Updated clinical practice guidelines for the prevention and treatment of mucositis
Updated Clinical Practice Guidelines for thePrevention and Treatment of Mucositis
Considerable progress in research and clinical application has been made since
the original guidelines for managing mucositis in cancer patients were published
in 2004, and the first active drug for the prevention and treatment of this condi-
tion has been approved by the United States Food and Drug Administration and
other regulatory agencies in Europe and Australia. These changes necessitate an
updated review of the literature and guidelines. Panel members reviewed the bio-
medical literature on mucositis published in English between January 2002 and
May 2005 and reached a consensus based on the criteria of the American Society
of Clinical Oncology. Changes in the guidelines included recommendations for
the use of palifermin for oral mucositis associated with stem cell transplantation,
amifostine for radiation proctitis, and cryotherapy for mucositis associated with
high-dose melphalan. Recommendations against specific practices were intro-
duced: Systemic glutamine was not recommended for the prevention of gastro-
intestinal mucositis, and sucralfate and antimicrobial lozenges were not
recommended for radiation-induced oral mucositis. Furthermore, new guidelines
suggested that granulocyte–macrophage-colony stimulating factor mouthwashes
1 Department of Medical Oncology, Royal Ade-
not be used for oral mucositis prevention in the transplantation population.
laide Hospital, Adelaide, Australia.
Advances in mucositis treatment and research have been complemented by an
2 School of Dentistry, University of Washington,Seattle, Washington.
3 Department of Biostatistics, The University ofTexas M. D. Anderson Cancer Center, Houston
The opinions or views expressed in this pro-
fessional review are those of the authors and
Adam S Garden, Ian Hewson, Fred Spijkervet,
do not necessarily reflect the opinions or
Department of Surgery Research, Brigham and
recommendations of the publisher or the com-
Mike Brennan, Andrea Stringer, Andrei Bar-
Women’s Hospital, Boston, Massachusetts.
panies that provided grants toward this pro-
asch, Kathryn Damato, Sharon Elad, Arnold
5 Department of Hematology, Leiden University
cess. This article is being published with the
Altman, Loree Oberle-Edwards, Judith John-
Medical Center, Leiden, the Netherlands.
full knowledge and consent of the authors.
son, Patricia Wienandts, M. Elvira P. Correa,
This article may discuss pharmaceutical pro-
Rene-Jean Bensadoun, and Rajesh V. Lalla.
6 Department of Diagnostic Sciences, NOVA
ducts and/or uses of products that have not
Southeastern University, Fort Lauderdale, Florida.
Address for reprints: Dorothy M. Keefe, MD,
7 School of Nursing, University of Maryland, Bal-
Administration or other regulatory authorities
Department of Medical Oncology, Royal Ade-
outside of the United States. For approved
laide Hospital Cancer Centre, Royal Adelaide
product information, consult the manufac-
Hospital, North Terrace, Adelaide, South Aus-
8 Research Medical Library, The University of
turer’s prescribing information or the applica-
tralia 5000, Australia; Fax: (011) 618-8222-
Texas M. D. Anderson Cancer Center Houston,
ble regulatory authority. Dosages, indications,
4358; E-mail: email@example.com
and methods of use for compounds that are
referred to in this article may be derived from
School of Dental Medicine, University of Con-
Mark M. Schubert is currently an advisory
the professional literature or other sources. In
necticut Health Center, Farmington, Connecticut.
board participant for MGI Pharma and on the
vitro and animal data may not correlate with
speakers’ bureau (Kepivance) for Amgen; pre-
clinical results and do not demonstrate clinical
viously he has served as an advisory board
Supported by unrestricted educational grants to
participant for McNeil Pharmaceuticals and on
the Mucositis Study Section of the Multinational
Association of Supportive Care in Cancer and the
International Society for Oral Oncology (MASCC/
Chastain in the preparation of this article.
Received October 5, 2006; revision received
ISOO). Corporate sponsors included Novartis, MGI
The Mucositis Study Section of MASCC/ISOO
Pharma, Curagen, RxKinetics, and Laclede.
included Marisol Michelet, Elenir Avritscher,
DOI 10.1002/cncr.22484Published online 5 February 2007 in Wiley InterScience (www.interscience.wiley.com).
Updated Mucositis Practice Guidelines/Keefe et al.
increased rate of publication on mucosal injury in cancer. However, additional and
sustained efforts will be required to gain a fuller understanding of the pathobiology,
impact on overall patient status, optimal therapeutic strategies, and improved edu-
cational programs for health professionals, patients, and caregivers. These efforts
are likely to have significant clinical and economic impact on the treatment of
cancer patients. Cancer 2007;109:820–31. Ó 2007 American Cancer Society.
KEYWORDS: cancer therapy, clinical practice guidelines, mucosal barrier injury,mucositis (alimentary, gastrointestinal [GI], oral), mucositis pathogenesis.
In 2004, the Mucositis Study Group of the Multina- MATERIALS AND METHODS
tional Association of Supportive Care in Cancer
(MASCC) and the International Society for Oral On-
Our panel consisted of 30 mucositis-involved health
cology (ISOO) published 2 articles as a supplement
care professionals, including oral oncologists, radia-
in the journal Cancer. The first article addressed the
pathogenesis, measurement, epidemiology, and con-
nurses, dentists, dental hygienists, basic scientists,
sequences for patients of oral and GI mucositis1; the
epidemiologists, outcomes researchers, and a medi-
second article provided evidenced-based clinical
practice guidelines for the management (preventionand treatment) of the condition.2 However, few spe-
cific guidelines were possible based on the published
Using the Ovid interface to Medline and a publication
literature available at that time. We anticipated that
time frame of January 2002 to May 2005, we retrieved
an updated review would be required approximately
3974 articles, only 622 of which were of sufficient qual-
every 3 years given the pace and direction of
ity and relevance to be included in our final recom-
advances in the field: The current report represents
mendations. At the time of the search, mucositis was
not a Medical Subject Heading (MeSH); thus, we
Management strategies for oral and GI mucositis
searched for mucositis as a text word in article titles and
increasingly are driven by key scientific advances.
abstracts. We also searched for the following terms to
These strategies are setting the stage for regulatory
identify all publications that had addressed mucositis:
approval of drugs and devices, which, in turn, pro-
stomatitis, a MeSH that we exploded to include related
vide opportunities for multidisciplinary expert panels
terms of Stevens-Johnson syndrome and stomatitis
to produce evidence-based guidelines. Table 1 shows
(aphthous, denture, herpetic); mucous membrane, a
the history of mucositis research over the last 40
MeSH that we exploded to include related terms of gas-
years and delineates the temporal relations between
tric mucosa, goblet cells, intestinal mucosa, mouth mu-
important developments in scientific discovery, phar-
maceutical products, cancer treatment and support-
ive care, and related professional organizations,
pathophysiology, and radiation effects and injury to
conferences, regulations, protocols, and guidelines.
narrow the retrieval to publications in which the mu-
Such factors are likely to have had multidirectional
cosa was injured and to limit the search to specific
influence on the growth of this field, resulting in
subject areas that were assigned to the various
incremental gains as well as sudden significant
reviewers. By exploding the MeSH term neoplasms,
we limited the search to neoplastic disease. Our final
Mucositis remains a morbid side effect of many
step was to limit the retrieval to articles that were
anticancer treatments. Alimentary mucositis (AM) is
a term we recommend to describe cancer therapy-associated mucosal injury of the alimentary tract(mouth to anus). This unifying term acknowledges
the similarities along the entire GI tract while allow-
The medical librarian conducted separate literature
ing for regional differences that require discussion
reviews, working closely with the group leaders for
of oral and GI mucositis separately at times based
each of 8 subject domains: 1) epidemiology, econom-
on pathophysiologic responses and clinical charac-
ics, and outcome; 2) pathogenesis; 3) terminology,
definition, and scales; 4) growth factors and cyto-
Updated Mucositis Practice Guidelines/Keefe et al.
kines; 5) antimicrobials, mucosal coating agents,
anesthetics, and analgesics; 6) alternative and natural
therapies, laser, ice, etc; 7) basic oral care, bland
A recommendation is reserved for guidelines that
rinses, protocol development and education, and
are based on Level 1 or Level 2 evidence.
good clinical practice; and 8) anti-inflammatory
A suggestion is used for guidelines that are based
agents and amifostine. Each group reviewed both
on Level III, Level IV, and Level V evidence; this implies
preclinical and clinical articles relating to the entire
panel consensus on the interpretation of this evidence.
alimentary tract. The systematic weighting of both
No guideline possible is used when there is insufficient
evidence on which to base a guideline; this conclusion
level and grade of evidence followed the same pro-
implies 1) that there is little or no evidence regarding the
cess that was used for the original guidelines based
practice in question, or 2) that the panel lacks a consensus
on criteria of the American Society of Clinical Oncol-
on the interpretation of existing evidence.
ogy that rated the level of evidence on a scale from Ito V and refined this by grading each recommenda-
* Used with permission from the publisher. Adapted from: Somerfield M, Padberg J, Pfister D, et al.
ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Classic Pap Curr Com-
tion from A to D.3,4 Level I evidence is reserved for
meta-analyses of randomized controlled trials or ran-domized trials with high power. Level II evidenceincludes randomized trials with lower power, and
attended the workshop, nor were they allowed access
Level III evidence includes nonrandomized trials,
to the guidelines prior to publication. The guideline-
such as cohort or case-controlled series. Level IV evi-
development process was determined entirely by the
dence includes descriptive and case studies, and
panel. Each panel member completed a conflict-of-
Level V evidence includes case reports and clinical
interest disclosure form that revealed all relation-
examples. Grade A is reserved for Level I evidence or
ships with pharmaceutical companies that could be
consistent findings from multiples studies of Level II,
affected by the development and publication of these
III, or IV evidence. Grade B is for Level II, III, or IV
evidence with generally consistent findings. Grade Cis similar to grade B but with inconsistencies; and
Grade D implies little or no evidence.
Revision planThe panel will continue to review the literature every
2 to 3 years and will publish updates to guidelines as
We distributed the publications in the finalized set of
necessary. The current process has created the op-
literature to each group with instructions based on
portunity for Web-based storage of the publication
methods for reviewing and scoring the literature
inventory as well as for future reviews.
published by Hadorn et al.4 At least 2 panel membersreviewed each article. Preclinical studies were not
used to create guidelines per se; rather, they were
In recognition of the importance and challenge of
used as indicators of future directions for preclinical
disseminating and using these guidelines in clinical
and clinical studies. Each group presented its report
oncology practice, the review team is considering co-
and draft of guideline revisions at a workshop in
operative strategies with other professional oncology
Geneva, Switzerland on June 27 and 28, 2005. The
organizations as well as methodologies to assess the
entire panel discussed each guideline to ensure that
scope and durability of the impact of the guidelines
it met the correct standards and to achieve a consen-
sus (see Table 2). The current report includes thenew guidelines that were developed based on thisprocess. Each group also has published a companion
article in Supportive Care in Cancer5–17 that elabo-
rates on the extent of preclinical and clinical litera-
Efforts to understand the biological basis for AM
include research of mechanism-based therapy, riskprediction, long-term toxicity, and associations with
Conflict of Interest and Financial Disclosure
other side effects of cancer treatment. GI toxicities
The costs for the workshop and for administrative
from the targeted cancer therapies have yet to be
assistance in guideline preparations were paid from
included in this field. It is likely that there are macro-
unrestricted educational grants made to the Mucosi-
scopic factors as well as molecular or cellular factors
tis Study Group of MASCC/ISOO. No representatives
that are fundamental to the expression of GI toxicity,
from any of the companies that provided grants
that both categories are generic or specific,7 and that
they will provide opportunities for intervention. In
els have continued to characterize oral and GI muco-
the future, it may be possible to predict an individual
sitis as a continuum of injury rather than biologically
patient’s risk of particular toxicities from radiother-
and clinically independent toxicities,23,27,28 new mod-
apy and from each different chemotherapy or combi-
els for the assessment of genetic risk for mucositis29
nation therapy. We recommend future research into
and the totality of impact for the condition23 may de-
mucotoxicity that focuses on identifying its generic
velop as research in this area progresses); 4) develop-
and tissue-specific causes, analyzing its genetic com-
ment of an epidemiological burden-of-illness study
ponents using genetic versus nongenetic controls,
by researchers from the Mucositis Study Group to
and establishing evidence-based grading for and
evaluate the impact of AM on patients after treatment
hierarchical characterization of mucotoxicity.
with standard-dose chemotherapy and/or radiother-apy; that study uses patient-reported outcome tools
to measure impact and investigates the relations
Advancements in terminology and in the assessment
between various patient-reported toxicities as well as
of AM in patients receiving cytoreductive cancer
the true regimen-related incidence and severity of
therapies have resulted in better patient management
practices and enhanced drug development to reduce
toxicity. Factors of note since publication of the origi-nal guidelines in 2004 include: 1) publication of the
Common Terminology Criteria for Adverse Events
version 3.0,18 which defines a comprehensive, multi-
Our literature searches did not identify any prospec-
modality grading system for both acute and chronic
tive studies of the incidence of mucosal toxicity asso-
effects of cancer treatment; 2) implementation of the
ciated with standard, multicycle chemotherapy for
term mucositis as a MeSH category, effective January
common solid tumors. Therefore, we reviewed 99
2006, which will improve future search capabilities
recent clinical trials of standard chemotherapy regi-
and increase the visibility of the term during related
mens for non-Hodgkin lymphoma or breast, lung, or
searches (this change was a direct result of a recom-
colorectal cancer for incidence of severe (grade 3 or
mendation to the National Library of Medicine in
4) oral mucositis, diarrhea, and esophagitis.8 We
February 2005 by the review group from the original
aggregated the estimates of incidence using pre-
Mucositis Guideline Project and, thus, represents an
viously described methods1 and weighted the esti-
important outcome of the original project); 3) publi-
mates based on the quality of the adverse event
cation and presentation of additional models depict-
reporting and the sample size for each trial. We
ing the potential impact of oral and GI mucositis
assigned quality points for the use of standardized
relative to symptom clusters19–26 (although the mod-
Updated Mucositis Practice Guidelines/Keefe et al.
TABLE 3Risk of Grade 3 or 4 Oral Mucositis and Diarrhea by Chemotherapy Regimen*
CHOP-14: Cyclophosphamide, doxorubicin, vincristine, and prednisone
CHOP-DI-14: Cyclophosphamide, doxorubicin, vincristine, and prednisone (dose-intensified)
CHOEP-14: Cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone
CEOP/IMVP-Dexa: cyclophosphamide, etoposide, vincristine, prednisone/ifosfamide,
A?T?C: Doxorubicin, taxane, and cyclophosphamide (administered sequentially)y
AC?T Doxorubicin, cyclophosphamide, and taxane (administered sequentially)
A?CT: Doxorubicin, cyclophosphamide, and taxane (administered sequentially)
A?T: Doxorubicin and taxane (administered sequentially)
FAC (weekly): 5-FU, doxorubicin, and cyclophosphamide
AC (weekly): Doxorubicin and cyclophosphamide
TAC: docetaxel, doxorubicin, and cyclophosphamide
FOLFOX: 5-FU, leucovorin, and oxaliplatin
95% CI indicates 95% confidence interval; NHL, non-Hodgkin lymphoma; 5-FU, 5-fluorouracil; XRT, radiotherapy.
* Adapted from Jones JA, Avritscher EBC, Cooksley CD, Michelet M, Bekele BN, Elting LS. Epidemiology of treatment-associated mucosal injury after treatment with newer regimens for lymphoma, breast, lung,or colorectal cancer. Support Care Cancer. 2006;14:505–515.8y Taxane is paclitaxel or docetaxel.
assessment of toxicity, and for midcycle assessment
patients with lung cancer who receive platinum-
of toxicity (as opposed to limiting assessments to
based doublets and triplets, even when radiotherapy
is administered concurrently. However, among thesepatients, severe (grade 3 or 4) radiotherapy-induced
Incidence of mucositis associated with standard,
esophagitis has been a major concern, occurring in
multicycle chemotherapy (with or without radiotherapy)
>15% of patients. Based on several studies8 that
included 280 patients, 18% (range, 14.2–22.9%) of
patients who receive carboplatin and paclitaxel plus
Table 3 shows that standard chemotherapy regimens
radiotherapy develop severe esophagitis. The risk of
for non-Hodgkin lymphoma occasionally have re-
severe esophagitis may be lower (10.6%; range, 2.1–
sulted in severe oral mucositis (3–10%) or diarrhea
20.2%) among patients who receive amifostine;
(1–3%). Similar rates of AM are observed among
although this estimate was derived from a single
women who receive standard doxorubicin- and tax-
study of 47 patients. Patients with advanced colorec-
ane-based regimens for breast cancer. Severe oral
tal cancers who receive common chemotherapy regi-
mucositis and severe diarrhea are rare among
mens have a low risk of severe oral mucositis but a
high risk (16%) of diarrhea overall, which approaches
preventive oral care regimen should be part of rou-
25% when both irinotecan and oxaliplatin are used.
tine supportive care along with a therapeutic oral
Reports of newly emerging standards of care using
care regimen if mucositis develops. Regular, system-
targeted therapies for lung and colorectal cancers fell
atic, oral care hygiene with brushing, flossing, bland
outside the time frame of the current review; thus,
rinses, and moisturizers using a standardized oral
the impact of these agents on the risk of mucosal
care protocol should be implemented for all patients.
damage and diarrhea has yet to be described.
It is noteworthy that an interdisciplinary approach tooral care (nurse, physician, dentist, dental hygienist,
Updated Clinical Practice Guidelines for the
dietician, pharmacist, and others as relevant) will
provide the most comprehensive means of providing
To provide clinicians with the current recommenda-
supportive care. Dental examinations and treatment
tions in a single document, the guidelines presented
are important prior to the start of cancer therapy for
in Table 4 represent the integration of the original
all patients, especially for those with head and neck
guidelines from 20042 plus the new guidelines devel-
cancer, and should continue throughout active treat-
oped at the Geneva workshop. The text below
addresses the guideline revisions only. The reader isreferred to the original Cancer supplement publica-tion for more detail on the original guidelines.2
Radiotherapy: Prevention and/or TreatmentAntimicrobial lozenge
Basic oral care and good clinical practice principles
Guideline. The panel recommends that antimicrobial
The results from a survey that was conducted by panel
lozenges not be used for the prevention of radiation-
members showed that incorporating management
induced oral mucositis (Level II evidence, grade B
guidelines into routine clinical practice will require the
recommendation). Despite the often postulated role
successful dissemination and adoption of the guide-
of infection in the pathogenesis of mucositis, no con-
lines, which can be achieved by educating relevant
clusive evidence for it has been published. Two new
target audiences.14 Barriers to such efforts include
studies of oral lozenges that contained polymixin,
challenges to dissemination, knowledge deficits, resist-
tobramycin, and amphoteracin B or bacitracin, clo-
ance to changing traditional practices, and a variety of
trimazole, and gentamicin showed no improvement
administrative issues.31 We have addressed some of
in the incidence or severity of radiation-induced
these barriers through a focus on education, quality-
improvement processes, and good clinical practices.
The panel suggests interdisciplinary development
of systematic oral care protocols that are geared to-
Guideline. The panel recommends that sucralfate not
ward the individual needs of the patient; educational
be used for the treatment of radiation-induced oral
approaches to promulgating them that include the
mucositis (Level II evidence, grade A recommenda-
patient, family, and staff; and quality-improvement
tion). Sucralfate is a mucosal coating agent that has
processes to evaluate them. It also suggests the use of
been postulated to offer protection to the mucosa. All
a soft-bristle toothbrush that is replaced on a regular
studies have been negative in the radiation arena,
basis. A lack of research in these areas renders out-
and the new randomized, controlled trial of sucralfate
come assessment an extremely important component
in radiation treatment has confirmed this lack of ben-
of oral supportive care to document the benefits of
efit, showing no difference between micronized
these practices. The updated guidelines also address
sucralfate and salt and soda mouth washes.34
good clinical practices that should occur regardless ofthe amount of research-based evidence.13
AmifostineGuideline. The panel suggests that intravenous ami-
Guidelines. Based on expert opinion and the limited
fostine at a dose 340 mg/m2 daily prior to radio-
published literature, the panel recommends the fol-
therapy may prevent radiation proctitis in patients
lowing: Regular assessment of oral pain is essential
who are receiving standard-dose radiotherapy for
and should be performed using validated, self-report
rectal cancer (Level III evidence, grade B recommen-
pain instruments. Topical anesthetics or other agents
dation). Amifostine is an organic thiophosphate that
should be considered to promote oral comfort. Initial
is used as a normal tissue protector during cytotoxic
and ongoing assessment of the oral cavity is essential
therapy.35,36 Most of the amifostine studies that have
using validated instruments that include both patient
been published since the initial guidelines were
self-report and professional examination. Use of a
established have been small, single-center studies
Updated Mucositis Practice Guidelines/Keefe et al.
TABLE 4Summary of Evidence-based Clinical Practice Guidelines for Care of Patients With Oral and Gastrointestinal Mucositis (2005 Update)
Basic oral care and good clinical practices
1. The panel suggests multidisciplinary development and evaluation of oral care protocols, and patient and staff education in the use of such protocols to reduce theseverity of oral mucositis from chemotherapy and/or radiation therapy. As part of the protocols, the panel suggests the use of a soft toothbrush that is replaced on aregular basis. Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health. The inclusion of dentalprofessionals is vital throughout the treatment and follow-up phases.
2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT. Regular oral painassessment using validated instruments for self-reporting is essential.
3. The panel recommends the use of midline radiation blocks and 3-dimensional radiation treatment to reduce mucosal injury.
4. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy.
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.
6. The panel recommends that antimicrobial lozenges not be used for the prevention of radiation-induced oral mucositis.
7. The panel recommends that sucralfate not be used for the treatment of radiation-induced oral mucositis.
8. The panel recommends that patients receiving bolus 5-FU chemotherapy undergo 30 minutes of oral cryotherapy to prevent oral mucositis.
9. The panel suggests the use of 20 to 30 min of oral cryotherapy to decrease mucositis in patients treated with bolus doses of edatrexate.
10. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.
11. The panel recommends that chlorhexidine not be used to treat established oral mucositis.
High-dose chemotherapy with or without total body irradiation plus HCST: Prevention
12. In patients with hematologic malignancies who are receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplantation, the panelrecommends the use of keratinocyte growth factor-1 (palifermin) in a dose of 60 lg/kg per d for 3 d prior to conditioning treatment and for 3 d posttransplantation for theprevention of oral mucositis.
13. The panel suggests the use of cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan.
14. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.
15. The panel suggests that GM-CSF mouthwashes not be used for the prevention of oral mucositis in patients undergoing HSCT.
16. The panel suggests the use of LLLT to reduce the incidence of oral mucositis and its associated pain in patients receiving high-dose chemotherapy orchemoradiotherapy before HSCT if the treatment center is able to support the necessary technology and training, because LLLT requires expensive equipment andspecialized training. Because of interoperator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel isencouraged by the accumulating evidence in support of LLLT.
Basic bowel care and good clinical practices
17. The panel suggests that basic bowel care should include the maintenance of adequate hydration, and that consideration should be given to the potential for transientlactose intolerance and the presence of bacterial pathogens.
18. The panel suggests the use of 500 mg sulfasalazine orally twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients receivingexternal beam radiotherapy to the pelvis.
19. The panel suggests that amifostine in a dose 340 mg/m2 may prevent radiation proctitis in patients who are receiving standard-dose radiotherapy for rectal cancer.
20. The panel recommends that oral sucralfate not be used to reduce related side effects of radiotherapy; it does not prevent acute diarrhea in patients with pelvicmalignancies undergoing external beam radiotherapy; and, compared with placebo, it is associated with more GI side effects, including rectal bleeding.
21. The panel recommends that 5-amino salicylic acid and its related compounds mesalazine and olsalazine not be used to prevent GI mucositis.
22. The panel suggests the use of sucralfate enemas to help manage chronic radiation-induced proctitis in patients who have rectal bleeding.
Standard-dose and high-dose chemotherapy: Prevention
23. The panel recommends either ranitidine or omeprazole for the prevention of epigastric pain after treatment with cyclophosphamide, methotrexate, and 5-FU ortreatment with 5-FU with or without folinic acid chemotherapy.
24. The panel recommends that systemic glutamine not be used for the prevention of GI mucositis.
Standard-dose and high-dose chemotherapy: Treatment
25. When loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy associated with HSCT, the panel recommends octreotide at a dose100 lg subcutaneously, twice daily.
Combined chemotherapy and radiotherapy: Prevention
26. The panel suggests the use of amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell lung cancer.
HSCT indicates hematopoietic stem cell transplantation; 5-FU: 5-fluorouracil; GM-CSF, granulocyte-macrophage–colony stimulating factor; LLLT: low-level laser therapy; GI, gastrointestinal.
with conflicting results that do not help to delineate
randomized, controlled studies. Prophylactic intrave-
the role of amifostine in the reduction of mucositis.
nous injections were given for 3 days prior to each
However, 4 small studies on the prevention of procti-
chemotherapy cycle in a Phase I study. Doses ranged
tis in patients receiving radiotherapy for pelvic can-
from 1 lg/kg per day to 80 lg/kg per day in 6 differ-
cers all showed a reduction in symptoms, suggesting
ent cohorts, and 1 group of patients was given pla-
cebo. The drug generally was tolerated well inbiologically active doses, and the results suggested a
positive effect on oral mucositis.44 In a double-blind,
Although no new guideline is possible for benzyda-
Phase III, multicenter study in which the effects of
mine, because no new trials have been published
palifermin were evaluated in 212 patients with hema-
since the 2004 supplement, it is important to note
tologic malignancies who were undergoing a stoma-
that a study in the United States sponsored by
totoxic conditioning regimen in preparation for
McNeil had aimed to confirm the results of an earlier
autologous hematopoietic stem cell transplantation
randomized, placebo-controlled American/Canadian
(HSCT), the incidence and duration of clinically
multicenter trial41 on which the original guideline
meaningful oral mucositis was reduced significantly
was based. However, the McNeil study was stopped
in patients who were receiving palifermin. Palifermin
early after the receipt of results from an interim anal-
(60 lg/kg per day) or placebo was administered for
ysis and the recommendations of the Data Monitor-
3 consecutive days immediately before the initiation
of myeloablation and on Days 0, 1, and 2 after trans-plantation. Palifermin also favorably affected the
High-dose Chemotherapy With or Without Total-body
incidence of blood-borne infections, the use of
parental opioids, and a variety of patient-reported
outcomes45 in a well-conducted, double-blind, ran-
domized, placebo-controlled, multicenter study.
Guideline. In patients with hematologic malignancieswho are receiving high-dose chemotherapy and total
body irradiation with autologous stem cell transplan-
Guideline. The panel suggests the use of cryotherapy
tation, the panel recommends the use of keratinocyte
to prevent oral mucositis in patients who are receiv-
growth factor-1 (KGF1) (palifermin) at a dose of
ing high-dose melphalan (as a conditioning agent in
60 lg/kg per day for 3 days prior to conditioning
HSCT; Level II evidence, grade A recommendation).
treatment and for 3 days post-transplantation for the
Cryotherapy was recommended in the previous guide-
prevention of oral mucositis (Level I evidence, grade
lines for the prophylaxis of oral mucositis in patients
A recommendation). In the previous review,2 clinical
who were receiving bolus 5-fluorouracil and possibly
studies on growth factors and cytokines for the pre-
etidronate (both drugs with short half-lives). Melpha-
vention and treatment of oral mucositis showed
lan is another such drug, and the studies, although
inconsistent results, and there was not enough evi-
small, showed consistent results in favor of using
dence to make any recommendations for clinical
cryotherapy,46,47 which obviously is a cost-effective
preventive strategy. For some patients, compliance
Recombinant human KGF1 (fibroblast growth
may be confounded by the physically uncomfortable
factor 7 [FGF-7] or palifermin) is a member of the
sensation they experience while holding ice in the
FGF super class. Initially, the tissue-protective capa-
city of palifermin was attributed to its mitogeniceffect, which results in increased thickness of muco-
Granulocyte–macrophage-colony stimulating factor
sal epithelium. However, palifermin also up-regulates
Guideline. The panel suggests that granulocyte–
the expression of transcription factor Nrf2 in kerati-
nocytes, which leads to the up-regulation of genes
mouthwashes not be used for the prevention of oral
that encode a series of reactive oxygen species-
mucositis in patients undergoing HSCT (Level II evi-
scavenging enzymes.42 It stimulates the generation of
dence, grade C recommendation). GM-CSF stimu-
the anti-inflammatory cytokine interleukin-13 (IL-13),
lates cells of the innate immune system in mucosal
which reduces tumor necrosis factor, a proinflamma-
tissues. GM-CSF for oral mucositis was evaluated in
tory cytokine that plays a key role in the pathogene-
4 studies48–51 with conflicting results. However, a
sis of mucositis. In addition, palifermin exerts
randomized, controlled study using a GM-CSF pro-
antiapoptotic effects and reduces angiogenesis.43
phylactic mouthwash51 and another randomized,
Palifermin was used to prevent oral mucositis in 2
controlled trial using a GM-CSF mouthwash as a
Updated Mucositis Practice Guidelines/Keefe et al.
Late-breaking Reports and Agents With Insufficient
patients who were receiving high-dose chemother-
apy48 demonstrated no positive effects on the dura-
Human KGF2 2 (repifermin) has been withdrawn
from study because of poor performance in a PhaseII study. The reasons for the poor performance areunclear and may relate to scheduling. It has been
Standard-dose and High-dose Chemotherapy: Prevention
reported in a Phase I trial that whey growth factor
extract reduced oral mucositis in the HSCT setting
Guideline. The panel recommends that systemic glu-
compared with historic controls.56 Well-designed,
tamine not be used for the prevention of GI mucositis
randomized, controlled trials are warranted before a
because of severe toxicity (Level II evidence, grade C
valid assessment of benefit can be made.
recommendation). Glutamine is an amino acid that
A single Phase III trial of Saforis (L-glutamine in a
is a favored food of the GI tract. It is necessary for
proprietary oral drug-delivery system) recently showed
cell mitosis. Multiple trials studying its effect on
a reduction in oral mucositis among patients who were
mucositis prevention and treatment in various parts
receiving anthracycline-based chemotherapy,57 but
of the alimentary canal have produced conflicting
further trials have been requested by the United States
results. Pytlik and colleagues performed a double-
Food and Drug Administration and are awaited.
blind, randomized trial in 40 bone marrow transplan-
RK-0202 is N-acetylcysteine in a proprietary
tation patients who received either intravenous ala-
mouth rinse formulation that was studied recently in a
nyl-glutamine dipeptide or placebo52 and observed
Phase II, double-blind, placebo-controlled trial among
that oral mucositis was more severe in the treatment
patients who were undergoing radiotherapy for head
group, although diarrhea was reduced, suggesting a
and neck cancer. In that trial, RK-0202 significantly
differential effect down the GI tract. However, those
reduced the incidence of oral mucositis (World Health
authors observed an increase in disease recurrences
Organization and National Cancer Institute clinical
grade >2) by 29% (P ¼ .04) and 46% (P ¼ .005), respec-
Major advances in the field of mucositis have
Updating the management guidelines for mucositis
occurred over the past 3 years, including increased
has been a productive enterprise, reflecting the pub-
understanding of the epidemiology and pathobiology
lished evidence to improve clinical practice in muco-
of the condition; a realization that symptom clusters
sitis management. The publication of guidelines is
occur in patients, suggesting that genetic risk predic-
only the first step toward ensuring that all patients
tion for toxicity soon may be a reality; and the avail-
have access to evidence-based protocols for the
ability of new mechanism-based treatments. The
management of their potential mucositis. Work needs
registration of palifermin and the recommendation
to be done on promulgation of the guidelines; devel-
for its use in the prevention of oral mucositis in the
opment of protocols that are based on them; educa-
HSCT setting is a first in the field. Other drugs are in
tion of patients, caregivers, and staff; and assessment
development, and rapid progress finally is being
of outcomes from their use. Improved risk assess-
made in this under-appreciated area.
ment needs to occur as well as continued research at
In the time after the endpoint for inclusion of
the basic and clinical levels into epidemiology, bur-
studies in the original guidelines (May 2002),2 the
den of illness, cost of care, prevention, and treat-
pace of publication of mucositis studies has in-
ment.16 Most patients are not followed for toxicity
creased. However, the quality of these studies
for sufficient duration in clinical trials; thus, these
remains variable, with many studies remaining small,
problems largely are underestimated. Although pro-
poorly designed, and, thus, unable to answer the
gress is being made toward addressing some of these
questions posed. Some of the recent studies indeed
areas, 2 important areas of assessment remain:
are of high quality, and it is those studies that have
led to the important changes in the guidelines (Table
agents, such as palifermin, are expensive and cannot
3). New agents continue to be developed. However,
be justified for prevention when the risk of severe
the panel is unable to incorporate these agents into
mucositis is low. However, if clinicians could predict
the guidelines until peer-reviewed clinical studies
which patients on standard-dose treatments would
appear in the literature.48–51,53–56 Future guideline
suffer mucositis, then the newer, more expensive
reviews will address the outcomes of those studies.
agents could be targeted in a cost-effective manner.
We anticipate that the new guidelines will need
16. Bensadoun RJ, Schubert MM, Lalla RV, Keefe D. Amifostine
updating in 2 or 3 years, and we look forward to
in the management of radiation-induced and chemo-
published studies on the burden of illness and risk
induced mucositis. Support Care Cancer. 2006;14:566–572.
17. Brennan MT, Bultzingslowen IV, Schubert MM, Keefe D. Al-
prediction as well as evaluations of strategies to
imentary mucositis: putting the guidelines into practice.
improve the uptake and use of the guidelines.
Support Care Cancer. 2006;14:573–579.
18. Trotti A, Colevas AD, Setser A, et al. Common Terminology
Criteria for Adverse Events version 3.0: development of a
comprehensive grading system for the adverse effects of
Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer
cancer treatment. Semin Radiat Oncol. 2003;13:176–181.
therapy-induced mucosal injury: pathogenesis, measure-
19. Cella D, Pulliam J, Fuchs H, et al. Evaluation of pain asso-
ciated with oral mucositis during the acute period after
Cancer. 2004;100(9 suppl):1995–2025.
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practice guidelines for the prevention and treatment of
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Annual Meeting Proc. 2006;5523. Abstract 5523.
La captura deslumbrante La exposición de dibujos de Clarina Vicens y Eduardo Vernazza es concebida, desde el guión curatorial, como una muestra de cámara. Usando ese carácter no sólo por la imposición de las salas, estrechas, techo bastante bajo, y, por su ausencia de aberturas, un tanto ensimismadas y propensas a la mirada cercana. El encuadre, entonces y de manera esencial, sur
The best ICHO-tasks of the last years According to the decision of the work shop of Amsterdam the delegation leaders of 8countries made an attempt to rank the ICHO-tasks of the years 1980 ~ 1990 into thecategoriesexcellent / good / not so good / not acceptableThe following pages indicate the ”top-twelve”, i.e. is the best tasks of the last years. Thiscollection should be an aid for the IC