Original Article

MASCC/ISOO Clinical Practice Guidelines for the Management

of Mucositis Secondary to Cancer Therapy
Sharon Elad, DMD, MSc1; Karis Kin Fong Cheng, RN, PhD2; Rajesh V. Lalla, DDS, PhD3; Noam Yarom, DMD4;
Catherine Hong, BDS, MS5; Richard M. Logan, BDS, MDS, PhD6; Joanne Bowen, PhD7; Rachel Gibson, PhD8;
Deborah P. Saunders, DDS9; Yehuda Zadik, DMD, MHA 10
; Anura Ariyawardana, BDS, MS11;
12 13 14
Maria Elvira Correa, DDS, PhD ; Vinisha Ranna, DDS ; and Paolo Bossi, MD ; for the Mucositis Guidelines Leadership Group
of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)

BACKGROUND: Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review
was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)
Clinical Practice Guidelines for the management of mucositis. METHODS: The literature was reviewed systematically to identify interven-
tions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria.
The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published
criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, sugges-
tion, or no guideline possible. RESULTS: The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucosi-
tis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous
guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there
was no new evidence for these interventions. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis
provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in
patients who have cancer. Cancer 2020;126:4423-4431. © 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of
American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs
License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and
no modifications or adaptations are made.

KEYWORDS: cancer, gastrointestinal, guidelines, mucositis, Multinational Association of Supportive Care in Cancer and International
Society for Oral Oncology (MASCC/ISOO), oral.

INTRODUCTION
Mucositis is a common complication of radiotherapy (RT), chemotherapy (CT), a combination of RT and CT (RT-
CT), and hematopoietic stem cell transplantation (HSCT). Mucositis is characterized by erythema and ulceration
of the mucosal lining of the gastrointestinal (GI) tract. Oral mucositis (OM) is associated with pain, difficulty in

Corresponding Author: Sharon Elad, DMD, MSc, Eastman Institute for Oral Health, University of Rochester Medical Center, 625 Elmwood Ave. Rochester, NY 14620
(SElad@[Link]).
1
Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York; 2 Yong Loo Lin School of Medicine, National University of Singapore,
Singapore, Singapore; 3 University of Connecticut School of Dental Medicine, UConn Health, Farmington, Connecticut; 4 Sheba Medical Center, Tel Hashomer, and Tel
Aviv University, Tel Aviv, Israel; 5 Faculty of Dentistry, National University of Singapore, Singapore, Singapore; 6 Adelaide Dental School, University of Adelaide, Adelaide,
South Australia, Australia; 7 Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; 8 School of Allied Health Science and Practice, University
of Adelaide, Adelaide, South Australia, Australia; 9 North East Cancer Center, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Ontario, Canada;
10
Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; 11 College of Medicine and Dentistry, James Cook University, Cairns, Queensland, Australia;
12
School of Medical Science, University of Campinas-Cidade, Zeferino Vaz University, Barao Geraldo, Brazil; 13 The Mount Sinai Hospital, New York, New York; 14 Medical
Oncology Department, University of Brescia, Brescia, Italy
The members of the Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology
(MASCC/ISOO) include: Praveen Arany, Abdul Rahman Al-Azri, Nicole Blijlevens, Allan Hovan, Eduardo Fregnani, Janet Fulton, Luiz Alcino Gueiros, Tanya Rouleau, Janet K.
Coller, Noor Al-Dasooqi, and Hannah Wardill. Other contributors include (in alphabetic order): Suzanne Ameringer, Héliton Spindola Antunes, Emma H. Bateman, Kivanc
Bektas, René-Jean Bensadoun, K. Ten Bohmer, Norman Brito-Dellan, Daniel Castillo, Karen Chiang, Charlotte de Mooij, June Eilers, Joel Epstein, Dimitra Galiti, Jane M.
Fall-Dickson, Margherita Gobbo, Hanan Issa Hazboun, Siri Beier Jensen, Jorgen Johansen, Jamie Joy, K. Joy, Abhishek Kandwal, Tomoko Kataoka, Dorothy Keefe, Charles L.
Loprinzi, Rachel Lubart, Anna Skripnik Lucas, Alessandra Majorana, Bronwen Mayo, Charlotte de Mooij, Takehiko Mori, Raj G. Nair, Narmin Nasr, Ourania Nicolatou-Galitis,
Giulia Ottaviani, Cesar Migliorati, Monica Pentenero, Lorraine Porcello, Douglas Peterson, Carin Potting, Judith Raber-Durlacher, Ysabella Z. A. van Sebille, Yoshihiko
Soga, Stephen Sonis, Andrea M. Stringer, Daniel Thorpe, Vanessa Tilly, Wim Tissing, Juan J. Toro, Nathaniel Simon Treister, Anusha Vaddi, Dianna Weikel, Marianne van de
Wetering, and Eyal Zur.
The MASCC/ISOO Mucositis Guidelines are developed to facilitate the evidence-based management of mucositis. Clinicians should also use their own judgment in
making treatment decisions for individual patients. The guideline authors and the MASCC/ISOO do not guarantee or take responsibility for clinical outcomes in individual
patients.
Additional supporting information may be found in the online version of this article.

DOI: 10.1002/cncr.33100, Received: April 13, 2020; Revised: May 25, 2020; Accepted: June 3, 2020, Published online July 28, 2020 in Wiley Online Library
­([Link])

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Original Article

eating and swallowing, the need for enteral or paren- as supporting evidence. A single RCT was considered
teral nutrition, increased opioid consumption, and in- insufficient to develop a guideline.
terruptions to cancer therapy.1,2 In immunosuppressed Studies comparing an agent with placebo were
patients, OM is associated with bacteremia, increased considered for the efficacy analysis, which focused on
inpatient hospitalization duration, and higher 100-day 4 types of effects: mucositis severity, mucositis dura-
mortality.1-3 GI mucositis is associated with nausea, tion, pain severity, and pain duration. Studies compar-
vomiting, diarrhea, bloating, intestinal cramping, and ing an agent with another active control were assessed
anal pain.4 separately.
Extensive research has been conducted globally to Findings from the reviewed studies were merged
prevent, treat, or alleviate the symptoms of mucositis. with the evidence reviewed in the previous MASCC/
To make use of the plethora of findings in an educated ISOO guideline update, thus covering the entire lit-
manner in the clinic, a systematic approach to weigh- erature. Findings were then organized into the new
ing the evidence and analyzing the clinical applicabil- guideline update based on the overall LoE for each in-
ity has been taken. The Multinational Association of tervention. Guidelines were classified as follows: recom-
Supportive Care in Cancer and International Society mendation, suggestion, or no guideline possible (NGP).
for Oral Oncology (MASCC/ISOO) conducted a sys- Negative guidelines were based on evidence showing
tematic review and first developed guidelines in 2004.5 lack of efficacy and not indicating that the agent is
The systematic review identified the interventions with harmful.
the strongest evidence and specified the clinical setting Guidelines were based on the following clinical set-
in which these interventions are most likely to be effec- tings: 1) the aim of the intervention (prevention or treat-
tive. These guidelines were updated in 2009 and 2014 ment), 2) the cancer treatment modality (RT, CT, RT-CT,
by the members of the Mucositis Study Group of the or high-dose conditioning therapy for HSCT), and 3) the
MASCC/ISOO.6,7 route of administration.
Considering the tremendous growth in mucositis Because of the large volume of literature, the proj-
research since the last guideline update, the MASCC/ ect was divided into 8 sections: 1) basic oral care; 2) an-
ISOO decided to perform a new systematic review and ti-inflammatory; 3) photobiomodulation (laser and other
update the clinical guidelines. The goal of this endeavor is light therapy); 4) cryotherapy; 5) antimicrobials, coating
to provide clinicians with a set of interventions for muco- agents, anesthetics, and analgesics; 6) growth factors and
sitis with strong evidence to support or refute their use in cytokines; 7) natural and miscellaneous agents; and 8) all
certain clinical circumstances. interventions for GI mucositis. The intervention keyword
list for each section is detailed in the article that provides
MATERIALS AND METHODS an overview of the methods.8
Our methods have been described in detail in a recent
publication.8 Briefly, a search for relevant papers in- RESULTS
dexed in the literature from January 1, 2011 to June 30, The literature search identified 14,690 articles, of which
2016 was conducted using PubMed/Web of Science/ 627 were retrieved for detailed evaluation. The evidence
EMBASE, with publications selected for review based from these articles was merged with 570 articles that were
on clear criteria. In addition, randomized clinical trials included in the previous systematic reviews.7 Taken to-
(RCTs) published between July 2016 and June 2019 gether, the guideline covers evidence from 1197 publica-
were reviewed. tions. The guidelines for each section are presented below.
Articles were reviewed by 2 independent review- For more detailed results, including lists of all reviewed
ers, and data were extracted using a standard electronic articles, please refer to the published article for each
form. Studies were scored for their level of evidence section.11-18
(LoE) based on the criteria reported by Somerfield and Guidelines that are new or were changed compared
McCrae,9 and flaws were listed according the criteria with the 2014 guidelines are discussed below and appear
reported by Hadorn et al.10 A study was considered to in Table 1. Guidelines for which there was new evidence
be well designed when no major flaws were identified but the statements remained unchanged appear in Table 1
according to the criteria of Hadorn et al. RCTs received only. The 2014 guidelines for which there was no new
the most attention, although non-RCTs were analyzed evidence appear in Supporting Table 1.

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MASCC/ISOO Mucositis Guidelines/Elad et al

TABLE 1. Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology
Clinical Practice Guidelines for Oral Mucositis

Section LoE Guideline Statement

BOC III • The panel suggests that implementation of multiagent combination oral care protocols is beneficial for the
prevention of OM during CT.
III • The panel suggests that implementation of multiagent combination oral care protocols is beneficial for the
prevention of OM during H&N RT.
III • The panel suggests that implementation of multiagent combination oral care protocols is beneficial for the
prevention of OM during HSCT.
III • No guideline was possible regarding the use of professional oral care for the prevention of OM in patients with
hematologic, solid, or H&N cancers because of limited and inconsistent data.
An expert opinion complements this guideline: Although there was insufficient evidence to support the use of profes-
sional oral care for OM prevention, the panel is of the opinion that dental evaluation and treatment as indicated
before cancer therapy are desirable to reduce risk for local and systemic infections from odontogenic sources.
III • No guideline was possible regarding the use of patient education for the prevention of OM in patients with
hematologic cancer during HSCT or CT because of limited and inconsistent data.
An expert opinion complements this guideline: The panel is of the opinion that educating patients about the ben-
efits of BOC strategies is still appropriate because this may improve self-management and adherence to the
recommended oral care protocol during cancer treatment.
III • No guideline was possible regarding the use of saline or sodium bicarbonate rinses in the prevention or treat-
ment of OM in patients undergoing cancer therapy because of limited data.
An expert opinion complements this guideline: Despite the limited data available for both saline and sodium
bicarbonate, the panel recognizes that these are inert, bland rinses that increase oral clearance, which may be
helpful for maintaining oral hygiene and improving patient comfort.
III • The panel suggests that CHX not be used in the prevention of OM in patients undergoing H&N RT.
Anti-inflammatory agents I • The panel recommends benzydamine mouthwash for the prevention of OM in patients with H&N cancer receiv-
ing a moderate dose RT (<50 Gy).
II • The panel suggests the use of benzydamine mouthwash for the prevention of OM in patients with H&N cancer
who receive RT-CT.
PBM I • The panel recommends the use of intraoral PBM therapy using low-level laser therapy for the prevention of OM
in adult patients receiving HSCT conditioned with high-dose CT, with or without TBI, using one of the selected
protocols listed in Table 2.
II • The panel recommends the use of intraoral PBM therapy using low-level laser therapy for prevention of OM in
adults receiving RT to the H&N (without CT) (Table 2); safety considerations unique to patients with oral cancer
should be considered.
I • The panel recommends the use of intraoral PBM therapy using low-level laser therapy for the prevention of OM
in adults receiving RT-CT for H&N cancer (Table 2); safety considerations unique to patients with oral cancer
should be considered.
• For all PBM guidelines, it is recommended that the specific PTPs of the selected protocol will be followed for
optimal therapy.
Cryotherapy II • The panel recommends using oral cryotherapy to prevent OM in patients undergoing autologous HSCT when
the conditioning includes high-dose melphalan.
II • The panel recommends using 30 min of oral cryotherapy to prevent OM in patients receiving bolus 5-FU CT
during the infusion of the CT.
Antimicrobials, coating agents, III • Topical morphine 0.2% mouthwash is suggested for the treatment of OM-associated pain in patients with H&N
anesthetics, and analgesics cancer who receive RT-CT.
II • Sucralfate (combined topical and systemic) is not recommended for the prevention of OM-associated pain in
patients with H&N cancer who receive RT.
II • Sucralfate (combined topical and systemic) is not recommended for the treatment of OM-associated pain in
patients with H&N cancer who receive RT.
II • Sucralfate (combined topical and systemic) is not recommended for the treatment of OM-associated pain in
patients with solid cancer who receive CT.
Growth factors and cytokines I • The use of KGF-1 intravenously is recommended for the prevention of OM in patients with hematologic cancer
undergoing autologous HSCT with a conditioning regimen that includes high-dose CT and TBI.
II • The evidence suggests that topical GM-CSF should not be used for the prevention of OM in patients undergo-
ing HSCT.
Natural and miscellaneous I • The panel recommends against the use of glutamine (parenteral) for the prevention of OM in patients undergo-
ing HSCT.
II • The panel suggests oral glutamine for the prevention of OM in patients with H&N cancer who receive receiving
RT-CT.
The suggestion is with caution because of the higher mortality rate seen in patients undergoing HSCT who receive
parenteral glutamine.
II • Honey is suggested for the prevention of OM in patients with H&N cancer who receive treatment with either RT
or RT-CT.
III • Chewing gum is not suggested for the prevention of OM in pediatric patients with hematological or solid cancer
who receive CT.

Abbreviations: 5-FU, 5-fluorouracil; BOC, basic oral care; CHX, chlorhexidine; CT, chemotherapy; GM-CSF, granulocyte-macrophage colony–stimulating factor;
Gy, grays; H&N, head and neck; HSCT, hematopoietic stem-cell transplantation; KGF-1, keratinocyte growth factor 1; LoE, level of evidence; OM, oral mucositis;
PBM, photobiomodulation; PTPs, photobiomodulation therapy parameters; RT, radiotherapy; TBI, total body irradiation.
a
For previous guidelines that are unchanged, see Supporting Table 1.

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Original Article

Basic Oral Care The suggestion against CHX for the prevention of
Basic oral care (BOC) includes all routine actions per- OM in patients undergoing RT to the H&N was main-
formed by the patient or care provider to reduce the bac- tained (Table 1). To clarify, this guideline only refers to
terial load in the oral cavity, to prevent infections, and to the effect of CHX on OM prevention; it does not exclude
provide comfort. This usually involves mechanical cleaning the other indications for CHX, such as prevention or
(tooth brushing, flossing), mouthwashes to reduce bacte- treatment of oral infection. If CHX is indicated because
rial build-up (bland rinses), and hydration and lubrication of concurrent oral infection and OM, it is acceptable to
(applying moisturizing agents) to the oral mucosal surfaces. use it for the oral infection. The new RCTs were based on
In this guideline update, the guidelines on BOC another patient population (RT-CT for H&N cancer)19
were divided into 5 subtopics11: or for another aim (treatment for OM rather than preven-
tion of OM).20
1. Patient education — educational interventions desi­ BOC remains an important best practice for pa-
gned to help patients understand the importance tients undergoing cancer treatments; however, as a re-
of oral care and to perform the recommended oral search area, there is limited evidence from high-quality,
practices during cancer therapy (this class of inter- rigorous studies. This was confirmed when patients with
vention is new to the guidelines); cancer were grouped according to treatment. To prevent
2. Multiagent combination oral care protocols — these misinterpretation of the guideline, the panel expanded it
protocols serve to increase the awareness of patients with expert opinion for the following areas: professional
and staff of the importance of good oral hygiene that oral care, patient education, and rinse with saline or so-
may lead to fewer and less severe oral complications; dium bicarbonate (Table 1). This approach was also used
typically, the protocols involved recommendations in the 2014 guidelines. In the current update, the phras-
with regard to the timing, frequency, and products ing differentiates between evidence-based guidelines and
used, which included various combinations of bland the panel’s expert opinions.
mouth rinses, toothbrushes, and flossing procedures;
3. Professional oral care — protocols delivered by dental Anti-Inflammatory Agents
professionals before or during cancer treatment; A new guideline was added for benzydamine12: a sugges-
4. Saline — saline rinses were compared with other types tion for the prevention of OM in patients with H&N
of bland rinses and chlorhexidine (CHX) rinses; cancer receiving RT and CT (Table 1).
5. Sodium bicarbonate — a mouthwash of sodium New data regarding other anti-inflammatory agents,
bicarbonate diluted in water was compared with other such as celecoxib, irsogladine maleate, misoprostol, and re-
bland rinses and CHX rinses; and bamipide, were found. The evidence for each of these agents
6. Chlorhexidine — CHX rinses were compared with was insufficient to support a guideline. Actually, when the
placebo rinses, bland mouth rinses, and other active- previous evidence was stratified according to the setting and
agent rinses. mode of application for misoprostol, there were too few
data to justify a positive or a negative guideline for a specific
The literature on mixed-medication mouth rinses was setting. Therefore, the 2014 suggestion against misopros-
reviewed but was excluded from analysis because of the tol mouthwash for the prevention of OM in patients with
heterogeneity of the ingredients. H&N cancer who received RT was reversed to NGP.
Several suggestions were made regarding multia-
gent combination oral care protocols for the prevention Photobiomodulation
of OM in patients during CT, RT to the head and neck The rapidly growing field of laser and light therapy using
(H&N), or HSCT (Table 1). Because the objective of low-level energy to stimulate biologic responses has been
these protocols was to increase awareness of the im- named photobiomodulation (PBM).21 Numerous RCTs
portance of oral hygiene and enhance compliance with and non-RCTs have been published about the application
routine BOC rather than test the effect of a particu- of PBM for the management of OM. The guideline de-
lar agent, we were able to formulate a suggestion for termination was influenced by RCTs that met strict clini-
each population of patients with cancer despite the rel- cal and scientific criteria; however, clinical studies with
atively small number of RCTs for each patient category. lower LoE were assessed and contributed to the guideline.
Furthermore, this trend was supported by numerous Studies with nonreproducible PBM therapy parameters
comparative studies. (PTPs) were excluded from guideline determination.

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MASCC/ISOO Mucositis Guidelines/Elad et al

The current guideline update has several new drugs to the oral tissue and reducing damage to the oral
insights13: mucosa. Considering that the cooling is temporary, this
treatment is only applicable for cytotoxic protocols that
1. A recommendation for the prevention of OM with are delivered over a short time or for cytotoxic agents with
intraoral PBM therapy in patients who undergo a short half-life.
HSCT (Tables 1 and 2)13—the current systematic The panel identified evidence to support a recom-
review reiterates the 2014 guidelines in this patient mendation guideline for 2 clinical situations (Table 1).
population and increases the range of PBM settings The new evidence enhanced the LoE for HSCT and
that may be used22; strengthened both 2014 guidelines.18
2. A recommendation for the prevention of OM with
intraoral PBM therapy in patients with cancer who Antimicrobials, Coating Agents,
receive H&N RT (without CT) (Tables 1 and 2)—this Anesthetics, and Analgesics
is an upgrade of the 2014 guidelines from a suggestion New evidence was identified for the following agents:
to a recommendation22; morphine (topical), sucralfate (topical/systemic), flu-
3. A recommendation for the prevention of OM with conazole (systemic), miconazole (topical and systemic),
intraoral PBM therapy in patients with cancer who re- mucoadhesive hydrogel (topical; MuGard), polyvi-
ceive H&N RT with CT (Tables 1 and 2)—this new nylpyrrolidone (topical; Gelclair), doxepin (topical),
guideline is based on recent evidence. and fentanyl (transdermal).17 The new evidence sup-
ported the suggestion in favor of topical morphine
In addition to the understanding described in the (Table 1).17
guidelines above, the critical review identified several New studies on sucralfate did not pertain to the
flawless studies suggesting that PBM could prevent clinical settings referred to in the 2014 guidelines.
OM in specific patient populations. These protocols Accordingly, the recommendations against sucralfate
are highlighted (Table 2) with a clarification that the for 3 clinical settings remained unchanged. A clarifica-
PBM settings mentioned in these protocols should be tion was added to the guideline explaining that it refers
followed exactly to optimize clinical efficacy. In other to the combined topical application and systemic ad-
words, each of the 5 suggested protocols stands alone. ministration of sucralfate (Table 1). in contrast, a pre-
Individual variations may be considered for a particular vious recommendation against the use of sucralfate for
patient; however, it is unclear how this will affect the the prevention of CT-associated OM was reversed to
clinical outcome. NGP in the current guidelines. It should be noted that
We identified several RCTs aimed at the treatment these guidelines do not refer to the new formulation of
of OM in pediatric patients undergoing mixed RT/RT- sucralfate that has become available (polymerized cross-
CT, mixed HSCT/CT, or CT for several types of cancer. linked sucralfate).
The results were promising; however, it is too early to base In the previous review, a suggestion was made in
a guideline on these findings. favor of doxepin mouthwash and for transdermal fentanyl.
Several authors suggested that PBM may have Considering the stringent criteria needed for a guideline
long-term carcinogenic effects.13,23 Recent long-term and the mixed study population in some of the relevant
follow-up studies on patients treated with PBM for studies, the updated guideline was changed to NGP.
the prevention of OM showed no increase in can- The previous 2014 recommendations against
cer recurrence. However, the analysis of these data is Iseganan, polymyxin, tobramycin, and amphotericin B
challenging.24,25 Considering the conflicting evidence (PTA) paste; and bacitracin, clotrimazole, and gentamicin
from animal models regarding the effect of PBM on (BCoG) lozenges remain unchanged because there were
tumor behavior, the clinician is advised to inform pa- no new data (see Supporting Table 1).17
tients about the expected benefits and potential risks of
PBM.23,26 Growth Factors and Cytokines
New evidence was identified for the following agents: ke-
Cryotherapy ratinocyte growth factor-1, granulocyte-colony stimulat-
Cryotherapy results in vasoconstriction of the superficial ing factor, granulocyte-macrophage colony-stimulating
blood vessels, thereby limiting the delivery of cytotoxic factor, epidermal growth factor, and erythropoietin.27

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Original Article

TABLE 2. Recommended Intraoral Photobiomodulation Therapy Protocols for the Prevention of Oral
Mucositisa

Cancer
Treatment Power Density Time per Energy Density
Modality Wavelength, nm (Irradiance), mW/cm2 Spot, s (Fluence), J/cm2 Spot Size, cm2 No. of Sites Duration
HSCT 632.8 31.25 40 1.0 0.8 18 From the d after ces-
sation of condition-
ing for 5 d
650 1000b 2 2.0 0.04 54-70 From the first d of
conditioning to d +
2 post-HSCT (for
7-13 d)
RT 632.8 24 125 3.0 1.00 12 Entire RT course
RT-CT 660 417b 10 4.2 0.24 72 Entire RT course
660 625b 10 6.2 0.04 69 Entire RT course

Abbreviations: CT, chemotherapy; HSCT, hematopoietic stem-cell transplantation; RT, radiotherapy.

a
For details, see Zadik et al, 2019.13
b
This involves a potential thermal effect; the clinician is advised to pay attention to the specific parameters.

The new evidence published for human recombi- In this guideline update, supersaturated calcium
nant keratinocyte growth factor-1 did not change the phosphate was included in the Natural and Miscellaneous
2014 guideline for this agent (Table 1).28 section. Because of conflicting evidence about this mouth-
The new data about granulocyte-macrophage col- wash in various populations of patients with cancer, no
ony–stimulating factor addressed a novel clinical setting; guideline was possible.15
therefore, the previous guideline has not been changed Honey, applied topically and administered system-
(Table 1).27 ically, has been suggested for the prevention of OM in
patients with H&N cancer who received either RT or RT-CT
Natural and Miscellaneous Agents (Table 1). Some of the RCTs had a mixed patient population
New evidence about the effects of various vitamins, min- (RT and RT-CT), small sample size, and different sources for
erals, and nutritional supplements on OM was assessed, the honey; therefore, only a suggestion was possible.
including glutamine, elemental diet, zinc, supersaturated New evidence was identified for several natural rem-
calcium phosphate rinse, vitamin E, selenium, folinic edies and herbs. However, it was insufficient to form a
acid, and calcitriol. guideline (a list is available in Supporting Table 2).15
A recommendation against the use of parenteral glu- New evidence about saliva stimulants and artificial
tamine in patients who undergo HSCT for the preven- moistening agents was reviewed as part of this update.15
tion of OM was determined (Table 1).15 The change from The lubricating effect of saliva as well as the protective pro-
the 2014 guidelines was an elevation of the LoE from II teins and growth factors in saliva (epidermal growth factor
to I after the publication of a well designed RCT.29 A new and fibroblast growth factor) could promote wound heal-
suggestion was made regarding oral glutamine tablets in ing. However, there was sufficient evidence that chewing
patients with H&N cancer who received RT-CT for the gum is not effective for the prevention of OM in pediatric
prevention of OM (Table 1). This guideline is based on patients with hematologic or solid cancers who received
2 RCTs showing that a glutamine dose from 10 to 30 mg with CT. Therefore, a suggestion against chewing gum was
daily during RT-CT may prevent OM. This guideline made (Table 1). This guideline does not preclude the use
for oral glutamine mentions the negative guideline for of chewing gum for any other purpose: saliva production,
parenteral glutamine and advises caution because of the flavor, refreshment, or simply pleasure.
higher relapse and mortality rates reported in 1 study of The previous guidelines (suggestion against) for pi-
patients who underwent HSCT and received parenteral locarpine and pentoxifylline in specific settings remain
glutamine.30 valid (see Supporting Table 1).7
The previous suggestion made for zinc in the 2014
MASCC/ISOO guidelines for patients with H&N cancer All Interventions for GI Mucositis
who received RT or RT-CT was reversed in the current The suggestions in favor of probiotics and hyperbaric
guidelines to NGP.7,15,31 oxygen were maintained (Table 3).14 The 2014 guidelines

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MASCC/ISOO Mucositis Guidelines/Elad et al

TABLE 3. Multinational Association of Supportive challenges also may play a role in the selection of the pre-
Care in Cancer and International Society of ferred treatment. Therefore, it is clear that the application
Oral Oncology Clinical Practice Guidelines for
of the guidelines will need to be adjusted according to the
Gastrointestinal Mucositisa
individual clinic’s considerations and patient’s preference.
LoE Guideline In the 16 years since publication of the first MASCC/
III The panel suggests that probiotics containing Lactobacillus ISOO Mucositis Guidelines, the landscape of mucositis
spp. may be beneficial for the prevention of RT-induced or research has changed.5 Over the years, we have noticed a
RT-CT–induced diarrhea in patients with pelvic malignancy.
II The panel suggests that hyperbaric oxygen is an effective dramatic increase in the number of interventions studied
way to treat RT-induced proctitis in patients with pelvic for mucositis and in the quality of the study design used
malignancy.
to assess the efficacy of these interventions. Our knowl-
Abbreviations: CT, chemotherapy; LoE, level of evidence; RT, radiotherapy.
a
edge on the pathogenesis of OM has also improved.32
For previous guidelines that are unchanged, see Supporting Table 1.
Although we reviewed a large body of evidence, there are
in favor of amifostine, octreotide, sucralfate enemas, and still clinical settings for which there is no recommended
sulfasalazine and the 2014 guidelines against the use of intervention. Until more research is available, pain relief,
oral 5-acetyl salicylic acid and related compounds (mesala- dietary support, and secondary infection prevention are
zine and olsalazine), oral sucralfate, and misoprostol sup- key elements in patient management.
positories in specific treatment settings were unchanged As the number of positive guidelines increases,
(see Supporting Table 1). it should be noted that they are not presented in order
New evidence was identified for antimicrobials (ci- of preference. All effective interventions for the specific
profloxacine and metronidazole), famotidine, a fat-mod- clinical setting described are reasonable. In addition, the
ified diet, formalin, glutamine, fiber, palifermin, sodium guidelines do not preclude other interventions that work
butyrate, and steroid. Because of inadequate and/or well in the hands of a clinician.
conflicting evidence, no guideline was possible for these Evidently, the biggest step up in the search for ef-
agents.14 fective therapy for mucositis was in the field of PBM.13
The current guidelines are based on stronger evidence,
address more clinical settings, and offer more PBM proto-
DISCUSSION
cols. Although the calibration of various PBM protocols
The MASCC/ISOO guidelines for the management of
was enigmatic, we advised that each protocol be applied
mucositis are a weighted summary of the best available sci-
as a whole. Research about the principles for calibration
entific evidence, framed in a practical clinical context. This
between various wavelengths and various PTPs will open
update of the guidelines was based on an extensive, system-
the door for many more effective PBM protocols.
atic review using meticulous methods that contribute to
Other types of mucositis have recently been reported
the robustness of the conclusions. Thirteen new guidelines
in association with targeted therapy and immunother-
were delineated, 11 previous guidelines were confirmed
apy. Although these types of mucositis meet the Medical
after a review of new evidence, and 13 previously estab-
Subject Heading definition of mucositis, they are not
lished guidelines were carried over to this version because
covered in the current set of clinical practical guidelines.
no new evidence was available for these interventions.
A long-term OM complication of cancer therapy was re-
Some of the interventions reported in this system-
cently reported called chronic OM33 and is not addressed
atic review have various formulas (eg, glutamine), may be
in this guidelines update.
absorbed differently, depending on the compound (eg,
The ultimate goal of these guidelines is to improve
zinc), may be manufactured from various sources (eg,
the supportive care for patients with cancer and provide
honey), or may be delivered over various time periods
directions for future trials. As new research is conducted,
(eg, cryotherapy). These factors may influence the clinical
new evidence will become available. To this end, the
outcome. To simplify the analysis and its implications the
Mucositis Study Group of the MASCC/ISOO plans to
information was generalized. These differences have been
continue updating the guidelines periodically.
clarified in the detailed articles.11-18,27
Furthermore, some of the interventions may only
be available in certain geographic areas (eg, certain FUNDING SUPPORT
Multinational Association of Supportive Care in Cancer and International
herbal compounds) or may have different regulations Society for Oral Oncology supported this project according to the
determined by local drug agencies (eg, PBM). Economic Multinational Association of Supportive Care in Cancer guidelines policy.

Cancer   October 1, 2020 4429

 10970142, 2020, 19, Downloaded from [Link] by Cochrane Portugal, Wiley Online Library on [02/07/2024]. See the Terms and Conditions ([Link] on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Original Article

CONFLICT OF INTEREST DISCLOSURES 8. Ranna V, Cheng KKF, Castillo DA, et al. Development of the MASCC/
According to Multinational Association of Supportive Care in Cancer ISOO clinical practice guidelines for mucositis: an overview of the
(MASCC) guidelines policy, employees of commercial entities were not methods. Support Care Cancer. 2019;27:3933-3948.
eligible to serve on this MASCC Guidelines Panel. Sharon Elad reports 9. Somerfield MR, McCrae RR. Stress and coping research.
consultation fees from Falk Pharma, outside the submitted work. Rajesh V. Methodological challenges, theoretical advances, and clinical applica-
Lalla reports institutional research support from Novartis, Oragenics, and tions. Am Psychol. 2000;55:620-625.
Sucampo Pharma, outside the submitted work; grants and personal fees from 10. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the qual-
Galera Therapeutics, outside the submitted work; personal fees from Alira ity of evidence for clinical practice guidelines. J Clin Epidemiol.
Health, Colgate Oral Pharmaceuticals, Eagle Pharma, Enlivity, Ingalfarma 1996;49:749-754.
SA, Meiji Seika Pharma, Monopar Therapeutics, Mundipharma, and 11. Hong CHL, Gueiros LA, Fulton JS, et al. Systematic review of basic
Sucampo Pharma, outside the submitted work; stock ownership in Logic oral care for the management of oral mucositis in cancer patients and
Biosciences; and has a patent pending (WO 2019/217536 A2; University clinical practice guidelines. Support Care Cancer. 2019;27:3949-3967.
of Connecticut, applicant). Deborah P. Saunders reports institutional 12. Ariyawardana A, Cheng KKF, Kandwal A, et al. Systematic review of
research support from Galera Therapeutics. Paolo Bossi reports personal anti-inflammatory agents for the management of oral mucositis in
fees from Merck Serono, Roche, Sanofi, Merck Sharp & Dohme, Sun cancer patients and clinical practice guidelines. Support Care Cancer.
Pharma, AstraZeneca, Kyowa Hakko Kyrin, AstraZeneca, Bristol-Myers 2019;27:3985-3995.
Squibb, Helsinn, and Glaxo-Smith-Kline, outside the submitted work. The 13. Zadik Y, Arany PR, Fregnani ER, et al. Systematic review of photobio-
remaining authors made no disclosures. modulation for the management of oral mucositis in cancer patients and
clinical practice guidelines. Support Care Cancer. 2019;27:3969-3983.
14. Bowen JM, Gibson RJ, Coller JK, et al. Systematic review of agents
for the management of cancer treatment-related gastrointestinal mu-
AUTHOR CONTRIBUTIONS cositis and clinical practice guidelines. Support Care Cancer. 2019;27:
Sharon Elad: Conception and design, collection of data, assembly of data, 4011-4022.
data analysis and interpretation, and writing, review and revision. Karis 15. Yarom N, Hovan A, Bossi P, et al. Systematic review of natural and
Kin Fong Cheng: Conception and design, collection of data, and writing, miscellaneous agents for the management of oral mucositis in cancer
review and revision. Rajesh V. Lalla: Conception and design, collection patients and clinical practice guidelines-part 1: vitamins, minerals, and
of data, data analysis and interpretation, and writing, review and revision. nutritional supplements. Support Care Cancer. 2019;27:3997-4010.
Noam Yarom: Collection of data, assembly of data, data analysis and inter- 16. Yarom N, Hovan A, Bossi P, et al. Systematic review of natural and
pretation, and writing, review and revision. Catherine Hong: Collection miscellaneous agents, for the management of oral mucositis in cancer
of data, assembly of data, data analysis and interpretation, and writing, patients and clinical practice guidelines—part 2: honey, herbal com-
review and revision. Richard M. Logan: Collection of data, assembly of pounds, saliva stimulants, probiotics, and miscellaneous agents. Support
data, and writing, review and revision. Joanne Bowen: Conception and Care Cancer. 2020;28:2457-2472.
design, collection of data, assembly of data, data analysis and interpreta- 17. Saunders DP, Rouleau T, Cheng K, et al. Systematic review of anti-
tion, and writing, review and revision. Rachel Gibson: Collection of data, microbials, mucosal coating agents, anesthetics, and analgesics for the
assembly of data, data analysis and interpretation, and writing, review and management of oral mucositis in cancer patients and clinical practice
revision. Deborah P. Saunders: Collection of data and writing, review and guidelines. Support Care Cancer. 2020;28:2473-2484.
revision. Yehuda Zadik: Collection of data, assembly of data, data analysis 18. Correa MEP, Cheng KKF, Chiang K, et al. Systematic review of oral
and interpretation, and writing, review and revision. Anura Ariyawardana: cryotherapy for the management of oral mucositis in cancer patients and
Collection of data, assembly of data, data analysis and interpretation, and clinical practice guidelines. Support Care Cancer. 2020;28:2449-2456.
writing, review and revision. Maria Elvira Correa: Collection of data, 19. Diaz-Sanchez RM, Pachon-Ibanez J, Marin-Conde F, Rodriguez-
assembly of data, data analysis and interpretation, and writing, review and Caballero A, Gutierrez-Perez JL, Torres-Lagares D. Double-blind, ran-
revision. Vinisha Ranna: Conception and design, collection of data, and domized pilot study of bioadhesive chlorhexidine gel in the prevention
writing, review and revision. Paolo Bossi: Conception and design, collec- and treatment of mucositis induced by chemoradiotherapy of head and
tion of data, data analysis and interpretation, and writing, review and revi- neck cancer. Med Oral Patol Oral Cir Bucal. 2015;20:e378-e385.
sion. All authors were accountable for all aspects of the work and approved 20. Roopashri G, Jayanthi K, Guruprasad R. Efficacy of benzydamine hy-
the final version of the article. drochloride, chlorhexidine, and povidone iodine in the treatment of
oral mucositis among patients undergoing radiotherapy in head and
neck malignancies: a drug trial. Contemp Clin Dent. 2011;2:8-12.
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