancer 3 157 11 7–15 NR MRGerm cell cancer 2 52 23 12–35 3 3–27Sarcoma cancer 2 86 5 2–9 7 2–13Glioma 1 13 8 4–23 NR NRUnknown primary 2 46 9 3–17 NR NRSolid tumors—various 22 734 12 10–14 7 5–9
95% CI: 95% confidence interval; NR: not reported (no mention of toxicity in the reports).a Source: Risk measures based on clinical reports.58–396
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quired in 80% of HSCT recipients. Sonis et al. reported
5.8 additional days of narcotics and 1.9 additional days
of total parenteral nutrition among HSCT recipients
who had oral ulceration compared with patients who
did not have ulceration.65 Those investigators also re-
ported 2 additional febrile days per patient with oralulcers compared with patients without oral ulcers. The
association between oral ulceration and infection was
observed previously by Ruescher et al, who reported
that oral ulceration was three times more common
among bone marrow transplantation recipients with
streptococcal bacteremias than among patients with-
out streptococcal bacteremias.66
Among patients with solid tumors who receive
myelosuppressive chemotherapy, infection occurs
during 73% of cycles complicated by mucositis, but
during only 36% of cycles with similar myelosuppres-
sion without mucositis. Fatigue also is more common
during cycles with mucositis than in cycles withoutmucositis (9% compared with 5%; P 0.0007).1 In the
same report, the high incidence of serious clinical
outcomes during cycles with mucositis led to an in-
crease of 2-fold in the average number of hospital
days per cycle (7.7 days vs. 3.9 days; P 0.0001).
Severe oral mucositis is a particularly ominous
clinical sign among children because of the risk of
airway compromise. Among pediatric bone marrow
transplantation recipients, airway compromise due to
oral mucositis was reported in 2–19% of all patients.
Death or anoxia-induced brain damage occurred oc-
casionally. Likewise, 90% of pediatric HSCT recipi-
ents with Grade 3–4 mucositis required feeding tubes,
total parenteral nutrition, and opioid analgesics.
These occasionally are associated with systemic infec-
tion. Although these interventions are required less
commonly for standard-dose chemotherapy regi-
mens, maintenance of proper nutrition is a particu-
larly important goal among children.
Because of its serious clinical consequences,
Grade 3–4 mucositis would be expected to be a finan-
cially significant event; however, the financial impli-
cations of mucositis have been reported only rarely.
Groener et al.166 reported that Grade 3–4 mucositis
accounted for 3% of resource utilization ($17) during cycles of raltitrexed and 21% of resource utilization
($113) during cycles of 5-FU and leucovorin. The ad-
ditional days of fever, hospitalization, narcotic usage,
and total parenteral nutrition reported by Sonis et al.
among HSCT recipients with oral ulcers also trans-
lated into additional hospital charges of $42,749 per
patient.65 Elting et al. reported incremental costs of
$2725 and $5565 per cycle for Grade 1–2 mucositis and
Grade 3–4 mucositis, respectively.1
The cost of GI mucositis has not been studied
formally, but includes a reduction in cure rate as a
result of treatment interruptions or inadequate treat-
ment as well as the cost of the symptom management
itself. Data regarding the influence of overall treat-
ment time outside of the head and neck are most
reliable for cervical cancer. The effect of prolonging treatment time reportedly results in a decrease in con-
trol of between 0.55% and 1.4% per day.399
Although this report focuses on acute manifesta-
tions and short-term outcomes, permanent damage to
both oral and GI mucosa may occur as a result of
radiotherapy. Yeoh et al.400,401 have shown that per-
manent damage and dysfunction occur in 70–90% of
patients undergoing radiotherapy, depending on the
treatment site and radiation dose. Radiotherapy also
causes changes in motility proximal to the site at
which radiation is administered.402–404 Because pa-
tients treated for pelvic or gastric cancer constitute the
majority of long-term cancer survivors, the prevalenceof chronic toxicity is significant. Moreover, some pa-
tients may be asymptomatic but still exhibit severe
functional changes, including reductions in B12 and
calcium absorption, which have the potential to cause
substantial problems.
CONCLUSIONSMucositis can be a frequent and clinically significant
event elicited by drug and radiation cancer therapy.
Although mucositis typically has been associated with
specific patient populations, such as those receiving
conditioning regimens for HSCT and radiotherapy for
head and neck cancer, its incidence and impact also
have been appreciated recently in other patients with
solid tumors. Defining the epidemiology of mucositis
has been confounded historically by a number of vari-
ables, including underreporting, differences in the ter-
minology used to describe it, differences in assess-
ment techniques and scales, and the correlation
between mucositis and other clinically important se-
quelae. However, establishing strong multiprofes-
sional and interdisciplinary collaborations has re-
sulted in marked advances in the improvement of
psychometric and utilization components of mucosi-
tis scales.The pathobiology of mucositis long has been con-
sidered to be limited to direct epithelial injury. A con-
tinuum of mechanistic studies conducted in recent
years has revealed that, in fact, mucositis is the cul-
mination of a series of biologically complex and inter-
active events that occur in all tissues of the mucosa.
Although the complete definition of mucositis as a
biologic process remains a work in progress, the cur-
rent understanding of cellular and molecular events
that lead to mucosal injury has provided a number of
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potential interventional targets. Consequently, for the
first time, directed, biologically rational therapies are
now in various stages of development. Furthermore,
mechanistically based risk prediction and disease
monitoring appear to be realistic goals for the not-too-
distant future.
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