Clinical Practice Guidelines for the Prevention and Gastrointestinal Mucositis

Transcription

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Mucositis: Perspectives and Clinical Practice Guidelines
Supplement to Cancer
Clinical Practice Guidelines for the Prevention and
Treatment of Cancer Therapy–Induced Oral and
Gastrointestinal Mucositis
Edward B. Rubenstein, M.D.1
Douglas E. Peterson, D.M.D., Ph.D.2
Mark Schubert, D.D.S., M.S.D.3
Dorothy Keefe, M.D.4
Deborah McGuire, R.N., Ph.D.5
Joel Epstein, D.M.D., M.S.D.6
Linda S. Elting, Dr.P.H.7
Philip C. Fox, D.D.S.8
Catherine Cooksley, Ph.D.7
Stephen T. Sonis, D.M.D., D.M.Sc.9
for the Mucositis Study Section of the
Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology.
1
Department of Palliative Care and Rehabilitation
Medicine, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas.
BACKGROUND. Oral and gastrointestinal (GI) mucositis can affect up to 100% of
patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving
radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary
track mucositis increases mortality and morbidity and contributes to rising health
care costs. Consequently, the Multinational Association of Supportive Care in
Cancer and the International Society for Oral Oncology assembled an expert panel
to evaluate the literature and to create evidence-based guidelines for preventing,
evaluating, and treating mucositis.
METHODS. Thirty-six panelists reviewed literature published between January 1966
and May 2002. An initial meeting in January 2002 produced a preliminary draft of
guidelines that was reviewed at a second meeting the same year. Thereafter, a
writing committee produced a report on mucositis pathogenesis, epidemiology,
and scoring (also included in this issue), as well as clinical practice guidelines.
RESULTS. Panelists created recommendations from higher levels of evidence and
suggestions when evidence was of a lower level and there was a consensus regard-
2
Department of Oral Diagnosis, University of Connecticut Health Center, Farmington, Connecticut.
3
Department of Oral Medicine, Fred Hutchinson
Cancer Research Center, Seattle, Washington.
4
Department of Medical Oncology, Royal Adelaide
Hospital, Adelaide, Australia.
5
School of Nursing, University of Pennsylvania,
Philadelphia, Pennsylvania.
6
Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, Chicago, Illinois.
7
Department of Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas.
8
Department of Oral Medicine, Carolinas Medical
Center, Charlotte, North Carolina.
9
Division of Oral Medicine, Brigham and Women’s
Hospital, Boston, Massachusetts.
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). Cor-
porate sponsors include Amgen (Thousand Oaks,
CA), GelTex Pharmaceuticals (Waltham, MA), Helsinn
Healthcare SA (Pazzallo, Switzerland), Human Genome Sciences (Rockville, MD), McNeil Consumer
and Specialty Pharmaceuticals (Fort Washington, PA),
MGI Pharma (Bloomington, MN), MedImmune (Gaithersburg, MD), OraPharma (Warminster, PA), and
RxKinetix (Louisville, CO).
Panelists included the following individuals: Andrei
Barasch, D.M.D., M.D.Sc., University of Detroit Mercy
School of Dentistry (Detroit, MI); B. Nebiyou Bekele,
Ph.D., The University of Texas M. D. Anderson Cancer
Center (Houston, TX); Rene-Jean Bensadoun, M.D.,
Center Antoine-Lacassagne (Nice, France); Michael
Brennan, D.D.S., M.H.S., Carolinas Medical Center
(Charlotte, NC); Mark Chambers, D.D.S., The University of Texas M. D. Anderson Cancer Center (Houston,
TX); Catherine Cooksley, Ph.D., The University of
Texas M. D. Anderson Cancer Center (Houston, TX);
Marcio Da Fonseca, D.D.S., M.S., University of Michigan School of Dentistry (Ann Arbor, MI); Kathryn L.
Damato, R.D.H., M.S., C.C.R.P., University of Connecticut Health Center (Farmington, CT); Betty
© 2004 American Cancer Society
DOI 10.1002/cncr.20163
Published online in Wiley InterScience (www.interscience.wiley.com).
Daniel, B.S.N., M.S., The University of Texas M. D.
Anderson Cancer Center (Houston, TX); J. Peter
Donnelly, Ph.D., University Hospital Nijmegen
(Nijmegen, The Netherlands); Linda Elting, Dr.P.H.,
The University of Texas M. D. Anderson Cancer
Center (Houston, TX); Loree Oberle-Edwards,
R.D.H., M.S., Scripps Center for Dental Care (La
Jolla, CA); Douglas Peterson, D.M.D., Ph.D., University of Connecticut Health Center (Farmington,
CT); Judith Raber-Durlacher, D.D.S., Ph.D., Leiden University Medical Center (Leiden, The Netherlands); Ann
Rose, Ph.D., Vicro (Washington, DC); Edward B. Rubenstein, M.D., The University of Texas M. D. Anderson
Cancer Center (Houston, TX); Mark M. Schubert, D.D.S.,
M.S.D., Seattle Cancer Care Alliance (Seattle, WA); Sol
Silverman, M.A., D.D.S., University of San Francisco (San
Francisco, CA); Stephen T. Sonis, D.M.D., D.M.Sc.,
Brigham and Women’s Hospital (Boston, MA); Fred Spijkervet, D.D.S., Ph.D., University Hospital Groningen
(Groningen, The Netherlands); Diane Talentowski,
D.D.S., Loyola University Medical Center (Maywood, Illinois); Inger von Bu¨ltzingslo¨wen, D.D.S., Ph.D., Go¨teborg
University (Gothenburg, Sweden); and Ralph Wong,
M.D., University of Manitoba (Winnipeg, MB, Canada).
Clinical Practice Guidelines for Mucositis/Rubenstein et al.
2027
ing the interpretation of the evidence by the panel. Panelists identified gaps in
evidence that made it impossible to recommend or not recommend use of specific
agents.
CONCLUSIONS. Oral/GI mucositis is a common side effect of many anticancer
therapies. Evidence-based clinical practice guidelines are presented as a benchmark for clinicians to use for routine care of appropriate patients and as a
springboard to challenge clinical investigators to conduct high-quality trials geared
toward areas in which data are either lacking or conflicting. Cancer 2004;100(9
Suppl):2026 –2046. © 2004 American Cancer Society.
KEYWORDS: stomatitis, oral mucositis, gastrointestinal mucositis, clinical practice
guidelines.
O
ral mucositis is a common complication of cytoreductive cancer chemotherapy and radiotherapy. It
is the dose-limiting toxicity of treatment modalities
like accelerated fractionation and hyperfractionated
radiotherapy and of interventions that combine chemotherapy and radiotherapy. Its counterpart, gastrointestinal (GI) mucositis, is a well recognized toxicity
associated with some standard-dose chemotherapy
regimens commonly used in cancer treatment and
with radiotherapy encompassing any area of the GI
tract.
Oral and GI mucositis may occur in up to 100% of
patients undergoing high-dose chemotherapy with
hematopoietic stem cell transplantation (HSCT). For
patients receiving this treatment, a 1-point increase in
an oral mucositis score has been found to be associated with a significant increase in days with fever, risk
of infection, additional days of total parenteral nutrition, use of intravenous narcotic analgesics, total hospital charges, and 100-day mortality.1 From the patient’s perspective, oral mucositis is one of
transplantation’s most debilitating side effects.2
Recognizing the dramatic clinical and psychologic
effects of mucositis and the barrier that this condition
sometimes becomes to what may be life-saving ther-
apy, physicians, oral oncologists, investigators at the
National Cancer Institute, and others have sought to
bring to the attention of the oncology community the
clinical and economic impact of mucosal injury secondary to high-dose cancer therapy.1 During the last 5
years, new models of the basic mechanisms of progression and healing and proposals for new research
and treatment strategies have emerged.1,3 Biotechnology and pharmaceutical industry researchers have
joined academic clinical investigators in their attempts to develop interventions to prevent or treat
oral and GI mucositis.
Although the basic mechanisms of mucosal barrier
injury still are being explored, several significant findings
have become evident from clinical investigations. First,
because researchers employ different mucositis scoring
systems, each one measuring different endpoints or using one-of-a-kind composite endpoints, comparisons
across studies are difficult to make. Furthermore, no
comprehensive battery of questions provides a means of
uniform evaluation. Second, variations among designs
of investigations have prevented generalization to related cohorts, preventing reproducibility and inhibiting
progress. Third, patterns of patient care appear to have
evolved from a variety of clinical practice domains, in-
Edward B. Rubenstein’s current address: MGI Pharma, Bloomington, Minnesota.
Address for reprints: Dorothy Keefe, M.D., Department of Medical Oncology, Royal Adelaide Hospital Cancer Center, Royal Adelaide Hospital, North Terrace, Adelaide,
South Australia 5000, Australia; Fax: (011) 618-8232-2148; E-mail: [email protected]
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 member of the advisory boards at Endo Pharmaceuticals, McNeil Consumer
and Specialty Pharmaceuticals, and OSI Pharmaceuticals.
Dr. Peterson has served as a paid consultant for Aesgen, Inc. (Princeton, NJ).
Dr. Schubert is a member of the advisory boards at Endo Pharmaceuticals, OSI Pharmaceuticals (Melville, NY), and McNeil Consumer and Specialty Pharmaceuticals.
Dr. Keefe has received research funding and speaker’s honoraria from Amgen.
Dr. Elting has received speaker’s honoraria from McNeil Consumer and Specialty Pharmaceuticals and from Endo Pharmaceuticals (Chadds Ford, PA).
Dr. Sonis has served as a consultant for Biomodels and Affiliates (Wellesley, MA).
Received December 19, 2003; accepted January 22, 2004.
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CANCER Supplement May 1, 2004 / Volume 100 / Number 9
TABLE 1
Levels of Evidence, Grades of Recommendation, and Guideline Hierarchya
Measure
Level of evidence
I
II
III
IV
V
Grade of recommendation
A
B
C
D
Guideline classification/hierarchy
Recommendation
Suggestion
No guideline possible
a
Source of evidence
Metaanalysis of multiple well designed, controlled studies; randomized trials with low false-positive and false-negative errors (high
power)
At least one well designed experimental study; randomized trials with high false-positive or high false-negative errors or both (low
power)
Well designed, quasiexperimental studies, such as nonrandomized, controlled, single-group, pretest-posttest comparison, cohort,
time, or matched case–control series
Well designed, nonexperimental studies, such as comparative and correlational descriptive and case studies
Case reports and clinical examples
Evidence of Type I or consistent findings from multiple studies of Type II, III, or IV
Evidence of Type II, III, or IV and findings are generally consistent
Evidence of Type II, III, or IV, but inconsistent findings
Little or no systematic empiric evidence
A recommendation is reserved for guidelines that are based on Level I or Level II evidence
A suggestion is used for guidelines that are based on Level III, Level IV, and Level V evidence; this implies panel consensus on the
interpretation of this evidence
No guideline possible is used when there is insufficient evidence on which to base a guideline; this conclusion implies 1) that there
is little or no evidence regarding the practice in question or 2) that the panel lacks a consensus on the interpretation of existing
evidence.
Adapted from: Somerfield M, Padberg J, Pfister D, et al. ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Classic Papers Current Comments. 2000;4:881–886.4
cluding oral oncology, radiation oncology, medical oncology, and hematology, and the effect of this amalgamation is unclear. Finally, because most current
treatments seem to have evolved from empiricism rather
than from evidence, a methodologically vigorous review
of the literature on which treatments were based seemed
appropriate.
In response to these findings and developments,
the Multinational Association of Supportive Care in
Cancer and the International Society for Oral Oncology (MASCC/ISOO) created the Mucositis Study Section in 1998 to bring together experts from a number
of disciplines in oncology to address important issues
in mucositis treatment and research. Accordingly, in
2000, the study section established a panel of experts
to develop evidenced-based guidelines for the prevention and treatment of oral and GI mucositis associated
with anticancer therapy. The resulting guidelines are
intended for oral health care specialists, oncology and
oral medicine patients, oncologists, clinical investigators, and policy makers. This report describes the objectives, methods, and results of the MASCC/ISOO
Mucositis Study Section’s deliberations.
MATERIALS AND METHODS
Expert Panel Composition
The panel was composed of 36 oral oncologists, radiation oncologists, hematologists, medical oncologists,
surgeons, pathologists, nurses, dental hygienists, basic
scientists, microbiologists, epidemiologists, outcomes
researchers, and a medical librarian from a comprehensive cancer center. The panel included established
basic science, clinical, and health services investigators whose research involves mucosal barrier injury
and who publish in the peer-reviewed literature.
Process Overview
Because of the anticipated scope of the literature
search results and the size of the panel, the topic was
subdivided into subtopics, which were assigned to
working groups of two to five members. These subtopics included terminology, epidemiology (primary
and agent-specific or therapy-specific), basic oral care
and oral care protocols, bland oral rinses, analgesics,
cryotherapy, topical anesthetics, antimicrobial agents
(systemic and topical), growth factors and cytokines,
biologic mucosal protectants, antiinflammatory
agents, complementary and alternative medicine (including natural agents), low-energy laser therapy, and
hemorrhage. The GI Mucositis Working Group was
responsible for initial review of all the same areas as
they related to GI mucositis. In their work, panelists
employed a systematic weighting of both level and
grading of the evidence (Table 1).4 – 6
Literature Review and Data Collection
A medical librarian, working with the panel cochairs,
conducted the initial Medline and cancer literature
search. Literature was drawn from as early as January
1966 and as late as November 21, 2001. Additional
work extended the search through May 31, 2002.
An initial search of the English-language medical
literature published from January, 1966 to October,
2001 produced more than 500,000 publications related
to cancer and its therapies. Mucositis is not a National
Library of Medicine medical subject heading (MeSH),
so stomatitis was used as the primary search term and
was combined with cancer. Because stomatitis is a
National Library of Medicine MeSH heading, articles
are indexed by that term, even if they use the term
mucositis. Although the term stomatitis is used widely
to refer to any mucosal inflammation, by definition, it
is restricted to inflammatory diseases of the mouth,
whereas the term mucositis has a broader definition
that encompasses inflammation of any mucous membrane.
After the literature was narrowed to articles about
cancer therapy–related mucosal toxicity, citations
were sorted using the topic areas defined for the
smaller working groups, as described above. Furthermore, panel members were encouraged to contact
other investigators and sources for unpublished information that could be used to assist in the guideline.
Guideline Development Based on Evidence
The literature was distributed to each group along
with instructions and scoring sheets based on methods for reviewing and scoring the literature, according
to Hadorn et al.7 Each group returned its scoring
sheets along with a bibliography of all publications
reviewed. These were collated, copied, and distributed
to each panel member at a guideline development
conference held in Houston, Texas, on January 16 –20,
2002. Each group presented draft guidelines before the
entire panel using the structured literature review and
guideline development methods of the American Society for Clinical Oncology.4 The guideline hierarchy
allows for two subtypes of guidelines: 1) recommendations and 2) suggestions (Table 1). The panel discussed each guideline to ensure compliance with published standards for guideline development.8
The panel updated the draft guidelines at its second meeting, on June 23, 2002, in Boston, Massachusetts. The article, which was prepared by a writing
committee with assistance from a medical editor, was
circulated to each panel member in two draft forms,
giving them two additional opportunities to comment
on the levels of evidence and grading of the recom-
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mendations. All panel members approved the final
version submitted for publication, and the guidelines
are presented herein (Table 2).
Conflict of Interest Disclosure and Financial Disclosure
The cost of the conference and administrative services
for developing the guidelines was paid from unrestricted educational grants in support of the MASCC/
ISOO Mucositis Study Section. The following companies provided grant support: Amgen (Thousand Oaks,
CA), GelTex Pharmaceuticals (Waltham, MA), Helsinn
Healthcare SA (Pazzallo, Switzerland), Human Genome Sciences (Rockville, MD), McNeil Consumer
and Specialty Pharmaceuticals (Fort Washington, PA),
MGI Pharma (Bloomington, MN), MedImmune
(Gaithersburg, MD), OraPharma (Warminster, PA),
and RxKinetix (Louisville, CO). Each company was
allowed to have representatives attend the guideline
development conference, but representatives were not
allowed to attend the closed administrative sessions or
participate in any of the discussions or deliberations
of the panel. Furthermore, companies were informed
that they would not be allowed access to the guidelines until after they were published. The methods for
the guidelines’ development, all drafts, and final content and style were controlled strictly by the panel.
Each panel member was required to complete a
standardized conflict of interest disclosure form requiring revelation of all ties to any health care company, companies, commercial products, or products
in development that potentially could be affected by
the guidelines’ development and promulgation. Disclosure included employment, consultancies, stock
ownership, speaking honoraria, research funding, expert testimony, and membership on company advisory boards. The panel made decisions on a case-bycase basis about whether a member’s role should be
limited as a consequence of a conflict of interest.
Revision Dates
The panel expects to review the guidelines annually as
a routine activity of the MASCC/ISOO Mucositis Study
Section and to reconvene every 3 years or more frequently, as information warrants, to discuss potential
changes to the guidelines.
BIOLOGIC BASIS AND PATHOGENESIS
Oral Mucosal Injury
Mucosal injury is the collective consequence of a
number of concurrent and sequential biologic processes. After radiotherapy or chemotherapy, oral mucositis is heralded by an initiation phase that is characterized by injury to tissues of the submucosa. After
the up-regulation of a series of early-response genes,
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TABLE 2
Summary of Clinical Practice Guidelines for Care of Patients with Oral and Gastrointestinal Mucositis
I. Oral mucositis
Foundations of care
1. The panel suggests the use of oral care protocols that include patient education in an attempt to reduce the severity of mucositis from chemotherapy or radiation therapy.
2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT.
Radiotherapy: prevention
3. To reduce mucosal injury, the panel recommends the use of midline radiation blocks and three-dimensional radiation treatment.
4. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiotherapy.
5. The panel recommends that chlorhexidine not be used to prevent oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy.
Standard-dose chemotherapy: prevention
6. The panel recommends that patients receiving bolus 5-FU chemotherapy undergo 30 min oral cryotherapy to prevent oral mucositis.
7. The panel suggests using 20–30 min oral cryotherapy in an attempt to decrease mucositis in patients treated with bolus doses of edatrexate.
8. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.
Standard-dose chemotherapy: treatment
9. The panel recommends that chlorhexidine not be used to treat established oral mucositis.
High-dose chemotherapy with or without TBI plus HSCT: prevention
10. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.
11. LLLT requires expensive equipment and specialized training. Because of interoperator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel
is encouraged by the accumulating evidence in support of LLLT. For centers capable of supporting the necessary technology and training, the panel suggests the use of LLLT in an attempt to reduce the
incidence of oral mucositis and its associated pain in patients receiving high-dose chemotherapy or chemoradiotherapy before HSCT.
II. Gastrointestinal mucositis
Radiotherapy: prevention
1. The panel suggests using 500 mg oral sulfasalazine twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients receiving external-beam radiotherapy to the pelvis.
2. Oral sucralfate does not prevent acute diarrhea in patients with pelvic malignancies undergoing external beam radiotherapy; and, compared with placebo, it is associated with more gastrointestinal side
effects, including rectal bleeding. Consequently, the panel recommends that oral sucralfate not be used.
3. The panel recommends that 5-aminosalicylic acid and its related compounds mesalazine and olsalazine not be used to prevent gastrointestinal mucositis.
Radiotherapy: treatment
4. The panel suggests the use of sucralfate enemas to help manage chronic, radiation-induced proctitis in patients with rectal bleeding.
Standard-dose and high-dose chemotherapy: prevention
5. The panel recommends either ranitidine or omeprazole for the prevention of epigastric pain after treatment with cyclophosphamide, methotrexate, and 5-FU or treatment with 5-FU with or without
folinic acid chemotherapy.
Standard-dose and high-dose chemotherapy: treatment
6. When loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy associated with HSCT, the panel recommends octreotide at a dose of at least 100 ␮g administered
subcutaneously twice daily.
Combined chemotherapy and radiotherapy: prevention
7. The panel suggests the use of amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell lung cancer.
HSCT: hematopoietic stem cell transplantation; 5-FU: 5-fluorouracil; TBI: total-body irradiation; LLLT: low-level laser therapy.
changes are observed in the endothelium, connective
tissue, and extracellular matrix that are mediated by
reactive oxygen species (ROS), the ceramide pathway,
and a number of transcription factors, including nuclear factor-kappa ␤ (NF-␬B). The initial injury precipitates connective tissue deterioration and the rapid
up-regulation of a second set of genes that results in
direct and indirect signaling and early apoptosis of
clonogenic stem cells in the basal epithelium. The
proinflammatory cytokines (tumor necrosis factor-␣,
interleukin 1␤, and interleukin 6) are likely to be
among signaling molecules. These signaling molecules also have the ability to amplify the up-regulation
of transcription factors (e.g., NF-␬B) further, leading to
production of additional proinflammatory cytokines,
tissue injury, and apoptosis. Reduced renewal of mucosal epithelium occurs despite focal bursts of hyperproliferative activity in response to the early up-regulation of genes associated with epithelium healing.
Epithelial apoptosis and necrosis exceed hyperproliferative activity and result in an ulcerative phase
in which full-thickness mucosal damage is apparent.
The ulcerative phase is exacerbated by local bacterial
colonization, which results in a barrage of cell wall
products penetrating into the submucosa and amplifying damaging mechanisms. Increased transcription
factor activity and levels of cytokines and other mediators drive additional local responses, including angiogenesis. Ultimately, healing occurs as healthy epithelium migrates from the wound margins, stimulated
by signals from the submucosa. A complete discussion
of the biologic basis and pathogenesis of oral and GI
mucositis may be found in the accompanying article
in this issue.9
GI Mucosal Injury
The pathobiology of mucositis in the alimentary tract
beyond the oral cavity is similar to that described
above for oral mucositis and poses the same potential
threat to successful therapy because of dose delays or
dose reductions. Setting the GI tract apart in its manifestation of mucosal injury are the morphologic and
functional differences between its sections. These
largely account for the differences in functional and
symptomatic outcomes between oral and GI mucositis
induced by cancer therapy.
The plethora of rapidly dividing cells in the GI
tract make the tract particularly vulnerable to cytotoxic chemotherapeutic agents. On Day 1 after chemotherapy, the first abnormality observed may be an
increase in apoptosis. Afterward, reductions in crypt
length, villus area, and mitotic index follow, with each
of these quantities reaching a nadir on Day 3. By Day
5, rebound hyperplasia is underway, and eventually,
normalization follows.10 Abdominal pain, bloating,
and diarrhea begin around Day 3 and settle by Day 7,
when oral symptoms typically are appearing. Functional changes, such as sugar permeability, however,
persist after recovery from symptoms and morphologic changes.11
Intestinal permeability is also one of a number of
changes that occur during fractionated radiotherapy.
Along with histologic injury, intestinal permeability
actually is maximal midcourse. These improve toward
the end of the radiotherapy course, despite persistent
injury and noticeably increasing symptoms, because
of compensatory changes.12,13 Nonetheless, in many
patients, radiation’s toxicities result in such chronic
functional disabilities as malabsorption and dysmotility, in contrast to chemotherapy’s more transient effects. Histologic changes include mucosal atrophy, intestinal wall fibrosis, and vascular sclerosis. Lifethreatening complications, including intestinal
obstruction, perforation, or fistula formation, can
characterize the clinical course.
Efforts to understand better the biologic and histologic mechanisms and the quantitative roles of different factors in GI mucositis are made more difficult
by the inaccessibility of significant GI segments and
the problems inherent in obtaining sequential biopsy
specimens. Approaches to alleviating toxicity also
have included efforts to elucidate the mechanisms of
action of newer drugs.12
EPIDEMIOLOGY
The incidence of oral and GI mucositis varies, depending on chemotherapy regimen and on treatment modality. Prolonged or profound oral and GI mucositis
leads to significant pain and morbidity, excess costs
for supportive care and hospitalization, increased frequency of infection, and chemotherapy dose delays
and reductions.15,16 Excluding very high-risk regimens, HSCT, and radiotherapy, rates of mucositis are
generally in the 5–15% range. However, administration of 5-flurouracil (5-FU), with or without leucovorin, is associated with oral mucositis in as much as
40% of patients.17 Grade 3– 4 oral mucositis approaches 10 –15% among 5-FU recipients.18 Similarly,
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administration of irinotecan often is associated with
severe GI mucositis, which affects ⬎ 20% of patients
receiving certain doses and regimens. Approximately
75– 85% of bone marrow transplantation recipients
experience mucositis, and in some studies, oral mucositis is the most common and most debilitating side
effect reported.1,2 Conditioning regimens that include
melphalan are associated with particularly high rates
of oral mucositis.19
The risk of radiation-induced mucositis varies
with the site of radiotherapy, dosage, and fractionation. Radiotherapy to the head and neck or to the
pelvis or abdomen is associated with an increased
incidence of Grade 3 and Grade 4 oral or GI mucositis,
respectively, often exceeding 50% of patients.20
Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long
after the conclusion of therapy.21 Accelerated fractionation increases the risk of mucositis to ⬎ 70% of patients in most trials.20 Oral mucositis is particularly
profound and prolonged among HSCT recipients who
receive total-body irradiation for conditioning.
CLINICAL PRACTICE GUIDELINES FOR CARE OF
PATIENTS WITH ORAL MUCOSITIS
Foundations of Care
Basic oral care
Lack of a consistent definition of which elements constitute basic oral care and highly variable study designs do not allow a guideline for basic oral care related to mucositis prevention or treatment. There is
insufficient evidence to conclude that actions such as
brushing teeth using foam ‘toothbrushes’ or swabs,
flossing, or using topical fluoride will prevent or treat
cancer therapy–induced mucositis. A number of topical agents (bland rinses, antimicrobial rinses) that
often are included in basic oral care are addressed in
other sections of the guidelines.
Nonetheless, it is important to recognize that although there is not sufficient scientific evidence to
provide a guideline for basic oral care, its importance
in maintaining mucosal health, integrity, and function
generally is accepted. The purpose of basic oral care is
to reduce the impact of the oral microbial flora, reduce cancer therapy–related symptoms of pain and
bleeding, and prevent soft tissue infections that may
have systemic sequelae. In addition, maintenance of
good oral hygiene will reduce the risk of dental complications, including caries and gingivitis. For these
reasons, basic oral care is an important component of
care of the patient with cancer.22 Although the importance of effective oral hygiene has been described in
many articles, the methods and techniques employed
typically are based on preference and anecdotal expe-
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rience. A single study23 demonstrated that tooth
brushing reduced the number of oral lesions in patients receiving cancer chemotherapy. Using foam
toothbrushes is not equivalent to toothbrushing and
cannot be recommended for plaque control or caries
prevention.
Oral care protocols and patient education
Guideline: The panel suggests the use of oral care
protocols that include patient education in an attempt
to reduce the severity of mucositis from chemotherapy or radiotherapy (level of evidence, III; grade of
recommendation, B).
Oral care protocols are used in an attempt to
prevent and manage mucositis, with an emphasis on
feasibility, adherence, and comprehensive patient education about mucositis and oral care. The current
review did not evaluate specific agents or approaches
used in protocols, and insufficient evidence prevents
the recommendation of one protocol over any other.
Because oral care has long been integral to nursing
practice,24,25 nurses are the health professionals who
usually provide oral care to patients with mucositis;
thus, many of the reports are drawn from the nursing
literature.
Implementation of oral care protocols is generally
a systematic process in which specific agents are not
the main focus. Rather, the important components of
this implementation include feasibility, adherence,
performance, and outcomes. Patient education refers
to comprehensive, theory-based, educational approaches that prepare individuals for medical procedures, including what to expect and how to cope, an
approach that also has been termed psychoeducation,26 because it addresses both physical and psychologic aspects of the symptoms (e.g., distress, anxiety).
Programmatic reports provided support (although not
empiric evidence) for the value of implementing institutionalized oral care protocols or standards. Three
randomized clinical trials, despite their flaws, and
three nonrandomized studies also yielded support.
The findings of these investigations form the foundation of the suggestion above.
With the specific objective of reducing mucositis,
Graham et al.27 initiated a unit-based oral care protocol and teaching program and documented a reduction in mucositis. Larson et al.28 used the PRO-SELF
Mouth Aware Program in a study of outpatients receiving chemotherapy and demonstrated feasibility of
the program in maintaining oral hygiene. To improve
the consistency of oral care, Yeager et al.29 implemented an oral care standard in two inpatient hematology/oncology units and demonstrated feasibility,
tolerability, and adherence in patients with leukemia
and those undergoing transplantation.
Improved oral status (i.e., reduced mucositis or
increased oral comfort) was reported in three randomized clinical studies,30 –32 and only one32 study reported no change in mucositis at the conclusion of the
study. Despite flaws, including failure to blind the
investigator in one of the studies, measurement issues, and a wide range of sample sizes (15–150 participants), the collective results suggest that using a systematic protocol improves patient outcomes. A fourth
randomized clinical trial33 did not show a statistically
significant difference between controls and those undergoing the intervention; however, participants who
were taught the protocols performed oral hygiene routines more frequently compared with the control
group and reported feeling more prepared to manage
their symptoms.
Three quasiexperimental, nonrandomized studies
of oral care protocols also support their use in reducing the incidence or severity of mucositis. Beck24 reported on the implementation and testing of an oral
care protocol in patients with cancer and found that
oral cavity physical condition improved and infection
decreased with implementation of an oral care protocol. Levy-Polack et al.34 reported that pediatric patients with leukemia who followed a daily preventive
protocol (plaque removal, chlorhexidine rinse, iodopovidone, and nystatin) experienced a significant
decrease in moderate mucositis and candidiasis and
had improved oral hygiene. Cheng et al.35 found that
an oral care protocol (tooth brushing, chlorhexidine
rinse [0.2%], and saline) resulted in a 38% reduction in
incidence and a significant reduction in severity and
associated oral pain in pediatric patients with cancer.
The remaining studies did not test oral care protocols formally but, rather, surveyed institutions or
health professionals about oral care. They revealed
widely disparate practices and little agreement on
standardized approaches to oral care.36 – 40
Palliative care (including pain management)
Palliation of mucositis and acute oral pain is an important component of patient care. Approaches include the use of systemic analgesics and other individual agents, palliative mixtures of agents
(sometimes called magic or miracle mouthwash),
coating agents, and topical anesthetics/analgesics.
Systemic analgesics. Guideline: The panel recommends patient-controlled analgesia (PCA) with morphine as the treatment of choice for oral mucositis
pain in patients undergoing HSCT (level of evidence, I;
grade of recommendation, A). Control of mucositis-
induced pain is achieved by PCA with intravascular
morphine sulfate.41– 49 Level I evidence supports PCA
for oral mucositis pain in patients who undergo HSCT,
but there is little evidence to recommend its use in
other patients and settings. Although other opiates
may achieve similar pain control, morphine appears
to require relatively lower drug doses and may be
tolerated better. Pediatric populations also can use
PCA efficiently. Initial studies of transdermal fentanyl
have been published,44,49 but further study is required
to confirm its efficacy.
Despite the limited evidence described above, in
general, pain management for mucositis should be
governed by prevailing clinical practice guidelines,
such as those promulgated by the World Health Organization and the Agency for Healthcare Research and
Quality for managing acute pain.50,51 These guidelines
include accepted approaches for the use of nonopioids, opioids, adjuvant medications, and assessment
tools. Depending on the individual patient population, numerous routes may be considered, including
oral, transmucosal (oral and rectal), and transdermal
routes, as well as various intravenous approaches
(continuous infusion, bolus, and PCA).
Topical preparations and other approaches. Various
topical preparations have been in widespread use for
the treatment of mucositis and its accompanying pain.
The most common ingredients include viscous lidocaine, benzocaine, milk of magnesia, kaolin, pectin,
chlorhexidine, and dyphenhydramine. Topical analgesics that can be considered include the single agents
benzydamine (see below) and morphine.52
Many topical agents have been compounded in
mixtures. There is no significant evidence of the effectiveness or tolerability of these mixtures.31,34,53– 61
Some of these preparations may be minimally superior to normal saline, although the evidence is not
convincing. Thus, the lack of compelling evidence prevents the panel from recommending any palliative
mixture for therapeutic intent in oral mucositis. However, because concern exists regarding absorption of
amide anesthetics (e.g., lidocaine) through damaged
mucosal surfaces, both individual agents and palliative mixtures require further study to determine their
toxicity and efficacy.
Radiotherapy: Prevention
Use of blocks and three-dimensional treatment delivery
Guideline: To reduce mucosal injury, the panel recommends the use of midline radiation blocks and
three-dimensional radiation treatment (level of evidence, II; grade of recommendation, B). The effects of
altering the delivery of cytotoxic therapy, without sig-
2033
nificant dose modification, have been studied. The
quality and modest numbers of publications describing these methods preclude the establishment of specific guidelines. However, it has been shown that oral
mucosal injury secondary to radiotherapy may be reduced significantly by the use of midline radiation
blocks62 and by three-dimensional treatment delivery,
which reduces the volume of mucosa exposed to irradiation.63
Benzydamine
Guideline: The panel recommends benzydamine for
the prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderatedose radiotherapy (level of evidence, I; grade of recommendation, A). Benzydamine hydrochloride is a
unique agent with antiinflammatory effects. It is a
nonsteroidal drug (although not a classic nonsteroidal
antiinflammatory drug) that is applied topically. In
addition to its antiinflammatory properties, benzydamine has analgesic, anesthetic, and antimicrobial
capabilities, which make exact classification of this
drug difficult. Recent studies have demonstrated that
benzydamine also inhibits the production and effects
of proinflammatory cytokines, particularly TNF-␣.
These findings favor antiinflammatory effects as the
main mode of action for this agent. It has been shown
in single-center and multicenter, randomized, controlled clinical trials that topical benzydamine reduces
the frequency and severity of ulcerative oral lesions
and decreases pain in radiation-induced oral mucositis.64 – 68 Although it is not currently available in the
United States, a pivotal Phase III trial of this agent is
enrolling patients actively.
Benzydamine hydrochloride has been studied
most extensively for the prevention and reduction of
the severity of radiation-induced mucositis of the oral
cavity. Several small, double-blinded, randomized trials were reported in the 1980s. Two early studies64,67
suggested that benzydamine was effective in reducing
the severity of the pain associated with oral mucositis.
In 2001, the results of a large, multicenter, doubleblinded, randomized trial were published68 and demonstrated that benzydamine improved the ulcer-free
rate and diminished the incidence of ulceration and
erythema. That study used a sophisticated mucositis
scoring system that measured the severity of mucositis
and duration of mucositis by using an area-under-thecurve analysis. The study also demonstrated a delay in
the need for analgesics in patients who were treated
with benzydamine compared with patients who were
treated with placebo. The study’s conclusions were
based on cumulative radiation doses of 50 grays (Gy),
and the efficacy of the drug with higher doses or with
2034
combination chemotherapy was not established. In a
small subgroup of patients who received accelerated
radiation, benzydamine was not effective.
Chlorhexidine
Guideline: The panel recommends that chlorhexidine
not be used to prevent oral mucositis in patients with
solid tumors of the head and neck who are undergoing
radiotherapy (level of evidence: II; grade of recommendation, B). Chlorhexidine is a broad-spectrum, topical
antiseptic. The evidence from three studies was consistent in showing that this agent had no impact in
preventing the development of oral mucositis in patients with solid tumors of the head and neck undergoing radiotherapy.69 –71 Chlorhexidine may be used
for its antiplaque and antifungal properties as part of
an oral care protocol.
Standard-Dose Chemotherapy: Prevention
Cryotherapy
Cryotherapy with bolus doses of 5-FU. Guideline: The
panel recommends that patients receiving bolus 5-FU
chemotherapy undergo 30 minutes of oral cryotherapy to prevent oral mucositis (level of evidence, II;
grade of recommendation, A). It was hypothesized that
placing ice chips in the mouth, starting 5 minutes
before 5-FU bolus injection and continuing for a total
of 30 minutes, would cause cooling of the oral cavity,
which would lead to vasoconstriction. It was suggested that the vasoconstriction would allow less 5-FU
to reach the oral mucosa, thereby attenuating 5-FUinduced mucositis.
One randomized but nonblinded study of 95 patients was conducted in patients who were receiving
bolus 5-FU. Mucositis was evaluated by questionnaire.
Results from that trial illustrated that the group receiving oral cryotherapy exhibited a reduction of approximately 50% in mucositis.72 Cascinu et al.73 randomly
allocated 84 patients who were receiving 5-FU to receive oral cryotherapy, and again, a reduction of approximately 50% in mucositis was observed among
those who received oral cryotherapy.
A subsequent randomized clinical trial of oral cryotherapy for either 30 minutes or 60 minutes reported
that extending the duration of oral cryotherapy did not
provide additional benefit; therefore, 3-minute cryotherapy was recommended.74 A study of ocular cryotherapy
(cold packs over the eyes) also showed reduction in
5-FU-induced conjunctivitis (P ⫽ 0.001).75
Cryotherapy with edatrexate. Guideline: The panel
suggests using 20 –30 minutes of oral cryotherapy in
an attempt to decrease mucositis in patients who are
treated with bolus doses of edatrexate (level of evi-
dence, IV; grade of recommendation, B). Recent nonrandomized studies suggest that oral cryotherapy may
reduce oral mucositis related to edatrexate.76 –78 The
rationale for its use in this situation is related to the
short serum half-life of edatrexate.
It should be noted that oral cryotherapy is not
expected to be useful in preventing oral mucositis in
patients receiving 5-FU by continuous infusion or in
patients undergoing administration of such agents as
methotrexate, doxorubicin, or other agents with a long
serum half-lives. This therapy’s low cost and minimal
toxicity justify its use.
Acyclovir
Guideline: The panel recommends that acyclovir and
its analogues not be used routinely to prevent mucositis (level of evidence, II; grade of recommendation, B).
Acyclovir is effective in reducing herpes simplex virus
(HSV) infection in patients with leukemia or lymphoma,79,80 but oral mucositis still develops in patients
routinely receiving acyclovir or one of its prodrugs for
prophylaxis. This suggests that HSV infection plays
little or no role in causing oral mucositis.
Standard-Dose Chemotherapy: Treatment
Chlorhexidine
Guideline: The panel recommends that chlorhexidine
not be used to treat established oral mucositis (level of
evidence, II; grade of recommendation, A). Research
has failed to produce evidence that supports the use of
chlorhexidine to treat established mucositis. A well
designed, multicenter, double-blind clinical trial conducted in 23 outpatient and office settings evaluated
the effectiveness of a standardized oral care protocol
(PRO-SELF) plus ‘magic’ mouthwash, salt and soda
rinses, and chorhexidine in reducing the duration of
pain associated with oral mucositis induced by stomatotoxic chemotherapy.58 Patients initially were evaluated by a physician or nurse to confirm the presence
of oral mucositis. Patients then underwent a standardized oral care protocol that taught self-care, and they
subsequently received a 12-day supply of study
mouthwash. There was no difference in the efficacy of
the three treatments in time to resolution of mucositis
or in pain relief; however, the salt and soda rinses
represented the least costly option. This study clearly
demonstrated no significant difference in pain ratings
among the treatment groups, despite the fact that
magic mouthwash included lidocaine and the chlorhexidine mouthwash contained alcohol, which can
sting on contact with oral mucosa. Other studies also
failed to find any benefit of chlorhexidine as a treatment for established oral mucositis.81,82
High-Dose Chemotherapy With or Without Total-Body
Irradiation plus HSCT: Prevention
Pentoxifylline
Guideline: The panel does not recommend the use of
pentoxifylline to prevent mucositis in patients undergoing HSCT (level of evidence, II; grade of recommendation, B). Six clinical trials utilizing pentoxifylline to
prevent mucositis were evaluated.83– 88 Five of six trials
had no placebo control and no investigator blinding.
No randomization was made in four of the six clinical
trials. Of the six trials, four had significant flaws in
their designs. Both of the well designed, randomized
trials87,88 demonstrated that pentoxifylline failed to
prevent the development of mucositis.
Low-level laser therapy
Guideline: Low-level laser therapy (LLLT) requires expensive equipment and specialized training. Because
of interoperator variability, clinical trials are difficult
to conduct, and their results are difficult to compare;
nevertheless, the panel is encouraged by the accumulating evidence in support of LLLT. The panel suggests
that at centers that are capable of supporting the
necessary technology and training, LLLT should be
used in an attempt to reduce the incidence of oral
mucositis and its associated pain in patients who are
receiving high-dose chemotherapy or chemoradiotherapy prior to HSCT (level of evidence, II; grade of
recommendation, B).
Over the last several years, appropriate laboratory
and clinical evidence has been accumulating steadily
to support the use of LLLT to promote biostimulation
applications. It has been reported that LLLT promotes
wound healing and reduces pain and inflammation.
Different effects appear to be related to laser characteristics (wavelength and energy dose) and the particular type of tissue being treated.
Helium-neon (He-Ne) laser (␭ ⫽ 632.8 nm) treatment has been the most frequently studied form of
LLLT for the prevention or reduction of oral mucositis
and oral pain associated with cancer therapy (including HSCT).89,90 Research currently is underway on the
use of diode lasers with wavelengths ranging from 650
to 905 nm. It appears that laser therapy produces no
toxicity and is atraumatic to patients. However, LLLT
requires specific (often expensive) equipment, and
treatment can be time consuming.
CLINICAL PRACTICE GUIDELINES FOR THE
PREVENTION AND TREATMENT OF GI MUCOSITIS
Radiotherapy: Prevention
Sulfasalazine
Guideline: The panel suggests the use of 500 mg of
sulfasalazine orally twice daily to help reduce the in-
2035
cidence and severity of radiation-induced enteropathy
in patients receiving external-beam radiotherapy to
the pelvis (level of evidence, II; grade of recommendation, B). Radiation-induced enteropathy with abdominal pain and diarrhea occurs in 75–90% of patients
receiving external-beam radiotherapy for such common pelvic malignancies as prostate, rectal, or cervical
cancer and typically begins in the second or third
week of treatment. Kilic et al.91 conducted a well designed, randomized, double-blind controlled trial of
sulfasalazine (500 mg twice daily) or placebo in 87
patients who had a variety of pelvic malignancies and
were scheduled to receive 46 –50 Gy in 23–25 fractions
of external-beam radiotherapy to the whole pelvis.
Whereas the incidence of Grade 1– 4 diarrhea was 55%
among sulfasalazine-treated patients, it was 86%
among patients receiving the placebo (P ⫽ 0.001).
None of the patients in the sulfasalazine-treated group
experienced Grade 4 diarrhea, compared with 16% of
patients in the placebo group. There was no significant difference in toxicity between the two treatment
groups. Further work is required to explain the mechanism underlying the difference between sulfasalazine
and other closely related compounds such as 5-amino
salicylic acid (5-ASA), melsalazine, and olsalazine (see
below).
Sucralfate
Guideline: Oral sucralfate does not prevent acute diarrhea in patients with pelvic malignancies who are
undergoing external-beam radiotherapy. Compared
with placebo, sucralfate was found to be associated
with increased GI side effects, including rectal bleeding. Consequently, the panel recommends that oral
sucralfate not be used. (level of evidence, I; grade of
recommendation, A).
The North Central Cancer Treatment Group conducted a well designed, randomized controlled trial of
oral sucralfate (1.5 gm every 6 hours) and a placebo in
125 patients treated with 45–53.5 Gy external-beam
radiotherapy in fractions of 1.7–2.1 Gy per day. Among
the 123 evaluable patients, diarrhea was moderate to
severe in 53% of patients receiving sucralfate but only
41% of patients receiving placebo. Significantly more
patients in the sucralfate group reported fecal incontinence, the need for protective clothing, and more
intense nausea compared with the placebo group (P
⬍ 0.05 for all comparisons).92
In a multicenter, double-blind trial involving patients with clinically localized prostate malignancies
who were scheduled to receive definitive radiotherapy
(ⱖ 60 Gy, with a superior limit of field below the
greater sciatic notch), 335 patients were randomized
to receive either 3 gm oral sucralfate twice daily or
2036
placebo.93 There was no significant difference in patient self-reports of stool frequency, consistency, mucus, or pain (P ⬎ 0.20 for all comparisons); however,
the sucralfate-treated group had an increased incidence of rectal bleeding (64%) compared with the
placebo group (47%; P ⫽ 0.001).
O’Brien et al.94 evaluated the use of sucralfate
rectal enemas versus a placebo, beginning at the
onset of radiotherapy for prostate malignancy and
continuing for 2 weeks after completion of radiotherapy, in preventing acute proctitis. Patients were
assessed monthly for 3 months and then every 6
months for 5 years. Sucralfate was no better than
placebo at reducing the risk of acute radiation-induced proctitis. Cox proportional hazards modeling
indicated that patient self-assessment of moderate
or severe rectal pain was the best predictor of subsequent development of late radiation-related toxicity. There were no significant differences in the
rates of late rectal bleeding between the sucralfatetreated and placebo-treated groups.94
5-ASA, mesalazine, and olsalazine
Guideline: The panel recommends that 5-ASA and the
related compounds mesalazine and olsalazine not be
used for the prevention of GI mucositis (level of evidence, I; grade of recommendation, A). In three separate studies,95–97 it was found that 5-ASA, mesalazine,
and olsalazine were of no benefit or caused more
diarrhea than placebo did in patients receiving pelvic
radiotherapy. Baughan et al.95 randomized 73 patients
who were undergoing pelvic radiotherapy to receive
either 5-ASA or placebo and reported more diarrhea (P
⫽ 0.070), more severe diarrhea (P ⫽ 0.014), and more
days per week with diarrhea (P ⫽ 0.026) in the 5-ASA
group compared with the placebo group. In a doubleblind, multicenter study, Resbeut et al.96 randomized
153 patients who were receiving ⱖ 45 Gy of externalbeam pelvic radiotherapy to receive either 4 gm mesalazine per day or placebo. Diarrhea rates were similar in both groups (69% with mesalazine, compared
with 66% with placebo; P ⫽ 0.22), although the mesalazine-treated group had more severe diarrhea at
Day 15 compared with the placebo group (P ⫽ 0.006).
Martenson et al.97 randomized patients who were undergoing pelvic radiotherapy to receive either 500 mg
olsalazine administered orally twice daily or placebo.
Those authors terminated the study early for the 58
evaluable patients, because diarrhea occurred more
frequently and was more severe among the olsalazinetreated patients.
Radiotherapy: Treatment
Sucralfate enemas
Guideline: The panel suggests using sucralfate enemas
to help manage chronic radiation-induced proctitis in
patients with rectal bleeding (level of evidence, III;
grade of recommendation, B). It is believed that
chronic radiation-induced proctitis or proctosigmoiditis is due to intestinal wall fibrosis along with vascular
sclerosis leading to ischemia. Its incidence ranges
from 2% to 20%. Risk factors for radiation-induced
proctitis include higher doses of radiotherapy, intracavitary radiation, and the use of radiosensitizers. This
condition may be more common in patients who have
experienced it previously. Clinical manifestations include diarrhea, tenesmus, urgency, and rectal bleeding, which frequently is severe enough to require
blood transfusions. Kochhar et al.98,99 randomized 37
consecutive patients with radiation-induced proctitis
to a 4-week course of sulfasalazine (3 gm orally plus
rectal prednisolone enemas twice daily) or rectal sucralfate enemas twice daily plus an oral placebo. Both
regimens were associated with significant clinical improvement and with improvement observed at endoscopic evaluation. In a second study, the same investigators evaluated 26 consecutive patients with
radiation-induced proctitis and persistent rectal
bleeding whose condition had failed to respond to
bulk-forming agents, sulfasalazine, and topical corticosteroids.99 All patients were treated with sucralfate
rectal enemas (20 mL 10% sucralfate suspension in
water twice daily). After 4 weeks of therapy, all 26
patients exhibited a reduction in the severity of rectal
bleeding (P ⬍ 0.01). At a median follow-up of 45.5
months, 17 patients had no further bleeding.
Other therapies for chronic radiation proctitis
with bleeding include argon beam coagulation, electrocoagulation, formalin treatment, and hyperbaric
oxygen treatment.100 –112 Although these therapies
have not been examined in randomized controlled
trials, the results from cohort studies are encouraging,
especially with respect to laser and formalin treatments. Because of the lack of randomized trials and
the limited experience with these therapies, the panel
believes that a specific guideline is not warranted at
this time.
Standard-Dose Chemotherapy: Prevention
Ranitidine and omeprazole
Guideline: The panel recommends either ranitidine or
omeprazole for the prevention of epigastric pain after
treatment with cyclophosphamide, methotrexate, and
5-FU or after treatment with 5-FU with or without
folinic acid chemotherapy (level of evidence, II; grade
of recommendation, A). In two well designed, randomized, controlled trials led by the same principal investigator,113,114 it was found that these two drugs were
beneficial. One hundred eighty-two patients with endoscopically normal gastric and duodenal mucosa (or
with ⬍ 3 erosions) were assigned randomly to receive
misoprostol (400 ␮g twice daily), omeprazole (20 mg
once daily), or placebo prior to treatment with cyclophosphamide, methotrexate, and 5-FU or with 5-FU
alone. Seven days after completing the second course
of chemotherapy, all patients underwent follow-up
endoscopy. Omeprazole was more effective than either misoprostol or placebo in reducing clinically significant epigastric pain and/or heartburn, and its use
was associated with fewer gastric and duodenal ulcerations.113 In a follow-up study,114 228 patients with
endoscopically normal epigastric and duodenal mucosae (or with ⬍ 3 erosions) were assigned randomly
to receive omeprazole (20 mg once daily), ranitidine
(300 mg once daily), or placebo before treatment either with cyclophosphamide, methotrexate, and 5-FU
or with 5-FU. Global endoscopic scores after chemotherapy were significantly higher than pretreatment
scores in patients who were randomized to receive
placebo or ranitidine, but not omeprazole. Acute ulcers were less common in patients who received omeprazole (P ⫽ 0.0001) or ranitidine (P ⫽ 0.0315) compared with patients who received placebo; likewise,
epigastric pain and heartburn were significantly less
common in the omeprazole (P ⫽ 0.00124) and ranitidine (P ⫽ 0.038) groups compared with the placebo
group.
Standard-Dose Chemotherapy: Treatment
Octreotide
Guideline: When loperamide fails to control diarrhea
induced by standard-dose or high-dose chemotherapy
associated with HSCT, the panel recommends octreotide at a dose of at least 100 ␮g administered subcutaneously twice daily (level of evidence, II: grade of
recommendation, A). Chemotherapy-induced diarrhea
is a common clinical problem associated with certain
drugs used to treat colon cancer and other solid tumors (5-FU, irinotecan) and with high-dose chemotherapy coupled with HSCT. Irinotecan-induced diarrhea occurs in 2 phases: an acute syndrome (within
the first 24 hours), which is mediated by acetylcholine
and blocked by atropine, followed by a delayed phase,
which is inflammatory. The rate of National Cancer
Institute Common Toxicity Criteria Grade 3– 4 delayed-phase diarrhea may approach 25%.
Octreotide, a somatostatin analogue, regulates intestinal water and electrolyte transport, inhibits gut
hormones (serotonin, vasoactive intestinal peptide,
2037
gastrin, insulin, secretin, glucagons, and pancreatic
polypeptide), and preserves epithelial barrier function. Multiple clinical trials of octreotide have demonstrated that it is effective in reducing chemotherapyinduced diarrhea associated with standard-dose
chemotherapy.115–120 Four studies involving patients
who received high-dose chemotherapy with HSCT
suggest that octreotide also is effective in that setting.
In preclinical models of fractionated radiotherapy,121,122 octreotide administration during radiation
and for 2 weeks after radiation was complete was
associated with a reduction in both acute and subsequent chronic intestinal toxicity. Additional research
is needed to determine the role of octreotide as a
mucosal protectant for patients receiving radiotherapy with or without concomitant chemotherapy.
Combined Chemotherapy and Radiotherapy: Prevention
Amifostine
Guideline: The panel suggests using amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell
lung cancer (level of evidence, III: grade of recommendation, C).
The use of combined-modality therapy, such as
concomitant radiotherapy and chemotherapy in nonsmall cell lung cancer, improves tumor control rates
but is associated with higher rates of acute and
chronic esophagitis.123 Consequently, investigators
have employed strategies utilizing radioprotectants to
minimize these toxicities. Recently, Komaki et al.124
reported interim results from a prospective randomized Phase III study of combined chemotherapy and
radiotherapy with and without amifostine for patients
with nonsmall cell lung cancer. Both groups received
1.2 Gy per fraction, with 2 fractions per day administered 5 times weekly, along with oral etoposide (50 mg
twice daily) administered 30 minutes before radiotherapy on Days 1–10 and repeated on Day 29 and
cisplatin (50 mg/m2) administered intravenously on
Days 1, 8, 29, and 36. The amifostine-treated group
received 500 mg amifostine intravenously twice
weekly before chemoradiation. Severe esophagitis (defined as the need for morphine intake to control pain)
was significantly lower in the group that received amifostine (7.4%) compared with the group that did not
receive amifostine (31%; P ⫽ 0.03). These preliminary
findings in 53 patients also revealed a lower rate of
acute pneumonitis (3.7%) among patients who received amifostine compared with the control group
(23%; P ⫽ 0.037). Transient hypotension was significantly more common in patients who received amifostine (70%) compared with the control group (3.8%;
2038
P ⫽ 0.0001); however, only 1 patient discontinued
therapy because of hypotension.
The panel has limited its suggestion to the specific
clinical situation described above and offers the following to clarify its view of the evidence. Amifostine is
a thiol-containing prodrug that is dephosphorylated
by alkaline phosphatase to its active metabolite WR1065, which acts as a potent scavenger of ROS. Theoretically, this mechanism of action would serve as a
rational basis for using amifostine as an agent to prevent the initiation of mucositis induced by chemotherapy, radiotherapy, and concomitant chemoradiotherapy. Currently, amifostine is approved by the U.S.
Food and Drug Administration (FDA) only for reducing the cumulative renal toxicity associated with repeated doses of cisplatin in patients with advanced
ovarian cancer or nonsmall cell lung cancer and for
reducing the incidence of moderate-to-severe xerostomia in patients undergoing postoperative radiotherapy for head and neck malignancies. Some reports
have demonstrated that the use of amifostine is associated with a reduction in mucositis in patients receiving radiotherapy to the head and neck,124 pelvis,125
and thorax,127 whereas other studies have failed to
demonstrate similar results.128 –130
The use of amifostine is complicated by its acute
toxicity (namely, nausea, emesis, hypotension, allergic
reactions, and taste disturbances), which may necessitate the interruption or discontinuation of amifostine therapy. Furthermore, it is not clear whether the
acute toxicity of amifostine can be reduced by performing subcutaneous administration, as opposed to
intravenous administration, which is the approved
technique.126,131 Another significant concern regarding the use of amifostine is the selectivity of its action
on normal tissues versus its action on tumor cells.
There are theoretic concerns that amifostine not only
may protect normal tissue but also may protect tumor
cells from the effects of radiotherapy. No adequately
powered trials addressing this issue have been published, although the clinical trials in the literature do
not suggest that amifostine-treated patients have a
survival disadvantage compared with control groups.
Accordingly, the panel considers the evidence on amifostine to be insufficient for the creation of guidelines
for the settings of radiotherapy alone and chemotherapy alone.
DISCUSSION
Using a modern, evidence-based approach, the
MASCC/ISOO panel evaluated the medical literature
of the last 36 years; in general, the quality of the
reported clinical trials failed to meet current standards. This is not to say that these studies do not have
value; however, the methodologic deficiencies compromised the panel’s ability to construct comprehensive, prescriptive guidelines. Consequently, the panel
offers the preceding guidelines as a benchmark and a
starting point for future revisions. Putting these findings in a current context also requires that the Writing
Committee summarize recent developments that were
reported after the close of the panel’s full review.
Since the panel last met, a number of agents for
the prevention and treatment of mucositis have been
reported at international meetings, in abstracts or articles, and in press releases from industry. Although
some of these agents appear promising, and the evidence supporting their use is of a high level, the panel
was unable to evaluate the evidence with the same
rigor it applied to the literature, which was subjected
to full panel review. Nevertheless, these agents are of
sufficient interest to warrant a brief summary.
Late-Breaking Reports
Human keratinocyte growth factor 2 (KGF-2; repifermin) was evaluated in a multicenter Phase II trial
involving 42 patients with various malignancies who
received conditioning regimens with chemotherapy
before undergoing autologous HSCT. Repifermin significantly reduced the incidence of Grade 2– 4 oral
mucositis.132 Recombinant human keratinocyte
growth factor 1 (rHuKGF-1; palifermin) was evaluated
in a multicenter, randomized, double-blind, placebocontrolled Phase II trial in patients with head and neck
cancer who received standard or hyperfractionated
radiotherapy with concomitant chemotherapy.133 The
palifermin-treated group had a lower incidence and
shorter duration of mucositis compared with the
group that received placebo. In a pivotal Phase III trial
involving patients undergoing transplantation for a
variety of hematologic malignancies, palifermin significantly reduced the incidence and duration of severe
oral mucositis (P ⬍ 0.0001).134
AES-14, which is L-glutamine administered in a
proprietary vehicle that increases its uptake, was evaluated in a Phase III trial in patients with solid tumors
who were at high risk for chemotherapy-induced oral
mucositis.135 Patients who received AES-14 had a
lower incidence of Grade ⱖ 2 mucositis compared
with patients who received placebo.
Iseganan, an analog of protegrin-1 and a naturally
occurring peptide with broad-spectrum microbicidal
activity, was evaluated in a randomized, double-blind,
placebo-controlled study in patients undergoing
transplantation who were receiving stomatotoxic therapy. Unfortunately, 102 patients (32%) were affected
by a drug-dispensing error caused by a flawed computerized allocation system. Between the 163 patients
who were randomized to receive iseganan and the 160
patients who were randomized to receive placebo, the
incidence of oral mucositis was not statistically significantly different.136 In a subgroup of patients who
were scheduled for HSCT and who underwent conditioning regimens with high potential for inducing mucositis, oral triclosan reportedly decreased the incidence and duration of ulcerative oral mucositis.137
In 2002, Gelclair was approved by the FDA as a
Class 1 medical device for the management and relief
of pain associated with oral lesions of various etiologies, including oral mucositis or stomatitis, which may
be caused by chemotherapy or radiotherapy. In an
open-label study involving 30 patients, Gelclair appeared to be safe and effective in improving pain
scores, swallowing endpoints, and nutritional endpoints. Controlled clinical trial data are not yet available for this mixture of polyvinylpyrrolidone, sodium
hyaluronate, and glycyrrhetinic acid.
Insufficient Evidence
To facilitate future research and to point out areas that
would benefit from well designed trials, the panel
provides a compilation of evidence that was reviewed
yet was considered insufficient to support a recommendation for or against the use of certain agents
(Table 3).57,60,124,127,138 –205 The rationales and potential mechanisms of action for agents investigated as
potential therapies are quite varied, and such agents
include mucosal surface protectants, antiinflammatory agents, antimicrobial agents, growth factors, and
agents that are difficult to classify. From a mechanistic
standpoint, some of these agents are potentially attractive, because they are associated with rationales
for targeting specific pathways known to be involved
in the etiology of mucositis; however, the evidence in
support of these agents’ efficacy is not rigorous
enough for the creation of a prescriptive guideline.
Amifostine is a good example of one such agent. The
rationale underlying the use of other potential agents
for the prevention or treatment of mucositis appears
to be limited, based on our current understanding of
the pathobiology of mucositis. Based on their proposed mechanisms, antimicrobial agents, such as
combined polymyxin E, tobrymycin, and amphotericin or single-agent iseganan, appear to have no associated mechanistic rationale for the prevention of mucositis and probably could provide benefit only for
patients with late-stage ulcerative mucositis, in which
bacterial superinfection occurs.
Lessons Learned and Future Directions
The panel believes that many of the agents studied are
potentially useful, but the trials’ shortcomings pre-
2039
vented the formulation of guidelines. Trials included
single studies that were underpowered, studies that
lacked an adequate control arm, studies that were not
investigator blinded or patient blinded, and studies
that suffered from other design deficiencies. In other
instances, multiple studies reported conflicting results, which prevented the panel from establishing
prescriptive recommendations or suggestions. New,
well designed, sufficiently powered, and appropriately
executed studies are needed to determine the value of
these various agents, which may or may not be effective in preventing or treating mucositis. To be useful
and to permit comparisons between studies, new investigations should include a control arm that represents the current standard of care, and they should use
a mucositis scoring scale with well established psychometric properties. Standardized oral care protocols should be the minimum for the control arm.
These standard elements should be coupled with protocol-prescribed analgesics and other supportive care
along with appropriate investigator and patient blinding. Future mucositis trials should have adequate
sample sizes for testing hypotheses.
Trials of radioprotectants should include longterm follow-up to calculate time to disease progression, along with response rates and survival rates, to
ensure that patients do not suffer from poor tumor
control in the interest of better supportive care. Furthermore, the studies should report withdrawal rates,
adverse event rates, and reasons for withdrawal. Differences in reasons for withdrawal are important, and
investigators should count patients who withdraw because of mucositis treatment failure or toxicity associated with the treatment agent as well as patients
who withdraw because of other toxicities associated
with anticancer therapy. Important secondary endpoints should include resource utilization, functional
outcomes, nutritional endpoints, infection rates, and
bleeding endpoints.
Alimentary tract mucositis, which encompasses
both oral and GI mucositis, is a complex process. It is
very unlikely that a single therapy will prevent or treat
this side effect of anticancer strategies. Local or topical
therapies may be useful in certain circumstances, or
they may be combined with other topical agents or
systemically active agents. The bioavailability of local
therapies should be evaluated early-stage to mid-stage
during development of clinical programs. It is likely
that in the future, combinations of agents will be used
to prevent or treat difficult mucositis problems like
those seen in patients receiving concomitant chemotherapy and radiotherapy for head and neck cancer or
lung cancer or in patients receiving high-dose chemotherapy with allogeneic stem cell transplantation. The
2040
TABLE 3
Agents with Evidence Insufficient to Support a Guideline
Agent
Oral
Amifostine
Azelastine
Chamomile
Chlorhexidine
Clarithromycin
Clindamycin
Coatings for surface, mucoadherent (various)
Cyanoacrylate-based tissue adhesives
Cytokines and growth factorsa
Granulocyte–colony-stimulating factor
Granulocyte-macrophage–colony-stimulating factor
Gelclair
Immunoglobulin
Nonsteroidal antiinflammatory drugs
Pilocarpine
Polaprezinc
PTA
Povidone iodine
Prostaglandin E2 analogue
Prostaglandin inhibitor
Silver nitrate
Sodium alginate
Steroids
Tetrachlorodecaoxide
Traumeel S
Tretinoin cream (0.1%)
Gastrointestinal
Amifostine
Butyric acid
Glutamine
Misoprostol
Use
Reference(s)
Prevention
Prevention
Prevention and
treatment
Prevention
Antonadou et al., 2001127; Komaki et al., 2002124
Osaki et al., 1994138
Carl and Emrich, 1991139; Fidler et al., 1996140
Prevention
Therapy
Pain
management
Pain
management
Prevention and
treatment
Prevention and
treatment
Treatment
Prevention
Treatment
Prevention and
treatment
Prevention
Treatment
Prevention
Prevention and
treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
McGaw and Belch, 1985141; Ferretti et al., 1990142; Rutkauskas and Davis, 1993143; Epstein et al.,
1992144; Dodd et al., 199657
Yuen et al., 2001145
Donnelly et al., 1993146
Ishii et al., 1990147; LeVeque et al., 1992148; Oguchi et al., 1998149; Redding and Haveman,
1999150; Yamamura et al., 1999151
Kutcher, 2001152; Perez et al., 2000153; Narang, 2001154
Crawford et al., 1999155; Schneider et al., 1999156; Mascarin et al., 1999157; Karthaus et al.,
1998158
Makkonen et al., 2000159; Tejedor et al., 2000160; Crawford et al., 1999155; Wagner et al., 1999161;
Chi et al., 1995162; Bez et al., 1999163; Saarilahti et al., 2001164; Hejna et al., 2001165; Sprinzl
et al., 2001166; van der Lelie et al., 2001167; Cartee et al., 1995168
Smith, 2001169; Innocenti et al., 2002170
Schedler et al., 1994171; Schedler et al., 1997172; Mose et al., 1997173
Pillsbury et al., 1986174; Rymes et al., 1996175; Tanner et al., 1981176
Warde et al., 2002177; Awidi et al., 2001178
Masayuki et al., 2002179
Bondi et al., 199760,b
Rahn et al., 1997180; Adamietz et al., 1998181
Matejka et al., 1990182; Porteder et al., 1988183; Pretnar et al., 1989184; Labar et al., 1993185;
Hanson et al., 1997186
Pillsbury et al., 1986174; Tanner et al., 1981176
Maciejewski et al., 1991187
Oshitani et al., 1990188
Leborgne et al., 1998189; Barrett, 1990190; Wolff et al., 1998191
Malik et al., 1997192
Oberbaum, 1998193; Oberbaum et al., 2001194
Cohen et al., 1997195
Kligerman et al., 1992198; Mitsuhashi et al., 1993199; Montana et al., 1992200
Vernia et al., 2000201
Daniele et al., 2001202; Savarese et al., 2000203; Decker-Baumann et al., 1999204
Khan et al., 2000205
PTA: polymyxin E, tobrymycin, and amphotericin.
a
For more information on cytokines and growth factors, see Discussion.
b
These investigators found that PTA was statistically significantly superior to a rinse containing diphenhydramine and local anesthetic, but they expressed doubt that the clinical effect would be significant.
incidence of mucositis in children receiving anticancer therapy has been widely reported. Furthermore,
studies of antimucositis agents in the pediatric population are rare. The panel encourages clinical development programs to begin testing promising agents in
children with cancer who are at risk of alimentary tract
mucositis, and clinical investigators are encouraged to
publish rates of mucositis from anticancer therapies in
a fashion similar to those published for adults (see the
accompanying article in this issue9). Finally, the field
of mucositis research needs to develop a scoring system or classification system to determine the mucotoxic potential of anticancer regimens. The panel encourages investigators reporting studies of newer
anticancer strategies to report mucositis rates of these
treatment modalities using standardized methods.
Lumping all grades of mucositis together prevents
supportive care experts from learning the mucotoxic
potential of newer treatments. This classification system is needed for use in clinical trials of newer agents
that can prevent or treat this significant side effect of
anticancer therapy and for making comparisons
among trials of promising agents.
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