Oral Toxicity Associated With Chemotherapy

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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Oral toxicity associated with systemic anticancer therapy

Authors: Robert S Negrin, MD, Nathaniel S Treister, DMD, DMSc, DABOM
Section Editor: Reed E Drews, MD
Deputy Editor: Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Dec 19, 2022.
INTRODUCTION
Oral complications resulting from systemic anticancer therapy include mucositis, saliva
changes, taste alterations, infection, and gingival bleeding. [1,2]. All of these complications can
cause pain and/or impair nutrition.
Disruptions in the function and/or integrity of the mucosal lining of the gastrointestinal tract
are a particularly important problem in patients receiving chemotherapy. Mucositis, which
reflects a short-term, self-limited adverse effect of treatment, can affect the entire alimentary
tract. The range of symptoms includes oral ulcerations, dysphagia and odynophagia,
esophagitis, gastritis, diarrhea, and malabsorption.
Chemotherapy-associated acute oral toxicity will be reviewed here. Oral mucositis in the setting
of high-dose chemotherapy and hematopoietic cell transplantation is discussed in detail
elsewhere, as are radiation-induced oral mucositis, osteonecrosis of the jaw related to use of
antiresorptive therapy and angiogenesis inhibitors in patients with advanced cancer, and late
oral toxicities in cancer survivors. (See "Management and prevention of complications during
initial treatment of head and neck cancer" and "Management and prevention of complications
during initial treatment of head and neck cancer", section on 'Mucositis' and "Oral health in
cancer survivors" and "Medication-related osteonecrosis of the jaw in patients with cancer" and
"Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
MUCOSITIS
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Oral mucositis affects on average 20 to 40 percent of patients receiving conventional-dose

cytotoxic chemotherapy [3-5]. The frequency is higher (up to 80 percent) in those undergoing
hematopoietic cell transplantation (HCT), particularly myeloablative allogeneic HCT, and in
those who are prepared with radiation-containing regimens and with the use of methotrexate
for graft-versus-host disease prophylaxis. An exception is in the setting of reduced-intensity or
non-myeloablative allogeneic HCT, where mucositis is rare. (See "Early complications of
hematopoietic cell transplantation", section on 'Oral mucositis'.)
Pathobiology — The pathobiology underlying damage to the oral mucosal barrier is complex,

and a series of stages has been described in patients treated with conventional cytotoxic
chemotherapy agents, summarized as follows [3-5]:
● Initiation – Chemotherapy and radiation therapy damage both DNA and non-DNA targets,
both as a direct effect and mediated through reactive oxygen species.
● Upregulation and generation of messenger signals – The initial injury activates the
transcription factor nuclear factor-kappa B, leading to the production of a variety of
biologically active proteins, including proinflammatory cytokines.
● Signaling and amplification – As proinflammatory cytokines accumulate, they damage

surrounding tissues directly, and the effect is amplified via feedback loops. This phase
precedes the development of overt clinical mucositis.
● Ulceration and inflammation – Loss of mucosal integrity results in clinically painful lesions
and allows secondary bacterial colonization.
● Healing – Mucositis generally is self-limited, and healing begins once the tissue insult is
withdrawn.
Etiology and risk factors — Multiple factors influence the extent and severity of mucositis,
including the specific drug, dose, route and frequency of administration, individual patient
tolerance, genetic variants in drug metabolizing pathways, immune signaling and cell
injury/repair mechanisms, and possibly smoking history [6]. The most robust data support
dosimetric parameters as key predictors of mucositis risk. A comprehensive list of cancer
treatment drugs with the potential to cause oral mucositis is provided in the following table
( table 1).
Specific anticancer agents
● Cytotoxic chemotherapy agents – In general, chemotherapeutic agents that are DNA cell
cycle specific (eg, bleomycin, fluorouracil [FU], and methotrexate) are more stomatotoxic
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than those that are cell phase nonspecific (eg, cyclophosphamide, cisplatin,
anthracyclines) [7]. Certain drugs (eg, methotrexate, etoposide) may be secreted into the
saliva [8-10], and it is postulated that this might increase the potential for stomatotoxicity.
The conventional cytotoxic drugs used to treat cancer that are most commonly associated
with mucositis are:
• Cytarabine
• Doxorubicin
• Etoposide (high-dose)
• Melphalan (high-dose)
• FU (bolus administration schedules)
• Methotrexate
● Molecularly targeted agents – The range of reported rates of stomatitis in patients

receiving molecularly targeted agents is broad, and depends on the class of agent:
• Oral mucositis is reported in 30 to 40 percent of patients receiving therapy with the

molecularly targeted agents sunitinib, sorafenib, lenvatinib, and regorafenib (which are
orally active receptor tyrosine kinase inhibitors that target, among others, vascular
endothelial growth factor receptors), in 25 percent of patients treated with the cyclin-
dependent kinase 4/6 inhibitor palbociclib, in 20 percent of patients treated with the
poly (ADP-ribose) polymerase (PARP) inhibitor niraparib, and in 10 to 46 percent of
patients treated with agents that target the epidermal growth factor receptor (EGFR),
such as cetuximab, erlotinib, dacomitinib, and mobocertinib; most cases are mild to
moderate [11-13].
• Higher rates of stomatitis (72 percent all grade, 9 percent grade 3 or worse) are
reported with afatinib, which blocks signaling from the EGFR1, (erbB1), EGFR2
(HER2/erbB2), and erbB4 [14], and with the oral fibroblast growth factor receptor
inhibitors erdafitinib (56 percent all grade, 9 percent grade 3 or worse), and infigratinib
(56 percent all grade, 15 percent grade 3 or 4) [15,16]. Most cases with all of these
agents are mild. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-
cardiovascular effects", section on 'Oral toxicity'.)
• In addition, oral mucosal lesions (both typical ulcerations caused by loss of mucosal
integrity and discrete aphthous-like ulcerations with an underlying inflammatory
mechanism) have been seen in up to 73 percent of patients treated with the
mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors
temsirolimus and everolimus; they are severe (grade 3 or worse, ( table 2)) in
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approximately 4 to 8 percent [12,17-25]. In a review, mTOR inhibitor-associated

stomatitis was the most frequent adverse event overall associated with these drugs (73
percent), accounted for almost 30 percent of dose reductions, and was the most
frequent dose-limiting toxicity (53 percent) [25].
● Immune checkpoint inhibitors – Mucosal toxicities associated with the use of immune
checkpoint inhibitors include periodontal disease and stomatitis, as well as oral lichen
planus, xerostomia, and rarely, a Sjögren's-like syndrome affecting the salivary glands, and
mucous membrane pemphigoid-like lesions [26,27]. This subject is discussed in detail
elsewhere. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors",
section on 'Mucosal toxicities'.)
Preexisting oral disease — Oral disease that is present prior to treatment is thought to

increase the risk of chemotherapy-induced mucositis. Within the general population, up to 75
percent have chronic periodontal disease [28-30]. (See "Epidemiology, pathogenesis, and
clinical manifestations of odontogenic infections".)
A number of dental conditions have been causally linked with an increased risk for
stomatotoxicity, based upon empiric evidence and published data [31,32]. These include:
● Poor oral hygiene

● Caries and associated periapical pathology
● Periodontal disease
Other factors — Younger patients have a relatively greater risk of chemotherapy-induced

stomatitis, perhaps related to a higher epithelial mitotic rate [33]. Other factors that may
modulate the severity of stomatitis include nutritional status, the specific treatment protocol,
the quality of oral care during treatment, pretreatment neutrophil counts, the use of
hematopoietic growth factor support during therapy, and differences in the oral microbiome
[5,32,34,35].
A role for genetic susceptibility (eg, inherited polymorphisms in drug-metabolizing enzymes

and proinflammatory cytokines) is likely but not yet proven [36-38].
Clinical manifestations
● Conventional cytotoxic agents – For conventional cytotoxic agents, direct stomatotoxic

effects typically start at day 7 and peak by day 10 to 14.
The initial clinical manifestation is soft tissue erythema of the buccal mucosa or soft palate
with a burning sensation in the mouth. This stage may be followed by the development of
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solitary, elevated, white desquamative patches that are slightly painful. With further
progression, epithelial sloughing results in multiple shallow ulcerations with a
pseudomembranous appearance ( picture 1), which coalesce to form large, painful
ulcerations and cause dysphagia and reduced oral intake.
The severity ranges from mild mouth soreness with a paucity of clinical findings to severe
erosive mucositis that is accompanied by severe pain and an inability to eat or drink.
Severe pseudomembranous or erosive mucositis can lead to secondary infection or sepsis
(particularly in the presence of concomitant neutropenia), and necessitate the use of
parenteral nutrition and/or opiates. In addition, oral or gingival bleeding can occur if the
patient becomes thrombocytopenic. Occasionally, pain may precede the mucosal changes.
(See 'Infectious complications' below.)
Mucositis is typically a self-limited phenomenon. Following conventional cytotoxic

chemotherapy, which is typically administered episodically in cycles, the mucosal lesions
spontaneously begin to resolve within several days and are usually completely healed
within 10 to 14 days after onset, frequently improvement is concurrent with neutrophil
recovery [30]. Severe (grade 3 or 4) symptoms may necessitate dose reduction during
subsequent treatment cycles. However, only rarely is cessation of therapy required
because of severe mucosal toxicity (eg, in a patient with dihydropyrimidine
dehydrogenase deficiency who is receiving FU). (See "Chemotherapy-associated diarrhea,
constipation and intestinal perforation: pathogenesis, risk factors, and clinical
presentation", section on 'Fluorouracil'.)
● Molecularly-targeted agents – In general, the oral mucositis seen with molecularly

targeted agents tends to be of a lesser severity than with conventional cytotoxic agents
[12,39]. (See 'Specific anticancer agents' above.)
The time to onset is typically earlier (two to three days after treatment initiation) with
molecularly targeted agents, especially with mTOR inhibitors. With episodic administration
(eg, cetuximab), mucositis is typically self-limited. However, for tyrosine kinase inhibitors
that are dosed continuously on a daily basis, mucositis may be continuous, although it
may lessen over time or with weeks off of therapy, depending on the specific agent.
The clinical appearance is distinct from that associated with conventional cytotoxic agents.
It is almost exclusively aphthous-like and well-defined ( picture 2 and picture 3).
● Immune checkpoint inhibitors –The mucositis associated with immune checkpoint

inhibitors has a variable presentation, but often with lichenoid features. Oral lichenoid
reactions typically present with reticulate, white streaks (Wickham striae) or erosive
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lesions. While the mucositis is potentially severe, it is generally low-grade. This subject is
discussed in detail elsewhere. (See "Mucocutaneous toxicities associated with immune
checkpoint inhibitors", section on 'Mucosal toxicities'.)
Grading severity — A variety of grading systems incorporating both subjective and objective
criteria have been utilized to define the severity of mucositis. The most commonly used, the
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), grades
the severity of mucositis on a scale from 1 to 5, based upon the clinical findings and
symptomatology; the most recent version is outlined in the table ( table 2).
The World Health Organization also has a grading scale, as follows:
● Grade 0 – No oral mucositis

● Grade 1 – Erythema and soreness
● Grade 2 – Ulcers; able to eat solid food
● Grade 3 – Ulcers; but requires liquid diet (due to mucositis)
● Grade 4 – Ulcers; alimentation not possible due to mucositis
Another scale, the University of Nebraska Oral Assessment Score, has been used to evaluate the
clinical course of mucositis in recipients of high-dose therapy and HCT [40]. It assigns a numeric
grade to eight different aspects of the oral assessment (possible range of scores, 8 to 24).
Patients with higher peak mucositis scores (≥18 versus <18) had a significantly greater
incidence of positive blood cultures (60 versus 30 percent) and a higher transplant-related
mortality rate (24 versus 4 percent). (See "Early complications of hematopoietic cell
transplantation", section on 'Oral mucositis'.)
Infectious complications — An intact oral mucous membrane creates a physical barrier to

pathogens and provides clearance of adhering microorganisms through the regular sloughing
of surface epithelial cells [4]. Breakdown of the mucosal barrier predisposes to bacterial, fungal
(especially Candida albicans), and viral superinfection, particularly as the hematologic nadir is
reached after chemotherapy. The incidence and severity of infectious complications rise when
the absolute neutrophil count (ANC) falls below 1000/microL.
An altered mucosal barrier can serve as the portal of entry for translocation of a variety of
pathogens, including viruses, fungi, and bacteria into the bloodstream [3,41,42]. A relationship
between mucositis and systemic bacteremia was shown in a study of 69 patients undergoing
autologous HCT [42]. Patients who developed alpha hemolytic streptococcal bacteremia (n = 24)
were significantly more likely to have ulcerative mucositis (62 versus 36 percent), and in turn,
the presence of ulcerative mucositis increased the likelihood of developing bacteremia
threefold.
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Oral candidiasis — As noted above, the most common superinfecting organism in

patients with chemotherapy-induced mucositis is Candida albicans. Many of these patients are
already at risk for superficial oral candidiasis because they are immunocompromised as a result
of their advanced cancer.
Mucositis also increases the risk that a superficial infection will disseminate [7,43]. As an
example, in one series of patients undergoing high-dose chemotherapy for acute leukemia,
systemic fungemia occurred almost exclusively in those with prior oropharyngeal candidiasis
[43]. (See "Esophageal candidiasis in adults".)
Superficial oropharyngeal candidiasis can be treated topically with clotrimazole troches or

nystatin suspension. Systemic therapy with oral fluconazole is generally not needed unless the
patient cannot tolerate topical therapy. Refractory infection may require oral or parenteral
fluconazole, or parenteral amphotericin B. (See "Oropharyngeal candidiasis in adults".)
HSV reactivation — Given the high risk of reactivation, antiviral prophylaxis is indicated

for herpes simplex virus (HSV)-seropositive patients who are undergoing either induction
chemotherapy for acute leukemia or receiving high-dose "conditioning" regimens followed by
HCT.
In the absence of antiviral prophylaxis, the oral cavity can be affected by viral pathogens. The
most common is reactivation of HSV type 1 infection, which occurs in 65 to 90 percent of
seropositive patients receiving high-dose chemotherapy followed by HCT [44].
Infection with HSV should be considered in the differential diagnosis of any patient who
presents with mucosal vesicles or unusually painful oral ulcerations after chemotherapy,
particularly if candidiasis is not clinically evident. Compared with the oral lesions typically
associated with mucositis, the erosions associated with HSV reactivation are more atypical,
irregular, and shallow, with a high degree of symptoms, with lesions more likely to present on
the keratinized (ie, gingiva, tongue dorsum, hard palate) as compared with nonkeratinized
mucosa. A swab of one of the lesions can be sent for viral culture; HSV is usually isolated within
72 hours. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus
type 1 infection".)
Particularly among patients who are HSV-1 seropositive with moderate to severe mucositis,
empiric antiviral therapy (ie, parenteral or oral acyclovir, or oral valacyclovir) can be initiated
while awaiting culture results [44]. In studies involving immunocompromised hosts with
mucocutaneous HSV infection (but not limited to those undergoing chemotherapy), the
administration of acyclovir (250 mg/m2 intravenous [IV] every eight hours) for seven days
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produced significantly shorter periods of viral shedding, more rapid lesion healing, and
decreased pain [45,46].
Antiviral treatment for HSV infection and prophylaxis for HCT recipients are discussed in detail
elsewhere. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent
adolescents and adults" and "Prevention of infections in hematopoietic cell transplant
recipients", section on 'Antiviral prophylaxis or pre-emptive therapy'.)
Management
Prophylactic oral care — For most patients we suggest prophylactic oral care during systemic
anticancer treatment, including a comprehensive oral examination before treatment initiation.
This recommendation is consistent with joint updated guidelines from the Multinational
Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)
[47,48] and the European Society of Medical Oncology (ESMO) [49].
● Prophylactic oral care – A comprehensive oral examination before the initiation of cancer
therapy is desirable for all patients if feasible [31]. A program of aggressive preventive oral
care appears to diminish the incidence of all oral complications of chemotherapy,
although the available data on the benefits for prevention of oral mucositis are limited [50-
54]. As an example:
• A benefit for weekly prophylactic oral care (teeth surface cleaning, scaling, and tongue
cleaning) was shown in a small randomized controlled trial conducted in 169 women
with metastatic breast cancer treated with everolimus [54]. Fewer patients who
received prophylactic oral care had grade 2 or worse mucositis (34 versus 54 percent),
and fewer had everolimus dose reduction because of a severe adverse effect (22 versus
32 percent), the most common of which was stomatitis.
• However, all studies examining the prophylactic benefit of oral care protocols have
major flaws, and a 2019 systematic review by the MASCC/ISOO concluded that no
guideline was possible regarding the use of professional oral care to prevent oral
mucositis in patients undergoing systemic anticancer therapy [47]. Nevertheless, an
expert guideline panel also concluded that, despite the lack of data, dental evaluation
and treatment prior to cancer therapy are desirable to reduce the patient's risk for local
and systemic infections from odontogenic sources [48].
Pretherapy oral hygiene protocols should include scaling and root planing, caries
treatment, and endodontic therapy, if needed. In cases of severe odontogenic pathology,
tooth extraction should be considered.
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● Pulpoperiapical disease – Periapical radiolucencies may represent pulpoperiapical dental

infection, especially in the presence of caries. However, these radiographic lucencies can
also be associated with other noninfectious conditions, such as postendodontic healing of
a treated infection in which the bone does not fill back in or, rarely, leukemic infiltrates at
dental root apices [7]. Thus, the incidental finding of an asymptomatic periapical
radiolucency requires no specific prechemotherapy intervention [55,56]. Dental or
endodontic therapy should be pursued only in patients with signs and/or symptoms that
are consistent with acute periapical infection [7].
● Periodontal disease – Pretherapy dental treatment is often recommended to eliminate

potential sources of odontogenic infection. However, few outcome-oriented trials have
been conducted that support prechemotherapy treatment of chronic periodontal disease
[34]:
• In one trial, 166 patients were randomly assigned to limited or intensive oral hygiene
care to prevent mucositis during high-dose therapy and HCT [57]. Patients receiving
intensive oral care had statistically significant (though clinically unimpressive) benefits
in the incidence (85 versus 93 percent) and duration (17 versus 19 days) of moderate or
severe mucositis.
• The effectiveness of a preventive oral protocol was evaluated in a prospective,

controlled study of 96 children (age 1 to 16 years) with acute lymphoblastic leukemia
[58]. Compared with the control children who only received treatment for dental
complications rather than prophylaxis, the children in the prophylactic group had
improved oral hygiene and a decreased incidence of mucositis and oral candidiasis.
• On the other hand, in a retrospective review of 58 patients undergoing allogeneic or

autologous HCT for a variety of malignancies, there was no significant difference in the
incidence of infection, mucositis, or post-transplant survival in the group who
underwent intensive dental evaluation and treatment pretransplant (n = 36), compared
with those who did not [59].
• A prospective pilot trial was conducted at the University of Chicago in which 48

consecutive adults with hematologic or solid malignant neoplasms were assessed for
periodontal health prior to chemotherapy, and no pretherapy dental treatment was
given to patients with chronic dental disease [60]. Of the 21 who had severe chronic
periodontal disease, only two developed acute periodontal infection following
chemotherapy, both of whom were managed with antibiotic therapy. In neither case
was there interference with chemotherapy or an adverse effect on oncologic outcomes.
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The authors concluded that patients with chronic dental pathology can safely proceed
with chemotherapy without dental intervention as conversion of chronic dental disease
to an acute state during chemotherapy occurs infrequently.
If an intertherapy dental infection does arise, it can usually be managed effectively

without interrupting therapy or adversely affecting oncologic treatment outcomes. An
exception is patients undergoing allogeneic HCT where the additional use of
immunosuppressive medications adds additional risks. All efforts should be made to
correct any ongoing dental issues prior to proceeding with transplantation.
Because chronic periodontal disease is associated with a substantial microbial burden

within the periodontal pocket, it should be suspected as a focus of infection in febrile
neutropenic patients [7]. Invasive manipulation of the soft tissues prior to chemotherapy
appears to have no adverse effect on the subsequent development of fever or bacteremia,
although instrumentation should be avoided during periods of neutropenia [61]. (See
"Overview of neutropenic fever syndromes".)
● Tooth extraction – Tooth extraction is commonly recommended prior to therapy for

patients with severe periodontal disease, and for those with nonrestorable teeth, necrotic
teeth, teeth with periapical infection in which endodontic therapy is not feasible, or
partially erupted third molars [7]. Pretherapy tooth extractions can be safely performed
without significant risk of postextraction complications [62,63]. However, recommended
guidelines include performing extractions at least 10 days prior to chemotherapy,
minimizing tissue trauma during the procedure, and obtaining primary closure of the
wound without the use of hemostatic packing agents. Platelet transfusion should be
considered prior to the procedure if the platelet count is less than 50,000/microL [64].
If tooth extraction is emergently needed in the setting of severe neutropenia (ANC less
than 500 to 1000/microL), antibiotic prophylaxis that provides appropriate coverage for
Gram-positive and anaerobic organisms (eg, clindamycin 600 mg prior to the procedure,
followed by a postextraction course of antibiotics) is adequate for most patients. Severely
immunocompromised patients or those with extensive prior antibiotic exposure may
benefit from broader-spectrum antibiotic coverage.
Issues related to invasive dentoalveolar procedures in patients who are receiving therapy
with antiresorptive agents (ie, bisphosphonates, denosumab) and angiogenesis inhibitors
for advanced cancer are discussed elsewhere. (See "Medication-related osteonecrosis of
the jaw in patients with cancer", section on 'Dentoalveolar surgery' and "Medication-
related osteonecrosis of the jaw in patients with cancer", section on 'Prevention'.)
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Patients receiving chemotherapy — A number of strategies have been employed to prevent

or minimize chemotherapy-induced mucositis [3]. Although the quality of evidence derived
from randomized trials is limited [65], updated evidence-based clinical practice guidelines
developed by the MASCC/ISOO identified oral cryotherapy, palifermin, and photobiomodulation
as beneficial in select clinical settings, as discussed below [48].
Preventive treatments that may be beneficial
Oral cryotherapy — For patients receiving bolus FU-containing chemotherapy we

recommend oral cryotherapy (ice chips swished around the mouth for 30 minutes). We also
suggest the use of oral cryotherapy in patients receiving high-dose melphalan chemotherapy
regimens as preparation for autologous HCT. The use of oral cryotherapy in patients receiving
other high-dose chemotherapy regimens as preparation for HCT is reasonable given the low
toxicity and low cost; however, there is less evidence for benefit.
● Techniques – Most patients achieve cooling of the oral mucosa through intraoral
administration of ice chips during chemotherapy administration. This is a cost effective
and proven beneficial treatment. Another alternative is use of the Cooral intraoral cooling
system. However, this is a more complex and more expensive alternative that is not
necessarily more effective or better tolerated than ice chips.
The Cooral system is a fitted device that is shaped and dimensioned to cool the gums,
cheeks, tongue, palate and base of the mouth by circulating chilled water continuously
within a closed channel [66]. The Cooral system was directly compared with intraoral
administration of ice chips in a phase III trial involving 172 patients beginning high dose
chemotherapy prior to autologous HCT for multiple myeloma or lymphoma [67]. Each
cooling method was started 30 minutes before the chemotherapy infusion, and continued
for 30 minutes after completion. Oral mucositis was quantified by an oral mucositis
assessment scale (OMAS; a composite score graded 0 to 3 for severity of ulceration, and 0
to 2 for erythema; total score range 0 to 5). Following treatment, oral mucositis of any
grade developed in 44 percent of the entire cohort (76 of 172) and was much more
frequent (81 versus 38 percent) and more severe (50 versus 14 percent) in those with
lymphoma rather than myeloma. Within the entire study cohort, there was no significant
difference between the two cooling methods in peak oral mucositis (OMAS 0.99 versus
1.24 for the cooling device and ice chips, respectively, p = 0.351). However, when the
analysis was limited to the 26 lymphoma patients, use of the intraoral cooling device was
associated with lower peak OMAS score (1.77 versus 3.08, p = 0.047). Secondary outcomes
(tolerability, pain score) also favored the intraoral cooling device.
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● Fluorouracil-containing regimens – Stomatitis is a major dose-limiting toxicity of FU

when it is administered as a short-term bolus, particularly using a monthly, rather than
weekly, schedule of administration (the so-called Mayo regimen). Mucositis is less of a
problem in patients who receive infusional FU-containing regimens. (See "Systemic
therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic
approach", section on 'Treatment-related toxicity'.)
Because FU has a short plasma half-life, it was postulated that oral cryotherapy around the
time of drug administration might induce local vasoconstriction, thereby reducing
exposure of the oral mucosa to FU and decreasing the incidence and/or severity of
mucositis.
Several controlled trials provide evidence for the benefit of oral cryotherapy in patients
receiving bolus FU [68-71].
• A Cochrane review of five trials totaling 444 individuals undergoing treatment with FU
concluded that oral cryotherapy probably reduces the severity of oral mucositis of any
severity (relative risk [RR] 0.61, 95% CI 0.52-0.72) and the incidence of severe oral
mucositis (RR 0.4, 95% CI 0.27-0.61). The number needed to treat to prevent severe oral
mucositis in one additional person was six (95% CI 5-9) [72].
• A 2020 systemic review conducted by MASCC/ISOO, which included seven trials of

chemotherapy using bolus FU, concluded that there was sufficient evidence to
recommend this practice, but that no recommendation could be made as to benefit in
the setting of continuous-infusion FU or other conventional-dose chemotherapy
regimens given the paucity of data [73].
The optimal duration of cryotherapy was addressed in another randomized trial of 178
patients receiving leucovorin-modulated bolus FU [74]. No additional benefit was seen
with 60, as compared with 30, minutes of cryotherapy.
Clinical practice guidelines from several groups recommend the use of oral cryotherapy
(ice chips swished around the mouth for 30 minutes) in patients receiving bolus FU-
containing regimens [48,49,75]. However, bolus FU regimens are not commonly used in
the clinic because of their less favorable toxicity profile, as compared with infusional
regimens. The benefit of cryotherapy in patients receiving infusional FU-containing
regimens is unknown. (See "Systemic therapy for nonoperable metastatic colorectal
cancer: Selecting the initial therapeutic approach", section on 'Treatment-related toxicity'.)
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● Conditioning regimens for autologous HCT – Although data are more limited,
cryotherapy may also be effective in preventing severe oral mucositis in patients receiving
high-dose melphalan or other high-dose chemotherapy regimens as conditioning for
autologous hematopoietic cell transplantation (HCT); most of the data are in patients
undergoing high-dose melphalan [76-80], but there is likely to be benefit with other
regimens as well [81,82]:
• The Cochrane review cited above included five studies, totaling 270 patients [72]. The
authors concluded that oral cryotherapy might reduce oral mucositis of any severity
(RR 0.59, 95% CI 0.35-1.01), but there was uncertainty surrounding the effect estimates;
the 95 percent CI ranged from two patients needed to treat to benefit one additional
person, to 111 needed to treat in order to harm one additional patient [72]. On the
other hand, severe oral mucositis was probably reduced (RR 0.38, 95% CI 0.20-0.72).
• A 2020 systematic review of five trials conducted by MASCC/ISOO concluded that the
data were sufficient to recommend cryotherapy for the prevention of oral mucositis in
the setting of autologous HCT using high-dose melphalan [73].
Year 2020 clinical practice guidelines from the MASCC/ISOO recommend the use of oral
cryotherapy for patients undergoing autologous HCT when high-dose melphalan is used
[48]; however, a guideline from ESMO is a "suggestion" rather than a "recommendation"
[49]. (See "Early complications of hematopoietic cell transplantation".)
The optimal cryotherapy regimen/schedule is unclear, but results seem to be better if the
oral cavity is kept cool continuously. In a randomized trial of 160 individuals receiving
busulfan/cytarabine conditioning regimens prior to allogeneic HCT, continuous oral
cryotherapy from the beginning of the conditioning regimen infusion until the end or
continuous cryotherapy from the midpoint of the conditioning regimen infusion until the
end both resulted in a lower incidence and severity of mucositis compared with twice-daily
application for 15 minutes each during the period of conditioning [81].
We suggest beginning oral cryotherapy 15 minutes prior to, and continuing through the
entire duration of, the chemotherapy infusion.
The clinical presentation, prevention, and management of oral mucositis after HCT are
discussed in more detail elsewhere. (See "Early complications of hematopoietic cell
transplantation", section on 'Oral mucositis'.)
Palifermin — We suggest palifermin to prevent oral mucositis in patients undergoing

autologous HCT with a preparative regimen containing total-body radiation, an approach that is
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consistent with updated guidelines from MASCC/ISOO and other expert groups. While the use
of palifermin to prevent oral mucositis in patients undergoing autologous HCT using any
preparative regimen with a high risk of significant mucositis is reasonable, the modest benefit
seen with this agent must be balanced against its expense, the lack of benefit in preventing
irritation of the rest of the gastrointestinal (GI) tract, and the lack of efficacy in other settings,
such as allogeneic HCT and induction therapy for acute leukemia. (See "Early complications of
hematopoietic cell transplantation", section on 'Oral mucositis'.)
For patients who develop severe (grade 3 or worse) mucositis during treatment with an FU- or
doxorubicin-based chemotherapy regimen, we suggest dose reduction for subsequent
chemotherapy cycles rather than prophylactic IV palifermin. While palifermin could be
considered in this setting, the drug is expensive, may not be reimbursed for this off-label use,
and there are no data demonstrating that outcomes are better as compared with dose
reduction.
Palifermin is a recombinant keratinocyte growth factor that stimulates proliferation and

differentiation of epithelial cells, including those of the GI tract [83]. The efficacy of prophylactic
IV palifermin is supported by the following data:
● Benefit was initially shown in a double-blind, placebo-controlled multicenter trial in which

212 patients undergoing autologous HCT for hematologic malignancies (with a
preparative regimen [fractionated total-body irradiation (TBI), etoposide, and
cyclophosphamide] known to be associated with a high incidence of mucositis) were
randomly assigned to receive either palifermin (60 mcg/kg per day) or placebo for three
days before and three days following stem cell infusion [84,85]. Significantly fewer patients
receiving palifermin had grade 3 or 4 mucositis (63 versus 98 percent with placebo), and
the duration of mucositis was shorter (median six versus nine days). These benefits were
associated with significantly less use of opioid analgesics and total parenteral nutrition
support.
Largely as a result of these data, palifermin was approved by the US Food and Drug
Administration (FDA) to decrease the incidence and severity of severe oral mucositis
associated with hematologic malignancies in patients receiving myelotoxic therapy in the
setting of autologous hematopoietic stem cell support (when the preparative regimen is
expected to result in mucositis grade 3 or worse in most patients).
● A systematic review of five randomized trials conducted by the MASCC/ISOO expert group
[86] concluded that palifermin was effective in preventing oral mucositis in patients
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undergoing autologous HCT that included TBI [85,87-89], but one trial did not show
benefit for patients undergoing autologous HCT without TBI [90].
Clinical practice guidelines, including those from MASCC/ISOO, ESMO, the American Society of
Clinical Oncology (ASCO; from 2008), and the National Comprehensive Cancer Network (NCCN;
from 2008) recommend the use of prophylactic palifermin in patients with hematologic
malignancies who are undergoing autologous HCT using preparative regimens that include TBI
[48,49,75,91]. However, since radiation-based conditioning regimens have largely been replaced
with chemotherapy-only-based regimens followed by autologous HCT, the use of palifermin is
relatively low. (See "Early complications of hematopoietic cell transplantation".)
Benefit of palifermin for prevention of oral mucositis in other settings is less certain:
● A randomized trial in the setting of allogeneic HCT failed to show any benefit for
prophylactic use of palifermin (incidence of grade 3 or 4 oral mucositis 81 versus 73
percent with placebo) [92].
● Similarly, a randomized placebo-controlled trial of palifermin in 160 patients undergoing

induction chemotherapy for acute myeloid leukemia with idarubicin, high-dose cytarabine,
and etoposide found no significant difference in the rate of grade 3 or 4 oral mucositis
(the primary endpoint) in the palifermin group (4 versus 10 percent), a finding that was
attributed to the lower-than-expected rates of mucositis in the control group [93]. While
there was a significantly lower rate of grade 3 and 4 GI adverse events (diarrhea, vomiting,
oral mucositis) overall with palifermin, this was mainly due to a reduction in severe
diarrhea.
● Two of three randomized trials suggest benefits from palifermin among patients receiving
less intense chemotherapy regimens (including ifosfamide plus high-dose doxorubicin and
FU-based chemotherapy for colorectal cancer) [94-96].
● A Cochrane review of six trials of HCT (five autologous [one with unpublished data], one
allogeneic [84,87,90,92,97,98]) and the four trials conducted in patients receiving
chemotherapy alone for other indications [93-96] came to the following conclusions [99]:
• There might be a reduction in the risk of moderate to severe oral mucositis in adults
receiving HCT after conditioning therapy for hematologic cancers (RR 0.89, 95% CI 0.80-
0.99, low-quality evidence). However, the level of benefit is uncertain because of
multiple factors in this population, including whether or not TBI was used and whether
the transplant was autologous or allogeneic.
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• It is likely that there is a reduction in the risk of moderate to severe oral mucositis in
adults receiving chemotherapy alone for mixed solid and hematologic cancers (RR 0.56,
95% CI 0.45-0.70, moderate-quality evidence).
● A 2020 systematic review by an expert panel of the MASCC/ISOO concluded that no

guideline recommendation was possible regarding the benefit of palifermin in individuals
undergoing chemotherapy outside of the setting of HCT.
Photobiomodulation (low-level laser therapy) — The use of photobiomodulation

(low-level laser therapy) to prevent oral mucositis in patients undergoing HCT conditioned with
high-dose chemotherapy, with or without TBI, may be helpful and is recommended in updated
guidelines from the MASCC/ISOO. Specific protocols are endorsed by MASCC/ISOO ( table 3).
However, in most parts of the world, photobiomodulation is rarely used in clinical practice. It
requires expensive equipment and specialized operator training, is limited to centers capable of
supporting the necessary technology and training, and the relative benefits of
photobiomodulation versus palifermin in patients undergoing autologous HCT have not been
addressed in any trial.
Several controlled trials suggest that pretreatment with an intraoral helium-neon laser (He-Ne
laser), a form of low-level laser irradiation, reduces the severity of mucositis in patients
undergoing conditioning therapy for HCT [100]. As examples:
● In one study, 30 patients undergoing HCT were randomly assigned to observation or He-
Ne laser treatment to the entire oral mucosa prior to myeloablative chemotherapy [101].
Those who received laser treatment had significantly lower cumulative mucositis scores
and required significantly less morphine for oral pain; however, there was no difference in
the need for parenteral nutritional support.
● In a second trial of 20 patients undergoing HCT, one side of each patient's oral cavity was
exposed to the He-Ne laser prior to high-dose chemotherapy, while the contralateral side
was sham treated and served as the control [102]. The severity of oral mucositis and pain
scores were significantly lower for the treated versus the untreated side of the mouth.
A similar degree of benefit has been reported from the application of a low-power diode laser,
which is less expensive and easier to use than the He-Ne laser [100,103-108]. As examples:
● In one trial, 38 patients undergoing autologous or allogeneic HCT were randomly

assigned to photobiomodulation or control [103]. A significantly higher number of
patients undergoing photobiomodulation prior to treatment had oral mucositis that was
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no worse than grade 2 (95 versus 32 percent in the control group), and fewer developed
large (9.1 to 18 cm2) areas of oral ulceration (5 versus 74 percent).
● In a second trial, 70 patients undergoing autologous or allogeneic HCT were randomly

assigned to one of two different low-level lasers (650 nm visible red and 780 nm infrared)
or placebo [104]. All active photobiomodulation patients received daily direct intraoral
laser treatment to the lower labial mucosa, right and left buccal mucosa, lateral and
ventral surfaces of the tongue, and floor of the mouth. Treatment with the 650 nm
wavelength (but not the 780 nm wavelength) significantly reduced the severity of oral
mucositis and pain scores. Photobiomodulation was well tolerated, and no adverse events
were noted.
A systematic review of biomodulation for management of oral mucositis in cancer patients

concluded that the level of evidence was strong to recommend low-level laser light therapy to
prevent oral mucositis in patients undergoing HCT conditioned with high-dose chemotherapy
with or without total-body radiotherapy [100]. No guideline was possible for patients
undergoing chemotherapy in other settings.
Photobiomodulation has been recommended in consensus guidelines, including those by the

MASCC/ISOO and ESMO, to reduce the incidence of oral mucositis in patients receiving a
conditioning regimen before HCT [48,49,100]. Two specific protocols have been endorsed in this
setting by the MASCC/ISOO ( table 3).
The clinical practice guidelines from the MASCC/ISOO also recommend photobiomodulation to
prevent treatment-related mucositis in patients with head and neck cancer who are undergoing
radiation therapy with or without chemotherapy. This subject is discussed in detail elsewhere.
(See "Management and prevention of complications during initial treatment of head and neck
cancer", section on 'Laser therapy (photobiomodulation)'.)
Because this therapy requires expensive equipment and specialized operator training, it is
limited to centers capable of supporting the necessary technology and training. The relative
benefits of photobiomodulation versus palifermin in patients undergoing high-dose therapy
and HCT have not been addressed in any trial. Because of these limitations,
photobiomodulation is rarely used in clinical practice.
Treatments that are not recommended
● Glutamine – Glutamine is a precursor for nucleotide synthesis and an important fuel

source for rapidly dividing cells, such as the lining epithelia of the GI tract. It is postulated
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to facilitate healing of the GI mucosa, following damage by either radiation therapy or

chemotherapy.
• Parenteral – Supplementation with parenteral glutamine has been studied in the

setting of HCT. There was no evidence of benefit in terms of mitigation of mucositis
incidence or severity [109], and updated clinical practice guidelines from MASCC/ISOO
recommend against the use of parenteral glutamine to prevent mucositis in patients
undergoing HCT [48]. These trials are discussed in detail elsewhere. (See "The role of
parenteral and enteral/oral nutritional support in patients with cancer", section on
'Glutamine supplementation'.)
• Oral – There are conflicting data regarding the benefit of oral glutamine supplements
for prevention of mucositis:
- Oral glutamine failed to prevent FU-related mucositis in at least two trials of

patients receiving standard-dose FU-based chemotherapy [110,111]. However, a
trial in children suggested a possible benefit from oral glutamine [112]. One
potential explanation for the conflicting results may be that the poor solubility of
glutamine may limit bioavailability to the mucosal surface. At least some data
support the view that local uptake by the mucosa (provided by swishing of the
product in the mouth) may be essential [113].
- An oral suspension formulation of L-glutamine (Saforis) may provide greater

bioavailability to the oral mucosa. In a phase III trial, 326 women with breast
cancer scheduled to receive an anthracycline and cyclophosphamide-based
regimen were randomly assigned to receive Saforis (2.5 g three times a day for 14
days) or placebo for the first cycle, crossing over to the alternate for cycle 2 of
treatment [114]. The incidence of mucositis grade ≥2 was significantly reduced in
the Saforis group during the first cycle (39 versus 50 percent with placebo), as was
the incidence of severe mucositis (grade ≥3, 1 versus 7 percent, ( table 2)).
Patients receiving Saforis in treatment cycle 1 had a lower-than-expected rate of
oral mucositis when crossed over to placebo for treatment cycle 2, indicating a
significant carryover effect.
Independent confirmation of benefit is needed before routine use of prophylactic

glutamine suspension can be recommended in any setting. A systematic review of the
literature on oral glutamine in 2019 considered the evidence in support of oral
glutamine to be insufficient, at least for the setting of HCT and solid tumors other than
head and neck cancer receiving chemoradiotherapy [115]. Updated 2020 guidelines for
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the prevention and treatment of oral mucositis from the MASCC/ISOO suggest the use
of oral glutamine to prevent oral mucositis in those with head and neck cancer
undergoing chemoradiotherapy, but makes no recommendation for other groups [48].
(See "Management and prevention of complications during initial treatment of head
and neck cancer", section on 'Management and prevention'.)
At present, there is no commercially available formulation of any oral glutamine

suspension that is approved for use in preventing oral mucositis. Saforis has not been
approved for marketing by the FDA or any other regulatory agency.
● Calcium phosphate rinse – Benefit for neutral supersaturated calcium phosphate rinse
(Caphosol artificial saliva) was suggested in a double-blind, placebo-controlled trial in
which 95 patients undergoing HCT were randomly assigned to calcium phosphate rinse
plus a topical fluoride versus topical fluoride alone [116]. Patients using the calcium
phosphate rinse had a significantly shorter duration of mucositis (3.7 versus 7 days), and
less pain and morphine use. Unfortunately, these results were not confirmed in a later
randomized trial conducted in 220 children undergoing allogeneic HCT for any indication
[117] and in a third trial compared with cryotherapy alone [118]. A year 2019 systematic
review from the MASCC/ISOO concluded that no guideline was possible on the utility of
calcium phosphate oral rinses for either prevention or treatment of oral mucositis [115],
and no recommendation was made in the updated 2020 MASCC/ISOO guidelines for
management of mucositis secondary to cancer therapy [48].
● Other approaches – Several other pharmacologic approaches have either failed to show
efficacy in controlled studies, or insufficient data are available to assess their benefit
[86,119]:
• Allopurinol mouthwash – Allopurinol mouthwashes have been used in an attempt to

inhibit the activation of FU to fluorodeoxyuridine monophosphate in mucosal cells.
Early reports of benefit [120,121] were not confirmed in a randomized trial [122].
• Propantheline – An anticholinergic agent, propantheline has been used to decrease

salivary flow and thereby reduce oral mucosal delivery of etoposide, a drug that is
secreted into saliva. In a small, randomized, placebo-controlled trial (n = 12),
propantheline was associated with a lower incidence and severity of mucositis [123].
A protective effect of propantheline-induced xerostomia was also suggested in a larger,

but uncontrolled, study of 31 patients receiving high-dose etoposide (3000 mg/m2) as a
component of the ICE regimen (high-dose ifosfamide, carboplatin, and etoposide) prior
to HCT [123]. Although mucositis developed in 29 (90 percent), it was severe in only
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three (10 percent). The authors inferred benefit based upon a comparison with a
published series of 46 patients treated with the same ICE regimen followed by
autologous HCT but without propantheline, in which mucositis developed in all patients
and was severe in 78 percent [124].
These data are insufficient to recommend the routine prophylactic use of

propantheline in any clinical setting.
• Hematopoietic colony-stimulating factors – The possibility that hematopoietic

colony-stimulating factors (CSFs) may protect against the development of
chemotherapy-induced mucositis was initially raised in a randomized trial that
examined the use of prechemotherapy granulocyte CSF (G-CSF) to maintain
chemotherapy dose intensity in patients with advanced bladder cancer [125].
Unexpectedly, G-CSF was associated with a significantly lower incidence (11 versus 44
percent) and severity of mucositis. Data from subsequent trials with mucositis as a
specific endpoint have been mixed:
- Benefit was confirmed in at least four controlled trials using either

subcutaneous/IV G-CSF or granulocyte-macrophage CSF (GM-CSF) in a variety of
clinical settings [126-129], but at least one trial was negative in the setting of HCT
[130].
However, a 2017 Cochrane review of interventions to prevent oral mucositis found

no compelling evidence of benefit for either GM-CSF or G-CSF [99].This conclusion
was also echoed in a 2020 systematic review by an expert panel from MASCC/ISOO
[86].
- Topical application of CSFs in a mouthwash formulation has been explored in at

least three randomized trials, one of which showed benefit [131], and the others,
no benefit [132,133]. The use of topical CSFs to prevent radiation-induced
mucositis is addressed elsewhere. (See "Management and prevention of
complications during initial treatment of head and neck cancer", section on
'Mucositis'.)
Updated MASCC/ISOO clinical practice guidelines specifically suggest not using CSFs
(parenteral or topical) to prevent oral mucositis in patients undergoing HCT [48], and
we agree with this position.
• Chlorhexidine – The benefit of chlorhexidine mouth rinses remains uncertain. Three

randomized trials assessing the effectiveness of chlorhexidine for mucositis prevention
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in patients receiving chemotherapy have yielded conflicting results [70,134,135]. Two

trials, one in patients undergoing HCT [134] and the other in those receiving standard-
dose bolus FU plus leucovorin [70], demonstrated a significant decrease in the
incidence of mucositis with chlorhexidine mouthwash relative to placebo. The third
trial, conducted in patients receiving a variety of mucositis-inducing regimens, did not
demonstrate a benefit compared with sterile water mouthwashes [135].
A 2019 systematic review from the MASCC/ISOO concluded that no recommendation

was possible for use of chlorhexidine mouthwashes to prevent oral mucositis in any
setting, given the conflicting data [47], although the 2020 updated guideline
emphasized that this did not exclude other indications for chlorhexidine, such as
prevention or treatment of oral infection [48].
• Other – Randomized, placebo-controlled trials have failed to confirm a consistent

prophylactic benefit for sucralfate [136-140], prostaglandins [141,142], chamomile
mouthwash [143], systemic pilocarpine, systemic pentoxifylline, and antimicrobial
lozenges [144] and mouthwashes derived from a variety of medicinal plants [145]. The
available data on amifostine are conflicting [146]. None of these agents can be
considered useful for the prevention of chemotherapy-associated mucositis [48,147].
The trefoil factor family of proteins comprises a group of GI peptides that are involved
in the protection of the mucous epithelium. Benefit from an oral spray containing
recombinant intestinal trefoil factor was suggested in a randomized, double-blind,
placebo-controlled phase II trial conducted in patients who developed moderate to
severe oral mucositis during the first cycle of FU-based chemotherapy for advanced
colorectal cancer [148]. Patients who received one of two doses of the recombinant
protein had a significantly lower incidence of moderate to severe mucositis during the
second chemotherapy cycle (9 to 12 versus 48 percent). Independent confirmation of
these results is needed. A 2017 Cochrane review of interventions to prevent oral
mucositis concluded that there was no compelling evidence of benefit from human
intestinal trefoil factor [99].
Treatment of established mucositis — Treatment of mucositis due to conventional

cytotoxic chemotherapy is supportive and aimed at symptom control. It consists of a
combination of oral care (including rinses with saline and/or sodium bicarbonate), topical
mucosal protectants, and either topical or systemic analgesia. With the exception of topical and
systemic analgesia, the evidence supporting benefit for intervention is weak. Updated
guidelines from the MASCC/ISOO specifically recommend against the use of sucralfate to treat
oral mucositis in patients with a solid cancer receiving cytotoxic chemotherapy, and consider
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the evidence to be insufficient to prompt a recommendation for any other form of treatment
[48]. We agree with this position.
Routine oral care — For patients with established mucositis, routine mouth care,
including removal of dentures, atraumatic cleansing, and oral rinses with a weak solution of salt
and baking soda (one-half teaspoon of salt and one teaspoon of baking soda in a quart of
water), should be performed every four hours. Although the data on saline or bicarbonate
rinses for the prevention or treatment of oral mucositis are limited, the MASCC/ISOO expert
panel recognized that these inert bland rinses that increase oral clearance may be helpful for
maintaining oral hygiene and improving patient comfort [48].
The oral cavity should be rinsed and wiped after meals, and dentures cleaned and brushed
often to remove plaque. A soft toothbrush or foam swab (Toothette) cleans teeth effectively but
may be too harsh for patients with moderate to severe stomatitis.
Hydrogen peroxide (diluted 1:1 with saline or water) may be used for gentle debridement.
Duration of use of hydrogen peroxide should be limited as chronic therapy may delay healing.
The diet should be limited to foods that do not require significant chewing; acidic, salty, or dry
foods should be avoided.
Analgesia — Both topical and systemic approaches have been used to manage pain
associated with mucositis:
● Topical lidocaine solutions provide pain relief but require frequent administration. In one
trial, topical viscous lidocaine (2 percent) was more effective than diphenhydramine and
saline, a kaolin and pectin suspension, or placebo [149].
● Topical lidocaine is frequently combined with cleansing and/or coating agents, a mixture
that is often referred to as "miracle mouthwash." There is no fixed formulation, and these
mixtures are compounded differently by individual pharmacies, most of which have no set
formula [150]. Commonly, these mouthwashes consist of astringent/anticholinergic
agents (eg, sodium bicarbonate, diphenhydramine), antacids and/or mucosal protective
agents (eg, magnesium aluminum hydroxide), and a topical anesthetic (eg, lidocaine). One
example consists of viscous lidocaine (50 mL of a 2 percent solution), sodium bicarbonate
(100 mL of a 1 mEq/mL solution), and diphenhydramine (50 mL of a 12.5 mg/5 mL
solution) in 500 mL normal saline (resultant fluid volume 700 mL) with instructions to
swish and expectorate 10 to 15 mL four to six times per day. Another type of "miracle
mouthwash" consists of a mixture of equal parts of viscous lidocaine, diphenhydramine,
and magnesium aluminum hydroxide (Maalox).
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A commercially available preparation that includes both lidocaine and diphenhydramine

plus a variety of coating agents is First Mouthwash BLM (swish and expectorate 10 to 15
mL four to six times daily).
Notably, a systematic review of the management of oral mucositis concluded that there
was no evidence supporting the use of mixed-medication mouthwashes for treatment of
chemotherapy- or radiation-induced mucositis [151]. Patients may have adverse effects
related to the diphenhydramine and lidocaine. Year 2020 guidelines from the Mucositis
Study Group of the MASCC/ISOO make no recommendations about the use of mixed-
medication mouthwashes [48], while the American Academy of Nursing (AAN) Choosing
Wisely statement (in conjunction with the Oncology Nursing Society [ONS]) explicitly
recommends against their use [152]. Instead, frequent and consistent oral hygiene with a
soft toothbrush and use of a homemade salt-and-soda mouth rinse (one teaspoonful each
of salt and sodium bicarbonate in a liter of water) can be used.
● Topical application of morphine sulfate (0.2%, 2 mg/mL in water, 15 mL swish for two
minutes and expectorate) may shorten the duration and intensity of mouth pain, even in
the absence of significant systemic absorption. One study of 26 patients who had
chemoradiotherapy for head and neck cancer, which compared a morphine mouthwash
versus a mixture of equal parts of viscous lidocaine, diphenhydramine, and magnesium
aluminum hydroxide, demonstrated statistically significantly shorter duration and lower
pain intensity with the morphine mouthwash [153]. However, most commercially available
oral preparations of morphine sulfate contain glycerin, ethanol, or both. These are not
suitable for topical application because alcohol can directly injure the mucosa while
glycerin can damage tissues because it is hygroscopic. There are no reliable data on
topical morphine in other populations. The updated 2020 MASCC/ISOO guidelines
suggested this approach be limited to those with head and neck cancer receiving
chemoradiotherapy, but a specific recommendation could not be made for other groups
[48].
● Topical doxepin rinse (0.5%) can provide clinically significant pain relief in patients with
mucosal damage from a variety of cancer treatments [154]. Although the year 2014
MASCC/ISOO guideline suggested in favor of doxepin mouthwash [155], in 2020, this was
changed to "no guideline possible" [48] based on the results of an updated systematic
review in 2019 [147].
● Pain may be severe enough to require systemic oral or parenteral opioids. Morphine is
recommended as the opioid of first choice for patient-controlled analgesia [156]. The oral
route is preferred if the patient can swallow. Another option that is suitable for patients
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who cannot swallow is transdermal fentanyl. (See "Cancer pain management with opioids:
Optimizing analgesia".)
Particularly for severe mucositis in the setting of HCT, patient-controlled analgesia using
morphine with appropriate lock-outs is recommended so that pain medications can be
delivered in a timely manner in hospitalized patients, especially those undergoing HCT
[48,155]. Typically, both a basal rate and intermittent bolus administrations of narcotics
are required to achieve adequate analgesia.
Treatments of uncertain benefit
● Mucosal protective agents – A variety of mucosal-protective agents have been used to

protect the mucosal surfaces of the oral cavity, including Gelclair, Orabase, Episil (a
patented mixture of soy phospholipid [lecithin] and glyceryl dioleate that forms a
bioadhesive barrier), topical kaolin/pectin, oral antacids, and propolis (a resinous
substance that is used in many parts of the world as a mouthwash) [145,157]. There is
little, if any, evidence from adequately powered randomized trials to support benefit from
any of these preparations, and two 2020 systematic reviews from expert MASCC/ISOO
panels concluded that no guideline was possible [119,147].
As an example, Gelclair is a bioadherent oral mucosal barrier gel containing (according to

the FDA label) maltodextrin, polyvinylpyrrolidone, and sodium hyaluronate (but no alcohol
or anesthetic agent). It provides a physical adherent barrier over mucosal surfaces,
thereby shielding oral lesions from the effect of food, liquids, and saliva [158]. A reduction
in oral discomfort within five to seven hours of initial treatment was observed in an
uncontrolled, open-label study of 30 hospice patients (only three of whom had
chemotherapy-related mucositis) [159]. Benefit continued for more than three hours after
each dose in most patients.
The manufacturer recommends that the contents of each packet be mixed in one
tablespoon of water, rinsed in the mouth for one minute, and expectorated three times
daily at least one hour before eating or drinking [160].
● Vitamin E – Two pilot studies suggest more rapid resolution of mucositis with topical
vitamin E treatment [161-163]. In one randomized, double-blind, placebo-controlled trial,
six of nine patients treated with vitamin E had complete resolution of lesions, compared
with only one of nine receiving placebo. Larger confirmatory studies are needed before
the topical application of vitamin E can be considered a standard approach.
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A 2019 systematic review concluded that no guideline was possible regarding the use of
topical vitamin E for treatment of oral mucositis in any clinical setting [115].
● Other treatments – Efforts to limit mucositis progression by blocking the mechanism of

chemotherapy-induced toxicity are ongoing, but so far, they have a relatively limited role.
Sucralfate (topical, systemic) is not recommended for treatment of oral mucositis-
associated patients with solid tumors treated with cytotoxic chemotherapy [136,147,164].
However, mucositis due to methotrexate may respond to allopurinol mouthwash [161,165]
or to the systemic administration of folic acid or leucovorin (folinic acid). (See "Major side
effects of low-dose methotrexate".)
Patients receiving molecularly targeted agents — The MASCC/ISOO guidelines for

management of mucositis secondary to cancer therapy [48] were not intended to apply to
individuals who develop mucositis while undergoing treatment with a molecularly targeted
agent. These include orally active receptor tyrosine kinase inhibitors that target, among others,
the epidermal growth factor and vascular endothelial growth factor receptors, and inhibitors of
the mTOR. (See 'Specific anticancer agents' above.)
There are few trials that have explored any treatment, preventive or otherwise, in this setting,
and the best approach is uncertain.
Dexamethasone mouthwash — Benefit for a preventive dexamethasone-containing

mouthwash in patients treated with mechanistic (previously called mammalian) target of
rapamycin (mTOR) inhibitors was suggested in the multicenter phase II SWISH trial, in which 92
postmenopausal women with metastatic, hormone-receptor-positive, HER2-positive breast
cancer prescribed everolimus (10 mg daily) and exemestane (25 mg daily) all received a daily
mouthwash containing dexamethasone, starting on the first day of the first cycle. Patients were
told to swish 10 mL of alcohol-free dexamethasone (0.5 mg/5 mL oral solution) for two minutes
and spit, four times daily for eight weeks, and not to eat for one hour after using the
mouthwash. The incidence of grade 2 or worse stomatitis at week 8 (the primary endpoint) was
2.4 percent, which compares favorably with the rate seen in a historical control group, women
with hormone-receptor-positive metastatic breast cancer treated with combined
everolimus/exemestane in the phase III, randomized BOLERO-2 trial of exemestane with or
without everolimus (33 percent) [166]. Overall, 90 percent of patients reported no need for
dietary restriction because of stomatitis. Although hyperglycemia was the most common
toxicity with the dexamethasone mouthwash, rates were not significantly higher than those
seen in the BOLERO-2 trial without prophylactic dexamethasone. (See "Treatment for hormone
receptor-positive, HER2-negative advanced breast cancer", section on 'Alternative front-line
options'.)
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Although these results (and others using alternative glucocorticoid-containing oral rinses [167])
are intriguing, the only way to definitively address the benefit of a prophylactic dexamethasone-
containing mouthwash in patients receiving mTOR inhibitors is with a properly performed,
randomized, placebo-controlled trial.
Case series further support benefit from local and systemic corticosteroid therapy to treat
mTOR inhibitor-associated stomatitis [168-170].
Guidelines from expert groups — Consensus-based guidelines from ESMO [49] endorse

expert opinion-based recommendations for prevention and treatment of stomatitis related to
molecularly targeted agents from at least three groups [168-170], which are summarized as
follows:
● Oral care protocols are suggested to prevent mucositis across all targeted therapy
modalities. (See 'Prophylactic oral care' above.)
● Patients should rinse their mouths with a bland nonalcoholic sodium bicarbonate-
containing mouthwash four to six times a day to prevent stomatitis. The frequency can be
increased up to hourly, if necessary, to treat stomatitis.
● Sugarless chewing gum or candy, salivary substitutes, or sialogogues can be suggested to

treat oral dryness.
● Adequate pain management (eg, anesthetic mouthwashes such as viscous lidocaine 2

percent, coating agents, or systemic analgesics) should be provided to treat pain from
stomatitis. Alternative administration routes, such as transdermal or intranasal routes,
may be considered if taking drugs by mouth is painful.
● For ulcers, topical high potency corticosteroids are suggested initially (eg, dexamethasone
mouth rinse 0.1 mg/mL in case several locations in the oral cavity are involved and/or it is
difficult to reach the ulcerations; clobetasol gel or ointment [0.05%] in case of limited
locations and easy-to-approach ulcers). If there is no ulcer resolution, referral to an oral
expert for intralesional steroid injection could be considered. For highly symptomatic
ulcers or recurrent ulcers, systemic glucocorticoid therapy can be considered as initial
therapy to bring symptoms under control quickly (high dose pulse 30 to 60 mg or 1 mg/kg
daily oral prednisone or prednisolone for one week, followed by dose tapering over the
second week).
Patients receiving immune checkpoint inhibitors — There are no widely accepted

preventive strategies. Dexamethasone mouthwash is a first-line treatment for patients who
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develop mucositis while receiving immune checkpoint inhibitor immunotherapy. This subject is
discussed in detail elsewhere. (See "Mucocutaneous toxicities associated with immune
checkpoint inhibitors", section on 'Mucosal toxicity'.)
XEROSTOMIA
Although more commonly attributed to radiation therapy exposure, changes in salivary gland
function can also be caused by chemotherapy (including doxorubicin, cyclophosphamide,
fluorouracil, methotrexate, vinblastine) [7,171,172]. Reduced salivary flow can also result from
anticholinergic medications given for therapy-induced nausea or diarrhea (eg, for irinotecan-
related early diarrhea) (see "Chemotherapy-associated diarrhea, constipation and intestinal
perforation: pathogenesis, risk factors, and clinical presentation", section on 'Irinotecan').
Clinical presentation is variable, with some patients presenting with dry mucous membranes of
varying severity, while others complain of excessive saliva with drooling as a result of dysphagia
or odynophagia. The major symptoms associated with xerostomia are dry, uncomfortable
mucosal tissues and thick, ropy saliva, which may impair speech and swallowing. Affected
patients may also complain of dysgeusia [7].
Chemotherapy-related xerostomia is typically reversible, with spontaneous resolution after

completion of chemotherapy [7]. Although it can compound other complications, such as
mucositis, this self-limiting form of xerostomia has no significant long-term effects on oral
health. Therapy is symptomatic (eg, rinsing with saline or the use of commercially available
saliva substitutes). Dry, cracked lips can be treated with petroleum lubricants. (See "Treatment
of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome".)
GINGIVAL BLEEDING
Chemotherapy-induced thrombocytopenia can result in spontaneous gingival bleeding,

especially if the platelet count falls below 15,000/microL [173]. Poor oral hygiene or minor oral
trauma (eg, from poor fitting dentures, over vigorous brushing of teeth) may worsen this
condition due to local inflammation. If brushing creates unacceptable tissue trauma or is
painful, plaque control can be achieved with regular use of chlorhexidine oral rinses [31].
Gingival bleeding is reported in patients treated with bevacizumab, a monoclonal antibody

targeting the vascular endothelial growth factor, but is rare [174,175].
Gingival hemorrhage is usually not a serious or life-threatening complication [7]. If significant

spontaneous bleeding occurs, gauze soaked in topical thrombin or aminocaproic acid can be
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locally applied to obtain hemostasis. Alternatively, custom-fitted mouth guards can be

fabricated to serve as a stent, with or without the application of hemostatic agents. Biting down
on a popsicle may aid in resolving persistent oozing. Platelet transfusions are rarely required,
and resolution occurs quickly as the platelet count begins to rise toward normal levels
spontaneously.
ALTERATIONS IN TASTE AND SMELL
Transient alterations in taste and smell are common in patients receiving chemotherapy and
may lead to reduced appetite, low energy intake, and weight loss [176-180]:
● In two series with prospective assessment of cancer patients undergoing chemotherapy

for a variety of cancer types, taste alterations were reported by 70 and 67 percent,
respectively [176,177]. In one of the reports, 49 percent reported olfactory changes during
chemotherapy [177].
● In another cohort of 87 patients receiving chemotherapy for breast cancer or a

gynecologic malignancy, the significant decrease in olfactory and gustatory function
during chemotherapy was restored almost completely to normal by three months
postchemotherapy [179]. Olfactory function of older patients was affected more than
younger patients.
The conventional cytotoxic agents that have been most associated with taste alterations include
anthracyclines, cyclophosphamide, methotrexate, platinum agents, taxanes, ifosfamide,
irinotecan, oxaliplatin, fluorouracil, and gemcitabine.
Taste alterations have also been reported in patients treated with molecularly targeted agents,
with the most common being imatinib, sorafenib, sunitinib, pazopanib, bevacizumab,
temsirolimus, everolimus, vismodegib, sonidegib, glasdegib, crizotinib, pertuzumab, and
lapatinib [181-191].
Chemotherapy and targeted therapeutics may affect taste by direct taste receptor stimulation
due to secretion of the drug in saliva or via gingival crevice fluid (patients frequently describe a
metallic or chemical taste when chemotherapy is delivered), or by altering the signal
transduction pathways that mediate taste [188]. In some cases, taste changes may persist after
drug clearance, presumably due to direct damage to the taste buds [1,192].
The diagnosis and treatment of disorders of taste and smell are discussed in more detail
elsewhere. (See "Taste and olfactory disorders in adults: Evaluation and management".)
3/29/23, 1:12 PM 1152
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Mouth sores from cancer treatment (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Types of oral complications – Oral complications resulting from systemic anticancer

therapy include mucositis, saliva changes, taste alterations, infection, and gingival
bleeding. All of these complications can cause pain and/or impair nutrition. (See
'Introduction' above.)
● Mucositis – The principal manifestation of oral toxicity in patients receiving cytotoxic

chemotherapy or molecularly targeted agents is mucositis. Risks are highest with
bleomycin, cytarabine, doxorubicin, bolus fluorouracil (FU) agents that block signaling
through the epidermal growth factor receptor and the fibroblast growth factor receptor,
and mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors.
(See 'Etiology and risk factors' above.)
• Prevention
- For all patients initiating systemic anticancer therapy we suggest prophylactic oral
care, including a comprehensive oral examination before the initiation of
treatment (Grade 2C). (See 'Prophylactic oral care' above.)
- For patients receiving bolus FU-containing cytotoxic chemotherapy we recommend

oral cryotherapy (ice chips swished around the mouth for 30 minutes) (Grade 1A).
3/29/23, 1:12 PM 1152
For patients receiving high-dose melphalan as preparation for autologous

hematopoietic cell transplantation (HCT), we also suggest oral cryotherapy (Grade
2B). The use of oral cryotherapy in patients receiving other high-dose
chemotherapy regimens as preparation for HCT is reasonable; however, there is
less evidence for benefit. (See 'Oral cryotherapy' above.)
- For patients undergoing autologous HCT with a preparative regimen containing

total-body irradiation (TBI) we suggest palifermin (Grade 2B). While use of
palifermin to prevent oral mucositis in patients receiving other high-risk
preparative regimens is reasonable, the modest benefit seen with this agent much
be balanced against its expense, the lack of benefit in preventing irritation of the
rest of the gastrointestinal tract, and the lack of efficacy in other settings, such as
allogeneic HCT and induction therapy for acute leukemia. (See 'Palifermin' above.)
For patients who develop severe (≥grade 3) mucositis during treatment with an FU-
or doxorubicin-based chemotherapy regimen, we suggest dose reduction for
subsequent cycles rather than prophylactic IV palifermin (Grade 2C).
- Photobiomodulation (low-level laser therapy) may be helpful in patients

undergoing HCT conditioned with high-dose chemotherapy, with or without TBI,
specific protocols are endorsed by expert groups ( table 3). However,
photobiomodulation requires expensive equipment and specialized operator
training, is limited to centers capable of supporting the necessary technology and
training, and the relative benefits versus palifermin have not been addressed in
any trial. (See 'Photobiomodulation (low-level laser therapy)' above.)
- Because of high reactivation rates, antiviral prophylaxis is indicated for herpes

simplex virus (HSV)-seropositive patients who are undergoing either induction
chemotherapy for acute leukemia or receiving high-dose "conditioning" regimens
followed by HCT. (See 'HSV reactivation' above.)
• Treatment – Treatment is supportive and mainly aimed at symptom control:
- Patients should remove and frequently clean dentures, perform atraumatic

cleansing of the oral cavity, and use oral rinses with a weak solution of salt and
baking soda (one-half teaspoon of salt and one teaspoon of baking soda in a quart
of water) every four hours. Rinsing with artificial saliva may lessen the duration
and severity of mucositis. A soft toothbrush or foam swab (Toothette) cleans teeth
effectively but may be too harsh for patients with moderate to severe stomatitis.
(See 'Routine oral care' above.)
3/29/23, 1:12 PM 1152
- Limit diet to foods that do not require significant chewing; avoid acidic, salty, or dry
foods. Patients unable to swallow foods or liquids, may require parenteral fluid
and/or nutritional support.
- Adequate analgesia can sometimes be provided topically (eg, viscous lidocaine),

but many patients require systemic opioids. (See 'Analgesia' above.)
- The benefit of compounded mixtures (such as "miracle mouthwashes") that

contain mucosal protective coating agents, often with topical anesthetics, is
uncertain, and for most patients we suggest against their use (Grade 2C). (See
'Treatments of uncertain benefit' above.)
- For patients receiving molecularly targeted agents, our suggested approach

includes prophylactic oral care protocols including mouth rinses with sodium
bicarbonate-containing mouthwashes adequate analgesia, and steroids (topical,
intralesional, or systemic) for patients who develop ulcers during therapy. (See
'Patients receiving molecularly targeted agents' above.)
● Xerostomia – Xerostomia is an uncommon complication of chemotherapy. Therapy is

symptomatic (eg, rinsing with saline or the use of commercially available saliva
substitutes). Dry, cracked lips can be treated with petroleum lubricants. (See 'Xerostomia'
above.)
● Gingival bleeding – Gingival bleeding is most commonly caused by thrombocytopenia. If

significant spontaneous bleeding occurs, gauze soaked in topical thrombin can be locally
applied to obtain hemostasis. Bleeding usually resolves rapidly as platelet counts increase
following the hematologic nadir. Platelet transfusions are rarely required. (See 'Gingival
bleeding' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Jean-Francois Bedard, DMD, and Joseph A Toljanic,
DDS, who contributed to earlier versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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Topic 1152 Version 71.0
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GRAPHICS
Chemotherapy agents associated with mucositis
Category Specific Drugs
Alkylating agents Busulfan
Carboplatin
Cisplatin
Cyclophosphamide
Ifosfamide
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Anthracyclines Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
6-Mercaptopurine
Antimetabolites
6-Thioguanine
Capecitabine
Cytarabine
Fludarabine
Fluorouracil
Gemcitabine
Hydroxyurea
Methotexate
Pemetrexed
Pralatrexate
Antitumor antibiotics Dactinomycin
Bleomycin
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Mitomycin
Taxanes Docetaxel
Paclitaxel
Topoisomerase inhibitors Etoposide
Irinotecan
Teniposide
Topotecan
Cabozantinib
Molecularly targeted agents
Cetuximab
Erlotinib
Everolimus
Lenvatinib
Palbociclib
Panitumumab
Regorafenib
Sorafenib
Sunitinib
Temsirolimus
Graphic 68013 Version 6.0
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NCI CTCAE v5.0 mucositis oral
Adverse
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
event
Mucositis oral Asymptomatic Moderate Severe pain, Life- Death

or mild pain or ulcer interfering threatening
symptoms; that does not with oral consequences;
intervention interfere with intake urgent
not indicated oral intake; intervention
modified diet indicated
indicated
Mucositis oral is characterized by ulceration or inflammation of the oral mucosa.
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.
Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National
Institutes of Health, National Cancer Institute. Available at:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf (Accessed
March 27, 2018).
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Chemotherapy-related mucositis
Image created by Sook-Bin Woo, MS, DMD, MMSc. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All right
3/29/23, 1:12 PM 1152
Stomatitis with aphthous-type ulcers in a patient treated with a mechanistic

(previously called mammalian) target of rapamycin (mTOR) inhibitor
(A) Multiple mIAS of the soft palate with mTOR inhibitor (everolimus).
(B) Typical mIAS with an erythematous halo onnonkeratinized mucosa (everolimus).
(C) A major aphthous-like ulceration with everolimus (mIAS).
mTOR: mechanistic (previously called mammalian) target of rapamycin; mIAS: mTOR inhibitor-associated
stomatitis.
Reprinted by permission from Springer: Supportive Care in Cancer. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by
anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer 2017; 25:1713. Copyright © 2017.
https://www.springer.com/journal/520.
3/29/23, 1:12 PM 1152
Oral mucositis in patients treated with chemotherapy agents that target the
epidermal growth factor receptor (EGFR) or human EGFR2 (HER2)
A) Grade 1 mucositis with panitumumab (monoclonal antibody targeting EGFR).
B) Mucositis induced by afatinib (pan-HER tyrosine kinase inhibitor).
C) Mucositis involving the labial mucosa induced by erlotinib in monotherapy (antiEGFR).
D) Diffuse radio-induced mucositis affecting the keratinized mucosa (dorsum of the tongue).
E) High-grade ≥3 mucositis induced by the association of head and neck radiotherapy and cetuximab.
F) Mucositis induced by cetuximab and chemotherapy (carboplatin and 5FU) in combination.
EGFR: epidermal growth factor receptor; HER: human epidermal growth factor receptor; 5FU: 5-fluorouracil.
Reprinted by permission from Springer: Supportive Care in Cancer. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by
anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer 2017; 25:1713. Copyright © 2017.
https://www.springer.com/journal/520.
3/29/23, 1:12 PM 1152
Recommended intraoral photobiomodulation (laser therapy) protocols for

prevention of oral mucositis from the MASCC/ISOO
Power Energy
Cancer Time per Spot Num
Wavelength density density
treatment Protocol spot size o
(nm) (irradiance; (fluence;
modality (seconds) (cm 2 ) sit
mW/cm 2 ) J/cm 2 )
HSCT #1 632.8 31.25 40 1.0 0.8 1
#2 650 1000 ¶ 2 2.0 0.04 54 t
RT #1 632.8 24 125 3.0 1 1
RT-CT #1 660 417 ¶ 10 4.2 0.24 7
#2 660 625 ¶ 10 6.2 0.04 6
MASCC: Multinational Association of Supportive Care in Cancer; ISOO: International Society of Oral
Oncology; HSCT: hematopoietic stem cell transplantation; RT: radiotherapy; CT: chemotherapy.
* The number of treated surface areas within the oral mucosa receiving laser therapy. Within these
areas, laser therapy was applied using a spot treatment technique to cover the entire surface area;
spot size was variable in the trials.
¶ Potential thermal effect. The clinician is advised to pay attention to the combination of specific
parameters.
References:
1. Barasch A, Peterson DE, Tanzer JM, et al. Heliumneon laser effects on conditioning-induced oral mucositis in bone
marrow transplantation patients. Cancer 1995; 76:2550.
2. Schubert MM, Eduardo FP, Guthrie KA, et al. A phase III randomized double-blind placebo-controlled clinical trial to
determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing
hematopoietic cell transplantation. Support Care Cancer 2007; 15:1145.
3/29/23, 1:12 PM 1152
3. Gautam AP, Fernandes DJ, Vidyasagar MS, et al. Low level laser therapy against radiation induced oral mucositis in
elderly head and neck cancer patients-a randomized placebo controlled trial. J Photochem Photobiol B 2015; 144:51.
4. Antunes HS, Herchenhorn D, Small IA, et al. Phase III trial of low-level laser therapy to prevent oral mucositis in head
and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol 2013; 109:297.
5. Oton-Leite AF, Silva GB, Morais MO, et al. Effect of low-level laser therapy on chemoradiotherapy-induced oral
mucositis and salivary inflammatory mediators in head and neck cancer patients. Lasers Surg Med 2015; 47:296.
Reprinted by permission from: Springer: Supportive Care in Cancer. Zadik Y, Arany P, Rodrigues Fregnani ER, et al. Systematic
review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines.
Support Care Cancer 2019; 27:3969. Copyright © 2019. https://link.springer.com/journal/520.
3/29/23, 1:12 PM 1152
Contributor Disclosures
Robert S Negrin, MD Equity Ownership/Stock Options: BioEclipse Therapeutics [Cellular
immunotherapy];Biorasi[CRO];Cell Source [Cellular therapy];Co-Immune Therapeutics [Cellular
therapy];Magenta Pharmaceuticals [Transplantation]. Grant/Research/Clinical Trial Support: Orca
Biosystems [Cellular therapy]. Consultant/Advisory Boards: Amgen [Immuno-oncology];Biorasi[CRO];Cell
Source [Cellular therapy];Co-Immune Therapeutics [Cell therapy];DualYX[Immune function];Garuda [Stem
cell biology and cell therapy];Kuur Therapeutics [Cell therapy];Lightstone Ventures[Cellular
therapy];Magenta Pharmaceuticals [Transplantation];Surrezon[GVHD treatment];Takeda [Cell therapy].
Other Financial Interest: American Society of Hematology [Editor in Chief of "Blood Advances"]. All of the
relevant financial relationships listed have been mitigated. Nathaniel S Treister, DMD, DMSc,
DABOM Consultant/Advisory Boards: MuReva Phototherapy [light based therapy for prevention of oral
mucositis]. All of the relevant financial relationships listed have been mitigated. Reed E Drews, MD No
relevant financial relationship(s) with ineligible companies to disclose. Sadhna R Vora, MD No relevant
financial relationship(s) with ineligible companies to disclose.
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Oral Toxicity Associated With Chemotherapy

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3/29/23, 1:12 PM 1152

Official reprint from UpToDate®

Oral toxicity associated with systemic anticancer therapy

Oral mucositis affects on average 20 to 40 percent of patients receiving conventional-dose

Pathobiology — The pathobiology underlying damage to the oral mucosal barrier is complex,

● Signaling and amplification – As proinflammatory cytokines accumulate, they damage

Specific anticancer agents

● Molecularly targeted agents – The range of reported rates of stomatitis in patients

• Oral mucositis is reported in 30 to 40 percent of patients receiving therapy with the

approximately 4 to 8 percent [12,17-25]. In a review, mTOR inhibitor-associated

Preexisting oral disease — Oral disease that is present prior to treatment is thought to

● Poor oral hygiene

Other factors — Younger patients have a relatively greater risk of chemotherapy-induced

A role for genetic susceptibility (eg, inherited polymorphisms in drug-metabolizing enzymes

● Conventional cytotoxic agents – For conventional cytotoxic agents, direct stomatotoxic

Mucositis is typically a self-limited phenomenon. Following conventional cytotoxic

● Molecularly-targeted agents – In general, the oral mucositis seen with molecularly

● Immune checkpoint inhibitors –The mucositis associated with immune checkpoint

The World Health Organization also has a grading scale, as follows:

● Grade 0 – No oral mucositis

Infectious complications — An intact oral mucous membrane creates a physical barrier to

Oral candidiasis — As noted above, the most common superinfecting organism in

Superficial oropharyngeal candidiasis can be treated topically with clotrimazole troches or

HSV reactivation — Given the high risk of reactivation, antiviral prophylaxis is indicated

● Pulpoperiapical disease – Periapical radiolucencies may represent pulpoperiapical dental

● Periodontal disease – Pretherapy dental treatment is often recommended to eliminate

• The effectiveness of a preventive oral protocol was evaluated in a prospective,

• On the other hand, in a retrospective review of 58 patients undergoing allogeneic or

• A prospective pilot trial was conducted at the University of Chicago in which 48

If an intertherapy dental infection does arise, it can usually be managed effectively

Because chronic periodontal disease is associated with a substantial microbial burden

● Tooth extraction – Tooth extraction is commonly recommended prior to therapy for

Patients receiving chemotherapy — A number of strategies have been employed to prevent

Preventive treatments that may be beneficial

Oral cryotherapy — For patients receiving bolus FU-containing chemotherapy we

● Fluorouracil-containing regimens – Stomatitis is a major dose-limiting toxicity of FU

• A 2020 systemic review conducted by MASCC/ISOO, which included seven trials of

Palifermin — We suggest palifermin to prevent oral mucositis in patients undergoing

Palifermin is a recombinant keratinocyte growth factor that stimulates proliferation and

● Benefit was initially shown in a double-blind, placebo-controlled multicenter trial in which

● Similarly, a randomized placebo-controlled trial of palifermin in 160 patients undergoing

● A 2020 systematic review by an expert panel of the MASCC/ISOO concluded that no

Photobiomodulation (low-level laser therapy) — The use of photobiomodulation

● In one trial, 38 patients undergoing autologous or allogeneic HCT were randomly

● In a second trial, 70 patients undergoing autologous or allogeneic HCT were randomly

A systematic review of biomodulation for management of oral mucositis in cancer patients

Photobiomodulation has been recommended in consensus guidelines, including those by the

Treatments that are not recommended

● Glutamine – Glutamine is a precursor for nucleotide synthesis and an important fuel

to facilitate healing of the GI mucosa, following damage by either radiation therapy or

• Parenteral – Supplementation with parenteral glutamine has been studied in the

- Oral glutamine failed to prevent FU-related mucositis in at least two trials of

- An oral suspension formulation of L-glutamine (Saforis) may provide greater

Independent confirmation of benefit is needed before routine use of prophylactic

At present, there is no commercially available formulation of any oral glutamine

• Allopurinol mouthwash – Allopurinol mouthwashes have been used in an attempt to

• Propantheline – An anticholinergic agent, propantheline has been used to decrease

A protective effect of propantheline-induced xerostomia was also suggested in a larger,

These data are insufficient to recommend the routine prophylactic use of

• Hematopoietic colony-stimulating factors – The possibility that hematopoietic