(Sonis Et Al, 2004)

8/19/2019 (Sonis Et Al, 2004)

1/31

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).

8/19/2019 (Sonis Et Al, 2004)

2/31

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

1996 CANCER Supplement May 1, 2004 / Volume 100 / Number 9

8/19/2019 (Sonis Et Al, 2004)

3/31

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).

Perspectives on Therapy-Induced Mucositis/Sonis et al. 1997

8/19/2019 (Sonis Et Al, 2004)

4/31

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-.


8/19/2019 (Sonis Et Al, 2004)

5/31

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-.


8/19/2019 (Sonis Et Al, 2004)

6/31

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-.


8/19/2019 (Sonis Et Al, 2004)

7/31

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-


8/19/2019 (Sonis Et Al, 2004)

8/31

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.


8/19/2019 (Sonis Et Al, 2004)

9/31

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


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


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.


8/19/2019 (Sonis Et Al, 2004)

10/31

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


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


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.


8/19/2019 (Sonis Et Al, 2004)

11/31

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-


8/19/2019 (Sonis Et Al, 2004)

12/31

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.


8/19/2019 (Sonis Et Al, 2004)

13/31

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


8/19/2019 (Sonis Et Al, 2004)

14/31

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


8/19/2019 (Sonis Et Al, 2004)

15/31

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


8/19/2019 (Sonis Et Al, 2004)

16/31

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


8/19/2019 (Sonis Et Al, 2004)

17/31

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.

REFERENCES1. Elting L, Cooksley C, Chambers M, Cantor S, Manzullo E,

Rubenstein E. The burdens of cancer therapy: clinical and

economic outcomes of chemotherapy-induced mucositis.Cancer. 2003;98:1531–1539.

2. Rubenstein EB, Peterson DE, Shubert M, et al. Clinical prac-

tice guidelines for the prevention and treatment of cancertherapy-induced oral and gastrointestinal mucositis. Can-cer. 2004;100(Suppl):2026–2046.

3. Lockhart PB, Sonis ST. Alterations in the oral mucosa caused

by chemotherapeutic agents. A histologic study. J Dermatol

Surg Oncol. 1981;7:1019–1025.

4. Sonis ST, Peterson RL, Edwards LJ, et al. Defining mecha-

nisms of action of interleukin-11 on the progression of ra-diation-induced oral mucositis in hamsters. Oral Oncol.

2000;36:373–381.5. Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the

primary lesion initiating intestinal radiation damage in

mice. Science. 2001;293:293–297.

6. Handschel J, Prott FJ, Sunderkotter C, Metze D, Meyer U,

Joos U. Irradiation induces increase of adhesion moleculesand accumulation of beta2-integrin-expressing cells in hu-

mans. Int J Radiat Oncol Biol Phys. 1999;45:475–481.

7. Wang J, Albertson CM, Zheng H, Fink LM, Herbert JM,

Hauer-Jensen M. Short-term inhibition of ADP-induced

platelet aggregation by clopidogrel ameliorates radiation-induced toxicity in rat small intestine. Thromb Haemost.

2002;87:122–128.

8. Hall PD, Benko H, Hogan KR, Stuart RK. The influence of serum tumor necrosis factor-alpha and interleukin-6 con-

centrations on nonhematologic toxicity and hematologicrecovery in patients with acute myelogenous leukemia. Exp Hematol. 1995;23:1256–1260.

9. Epstein JB, Silverman S Jr., Paggiarino DA, et al. Benzydam-

ine HCl for prophylaxis of radiation-induced oral mucositis:results from a multicenter, randomized, double-blind, pla-

cebo-controlled clinical trial. Cancer. 2001;92:875–885.

10. Gate L, Paul J, Ba GN, Tew KD, Tapiero H. Oxidative stress

induced in pathologies: the role of antioxidants. Biomed

Pharmacother. 1999;53:169–180.11. Culy C, Spencer C. Amifostine: an update on its clinical

status as a cytoprotectant in patients with cancer receiving

chemotherapy or radiotherapy and its potential therapeutic

application in myelodysplastic syndrome. Drugs. 2001;61:641–684.

12. Maddens S, Charruyer A, Plo I, et al. Kit signaling inhibits

the sphingomyelin-ceramide pathway through PLC gamma

1: implication in stem cell factor radioprotective effect.Blood. 2002;100:1294–1301.

13.Handschel J, Sunderkotter C, Prott FJ, Meyer U, Kruse-Losler B, Joos U. Increase of RM3/1-positive macrophages in

radiation-induced oral mucositis. J Pathol. 2001;193:242–

247.

14.Zheng H, Wang J, Hauer-Jensen M. Role of mast cells in

early and delayed radiation injury in rat intestine. Radiat

Res. 2000;153(5 Pt 1):533–539.

15. Dorr W, Spekl K, Martin M. Radiation-induced oral mucosi-

tis in mice: strain differences. Cell Prolif. 2002;35(Suppl 1):

60–67.

16.Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of

methotrexate: toxicity among marrow transplantation pa-

tients varies with the methylenetetrahydrofolate reductase

C677T polymorphism. Blood. 2001;98:231–234.

17. Sonis ST. The biologic role for nuclear factor-B in disease

and its potential involvement in mucosal injury associated

with antineoplastic therapy. Crit Rev Oral Biol Med. 2002;

13:380–389.

18. Carratu R, Secondulfo M, de Magistris L, et al. Assessment of

small intestinal damage in patients treated with pelvic ra-

diotherapy. Oncol Rep. 1998;5:635–639.

19. Hovdenak N, Fajardo L, Hauer-Jensen M. Acute radiation

proctitis: a sequential clinicopathologic study during pelvic

radiotherapy. J Radiat Oncol Biol Phys. 2000;48:1111–1117.

20. Fajardo L, Berthrong M, Anderson R. Alimentary tract radi-

ation pathology. Oxford: Oxford University Press, 2001:208–

247.

21. Hauer-Jensen M, Wang J, Denham JW. Mechanisms and

modification of the radiation response of gastrointestinalorgans. In: Milas L, Ang KK, Nieder C, editors. Biological

modification of radiation response. Heidelberg: Springer

Verlag, 2003:49–72.

22. Ijiri K, Potten CS. Response of intestinal cells of differing

topographical and hierarchical status to ten cytotoxic drugs

and five sources of radiation. Br J Cancer. 1983;47:175–185.

23. Ijiri K, Potten CS. Further studies on the response of intes-

tinal crypt cells of different hierarchical status to eighteen

different cytotoxic agents. Br J Cancer. 1987;55:113–123.

24. Keefe DM, Brealey J, Goland GJ, Cummins AG. Chemother-

apy for cancer causes apoptosis that precedes hypoplasia in

crypts of the small intestine in humans. Gut. 2000;47:632–

637.

25. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the

prevention of fluorouracil induced intestinal toxicity: a dou-ble blind, placebo controlled, randomised trial. Gut. 2001;

48:28–33.

26. Gibson RJ, Keefe DM, Thompson FM, Clarke JM, Goland GJ,

Cummins AG. Effect of interleukin-11 on ameliorating in-

testinal damage after methotrexate treatment of breast can-

cer in rats. Dig Dis Sci. 2002;47:2751–2757.

27. Keefe DM. The effect of cytotoxic chemotherapy on the

mucosa of the small intestine. Adelaide, South Australia:

University of Adelaide, 1998.

28. Pritchard DM, Potten CS, Hickman JA. The relationships

between p53 and dependent apoptosis, inhibition of prolif-

eration and 5-flououracil-induced histopathology in murine

intestinal epithelia. Cancer Res. 1998;58:5453–5465.

29. Gibson RJ, Keefe DM, Clarke JM, et al. The effect of keratin-

ocyte growth factor on tumour growth and small intestinalmucositis after chemotherapy in the rat with breast cancer.

Cancer Chemother Pharmacol. 2002;50:53–58.

30. Bowen JM. The expression of the Bcl-2 family members in

the small and large intestine. Adelaide, South Australia: De-

partment of Medicine Adelaide, University of Adelaide,

2001.

31. Gibson R, Bowen J, Inglis M, Cummins A, Keefe D. Irinote-

can causes severe small intestinal damage, as well as colonic

damage, in the rat with implanted breast cancer. Gastroen-

terol Hepatol. 2003;18:1095–1100.

32. Squier CA, Kremer MJ. Biology of oral mucosa and esopha-

gus. J Natl Cancer Inst Monogr. 2001;29:7–15.


8/19/2019 (Sonis Et Al, 2004)

18/31

33. Sartori S, Trevisani L, Nielsen I, Tassinari D, Abbasciano V.

Misoprostol and omeprazole in the prevention of chemo-

therapy-induced acute gastroduodenal mucosal injury. A

randomized, placebo-controlled pilot study. Cancer. 1996;

78:1477–1482.

34. Sartori S, Trevisani L, Nielsen I, Tassinari D, Panzini I, Ab-

basciano V. Randomized trial of omeprazole or ranitidine

versus placebo in the prevention of chemotherapy-induced

gastroduodenal injury. J Clin Oncol. 2000;18:463–467.

35.Ibrahim NK, Rahman Z, Valero V, Murray JL III, Frye D,

Hortobagyi GN. Phase I study of vinorelbine and docetaxel

with granulocyte colony-stimulating factor support in the

treatment of metastatic breast cancer. Cancer Invest. 2002;

20:29–37.

36. Dosik GM, Luna M, Valdivieso M, et al. Necrotizing colitis in

patients with cancer. Am J Med. 1979;67:646– 656.

37. Keidan RD, Fanning J, Gat

Documents

(Sonis Et Al, 2004)