Compounds Preventing Oral Mucositis <40

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A comprehensive review of the compounds for the
prevention or treatment of oral mucositis in patients
undergoing radio-chemotherapy: Part 1
Journal: Current Pharmaceutical Biotechnology
Manuscript ID: CPB-2015-0074
Manuscript Type: Invited Review
Date Submitted by the Author: 27-Jun-2015
Complete List of Authors: Panahi, Yunes; Chemical Injuries Research Center, Baqiyatallah University
of Medical Sciences,
Shadboorestan, Amir
Ahmadi, Amirhossein; Faculty of Pharmacy, Mazandaran University of
Medical Sciences,
Ghobadi, Roja
Keywords:
oncology, oral mucositis, oral ulceration, radiotherapy, chemotherapy,
cancer
https://mc04.manuscriptcentral.com/cpb
Current Pharmaceutical Biotechnology

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Abstract
Oral mucositis is considered a painful condition that occurs in cancer patients after radiotherapy
and chemotherapy. It appears as small patches to areas of extensive ulceration and hemorrhage in
the oral mucosa. Oral mucositis is a major clinical challenge in oncology, characterized by pain
and inflammation of the mucous membrane surface that particularly result from radiation therapy
for head and neck cancer or from chemotherapeutic agents. Manifestations range from a burning
sensation to ulcer formation that affect patients’ quality of life by producing pain and discomfort
on swallowing, ultimately leading to malnutrition and dehydration. Despite its frequency and the
severity of its clinical manifestations, no effective treatment exists for mucositis. Various types
of compounds have been used for the treatment of oral mucositis or to reduce the severity of its
symptoms. This comprehensive review aims to update the knowledge regarding the various
compounds that are effective against mucositis following radiotherapy and/or chemotherapy.
Keywords: oral mucositis; oral ulceration; radiotherapy; chemotherapy; oncology
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1- Introduction
Cancer may be generally described as an uncontrolled growth and spread of abnormal cells in the
body. Cancer is one of the most common diseases, annually occurring in more than 14.1 million
people worldwide [1, 2]. It has been reported that lung cancer, prostate cancer, colorectal cancer,
and stomach cancer are the most common cancers among men, whereas breast cancer, colorectal
cancer, lung cancer, and cervical cancer are the most common cancers among women [1]. Cur-
rently, combinations of radiation therapy, chemotherapy, surgery, and targeted therapies are the
therapeutic strategies for cancer [3, 4].
Cancer chemotherapy has a broad role in treating a wide range of solid tumors such as cancers of
the bladder, breast, cervix, colorectum, esophagus, stomach, ovaries, pancreas and those of the
head and neck. Although treatment is not often curative for these cancers, treatment significantly
reduces disease progression and increases patients’ survival duration [5]. Radiotherapy is one the
most common therapies for cancer and has been widely used internationally. Radiotherapy may
cure or alleviate the symptoms of many cancer patients. Its applications have high costs and its
implementation requires expert staff. Previously, studies suggested that approximately 50% of all
cancer patients should receive radiation [6]. In the U.S, an estimated 1.6 million people received
cancer therapy each year and worldwide the numbers are much higher. Although it appears that
progress in cancer therapy has improved survival rates for many tumor types, these therapies
have also produced several unfortunate side-effects, such as oral mucositis [7].
The term oral mucositis appeared in the late 1980s to characterize the adverse effects of radiation
or chemotherapy-induced inflammation of the oral mucosa [8]. Mucositis is a major clinical
challenge in oncology, characterized by pain and inflammation of the surface of the mucous
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membrane resulting from chemotherapeutic agents or particularly, from radiation therapy for
head and neck cancer [9]. The incidence and severity of mucositis may vary broadly among pa-
tients, which are affected by the type of antineoplastic treatment administered and by patient-
related factors. Two-thirds of patients being treated for cancers of the larynx or hypopharynx de-
velop mucositis [10] and overall, approximately 40% of patients treated with chemotherapy de-
velop mucositis. This condition significantly decreases quality of life and carries economic con-
sequences for patients. For example, in patients with head and neck cancer (HNC), oral mucosi-
tis was correlated to an increase in costs, which was conditional upon the mucositis severity,
ranging from $1700 to $6000 per patient. Table 1 indicates the incidence of oral mucositis
among cancer patients [7, 11-13].
The principal serious side effect of chemotherapeutic agents on the oral mucosa occurs during
the first days. The oral lesions resolve, occurring two weeks after the end of treatment [14]. Mu-
cositis may affect nutritional status, speech, and pain control status. Severe mucositis generally
occurs in patients who are treated with bone marrow transplant (BMT) and in up to 80% of pa-
tients receiving radiation for head and neck cancers [9, 15]. Despite its frequency and the severi-
ty of clinical manifestations, no effective treatment for mucositis exists [16]. Various types of
compounds have been used for the treatment of oral mucositis or to reduce the severity of its side
effects. Among these, much attention has been paid to the use of naturally occurring compounds
due to their high efficacy and their less severe adverse effects [17]. This review aims to update the
knowledge regarding various compounds that are effective against mucositis.
2- The pathobiology of mucositis
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Sonis revised and introduced the biologic progression phases of mucositis. His proposed mecha-
nisms involve five phases as described below [18]. Additionally, the schematic description of the
5 biologic progression phases of mucositis is shown in figure 1.
Initiation: The administration of radiation therapy or chemotherapy rapidly induces an initia-
tion phase. Chemotherapeutics and radiation significantly produce reactive oxygen species
(ROS) with the half-lives of these compounds, depending on the stability of the molecule,
varying from a few nanoseconds to several hours [19]. ROS include the oxygen radicals (su-
peroxide anion radical O2
•−
, hydroxyl radicals •
OH) and some non-radical derivatives of O2
(hydrogen peroxide H2O2, singlet oxygen, alkylperoxide).
Message generation: ROS are capable of inducing DNA, lipid and cell membrane dam-
age. Moreover, they affect the many biochemical pathways such as the c-Jun N-terminal ki-
nase (JNK)/mitogen-activated protein (MAP) kinase pathway, nuclear factor erythroid 2-
related factor 2 (Nrf2), ceramide pathway, p53 and NF-κB. The NF-κB family consists of
five transcription factors including RELA (p65), c-BEL, RELB, NF-κB1 (p50/p105), and
NF-κB2 (p52/p100), which play key roles in the immune system, in inflammation and in the
regulation of cell proliferation and survival. A variety of stimuli such as free radicals, in-
flammatory stimuli, cytokines, carcinogens, tumor promoters, bacterial and viral infections,
γ-radiation, UV light, and X-rays activate members of this transcription factor family [20].
TNF, interleukins, chemokines, COX-2, 5-LOX, and MMP-9 are all regulated via NF-kB. In
unstimulated cells, NF-κB proteins are associated with inhibitory IκB proteins that preserve
NF-κB in an inactive state in the cytosol. TNF and Toll-like receptor activation lead to the
recruitment of adaptor proteins that activate the IκB kinase, which phosphorylates IκB. Fol-
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lowing the phosphorylation, IκB is targeted by the proteasome for ubiquitination and degra-
dation. Released NF-κB translocates to the nucleus and induces the expression of its target
genes such as TNF-α, IL-1β and IL-6, cyclin D1, Bcl-2, Bcl-xL, MMP, and VEGF [21, 22].
Because of these responses, a biologic process has begun that leads to mucosal injury.
Signaling and amplification: Many of the proteins that have been produced in the previous
step act as a stimulus for other pathways, leading to worsening of the injury. For example, it
has been demonstrated that TNF may positively feedback on NF-κB to heighten its response,
leading to the activation of mitogen-activated protein kinase (MAPK) signaling [18]. The
mitogen-activated protein (MAP) kinases include a family of protein kinases whose function
and regulation have been conserved from yeasts to mammals. MAP kinases regulate a broad
range of processes such as cell growth and differentiation, gene expression, mitosis, cell mo-
tility, metabolism, cell survival and apoptosis by the phosphorylation of target protein sub-
strates [23, 24]. The classic MAP kinase family encompasses three sub-families: extracellu-
lar signal-regulated kinase (ERK; ERK1 and ERK2), c-Jun N-terminal kinase (JNK; JNK1,
JNK2, and JNK3), and p38-MAP kinase (a, b, d, and g).
In addition to the above-mentioned pathways, many others pathways are involved in oral
mucositis. TGF-β constitutes a part of a large family of polypeptide growth factors, which
has three isoforms. TGF-β signaling occurs through the activation of types I and II trans-
membrane serine/threonine kinase receptors, which leads to the phosphorylation of Smads 2
and 3. Smad 2 and Smad 3 complex, which then binds to Smad4 and translocates to the nu-
cleus to regulate gene expression. [25, 26]. Han et al showed that TGFβ protein and signal-
ing activities significantly increased in radiation-induced oral mucositis in mice and in hu-
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man oral mucositis lesions. Due to the TGFβ1 activation growth arrest of irradiated epitheli-
al cells and to the severity of the condition, the epithelial layers become thinned, leading to
the development to an ulcer [27]. Another mechanism suggested by Li et al is that TGFβ1
induced NF-κB activation that is followed by inflammation [28].
The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, exists in
two distinct complexes, mTORC1 and mTORC2, and its activity regulates the metastasis
cascades including those of cell growth, cell proliferation, cell motility, cell survival, inva-
sion, and migration. The canonical pathway of mTOR activation depends on mitogen-driven
signaling through PI3K/Akt, although alternative non-Akt dependent activation through the
Ras/MEK/ERK pathway is now identified. Iglesias-Bartolome et al indicated that the inhibi-
tion of the mTOR with rapamycin increases the clonogenic capacity of primary human oral
keratinocytes and their resident self-renewing cells by preventing stem cell senescence. They
showed that this effect is mediated by the following:
1- Increased expression of the mitochondrial superoxide dismutase MnSOD
2- Protection from the loss of proliferative basal epithelial stem cells upon ionizing radiation
in vivo [29].
Ulceration: One week after the initiation of treatment, the ulcerative phase occurs. A main
characteristic of this phase is penetration damage of the epithelium into the submucosa that
leads to colonization by oral bacteria, increasing the risk of sepsis. Due to this microbial
colonization, cell wall products (lipopolysaccharides, lipoteichoic acid, cell wall antigens,
and a-glucans) are released and stimulate the production of additional proinflammatory cy-
tokines [11, 18].
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Healing: The final phase of mucositis is healing, a phase that lasts for 12 to 16 days. The
healing phase is related to the initiation of signaling from the submucosal extracellular ma-
trix (ECM) that leads to the migration, proliferation, and differentiation of epithelial cells at
the margin of the ulcers [8, 13, 30].
3- Risk factors of mucositis
Mucositis risk has been divided into two groups, patient-related and treatment-related. The pa-
tient-related risk factors include age, gender, body mass index, smoking, oral health and hygiene,
renal function and genetic factors. Generally, younger patients are more apt to develop mucositis
due to their increased cell turnover rate and the presence of more epidermal growth factor recep-
tors, whereas in older patients oral mucositis correspondingly occurs due to the development of
decreased renal function [31, 32]. Genetic factors are other prominent risk factors. Several stud-
ies indicated that oral mucositis is related to genes associated with chemotherapy metabolism.
For example, Schwab et al demonstrated that the development of oral mucositis was linked to
dihydropyrimidine dehydrogenase (DPYD) variants. Additionally, the progression of human oral
mucositis is affected by the expression of TNFα receptors types 1 and 2 [33].
The treatment-related variables comprise the type of therapy, the dose, and the route of admin-
istration. Previously studies indicated that the type of therapy is an important factor with, for ex-
ample, allogeneic transplantation carrying greater risk for the development of mucositis than au-
tologous transplantation. Moreover, Sonis concluded that in patients with hypopharyngeal can-
cer, the probability of oral mucositis declines 50% because the oral cavity was not influenced by
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the radiation field. Concerning the dose of administration, as a rule it has been confirmed that the
higher concentration doses used in head and neck cancer increased the risk of mucositis devel-
opment. However, mucositis induced by chemotherapy mostly occurred in hematological cancers
due to more prolonged and intense myelosuppression [8, 18, 32]. The most common chemother-
apeutic drugs that are responsible for oral mucositis are shown in Table 2.
4- Clinical manifestations
The complications of radiotherapy may occur in three stages, which include the following:
1- 10–20 Gy induces hyperkeratosis of the oral mucosa
2- More than 20 Gy of radiotherapy induces erythema (considered as the ﬁrst clinical sign
of mucositis)
3- More than 30 Gy induces ulceration, which occurs usually after the third week of treat-
ment.
The symptoms of radiotherapy-induced oral mucositis vary from pain and discomfort to the ina-
bility to tolerate food or liquids. After the completion of radiotherapy, the resolution of mucositis
will spontaneously occur over 2–6 weeks. Generally, oral mucositis induced by chemotherapy is
more hazardous than that induced by radiotherapy. After 5 to 10 days from chemotherapy, the
symptoms of mucositis commence. The most common symptoms of thermotherapy-induced oral
mucositis include erythema, which progresses to edema, ulceration, and pain. After the end of
chemotherapy, the mucosa requires approximately 7–10 days to recover completely. Speaking,
swallowing, and eating may be affected by severe mucositis pain that may require the admin-
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istration of systemic analgesics for pain reduction in these patients. Additionally, many other
complications may also occur, comprising bacterial and fungal infections, xerostomia, weight
loss, dehydration, and nutritional deficiencies [11, 34].
5- Diagnosis of mucositis
Principally, the diagnosis of oral mucositis is dependent on clinical manifestations. Notwith-
standing, a protocol is necessary to grade the mucositis severity. A variety of assessment tools
and grading scales have been introduced. The most prevalently used scales are the World Health
Organization (WHO) scale and the National Cancer Institute-Common Toxicity Criteria (NCI-
CTC) scales. Other scales include the Oral Assessment Guide (OAG), the Oral Mucositis As-
sessment Scale (OMAS), the Oral Mucositis Index (OMI) of the Western Consortium for Cancer
Nursing Research (WCCNR), and that of the European Organization for Research and Treatment
of Cancer (EORTC). Each of these assessment protocols have a variety of strengths and weak-
nesses [35]. The benefit of the WHO scale is that it incorporates objective and subjective criteria;
however, both the WHO and NCI-CTC depend on a combination of signs, symptoms and func-
tional changes, which may trigger interference with accurate grading [36]. Table 3 summarizes
several of these tools and scales along with their useful and adverse properties.
6- Prevention and/or treatment of mucositis
Various prophylaxis and therapy protocols have been introduced for oral mucositis. Recently, the
multinational Association of Supportive Care in Cancer and International Society of Oral Oncol-
ogy (MASCC/ISOO) conducted a comprehensive evidence-based review of the management of
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mucositis secondary to cancer therapy [37]. The major groups of compounds and various sub-
groups of substances used for the prophylaxis and treatment of oral mucositis are shown in table
4.
6-1- Oral care components
The main components of oral cavity care include evaluation, patient education, tooth brushing,
flossing, and the use of bland rinses such as normal saline or sodium bicarbonate along with cal-
cium phosphate that may be considered before starting and during cancer treatment. Combina-
tions of mouthwashes have occasionally been used. The mechanism through which these com-
pounds affect oral care is not well recognized. However, oral care may probably reduce the pres-
ence of microbial flora, the development of pain and bleeding, and prevent infections [35, 38].
The suggested MASCC/ISOO oral care protocol provides useful and effective approaches for the
prevention of oral mucositis. This protocol includes a combination of tooth-brushing, flossing,
and more than 1 type of mouth rinse to maintain oral hygiene. Additionally, MASCC/ISOO has
reported that chlorhexidine mouthwash should not be used for the prevention of oral mucositis in
patients receiving head and neck cancer radiotherapy [37].
6-1-1- Calcium phosphate rinses
Numerous studies have been conducted to date to evaluate the efficacy of calcium phosphate on
oral mucositis induced by chemotherapy and radiotherapy. The majority of these studies con-
cluded that calcium phosphate may significantly reduce the grade and/or duration, as well as the
pain and hospitalization associated with oral mucositis [39]. Quinn and colleagues’ proposed
guideline includes the use of Caphosol (a neutral supersaturated Ca2+
/PO4
3-
oral rinse), 4–10
times daily, starting from the ﬁrst day of chemotherapy and/or radiotherapy [40].
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The main reason for the use of Caphosol in cancer patients is to recover the normal ionic and pH
balance in the oral cavity [41]. Markiewicz et al suggested that these highly concentrated ions
exert their advantageous effect by spreading out into the intercellular spaces in the mucosal epi-
thelium. Ca2+
ions have a prominent function in several processes such as tissue repair, the in-
flammatory process, the blood-clotting cascade, and fibrin production. Moreover, PO4
3-
ions play
significant roles that include the facilitation of intracellular signaling and the regulation of the
voltage potential inside the cell, both of which have been indicated as critical for repairing and
protecting damaged mucosal surfaces. Additionally, with the reduction of acidity in the oral cavi-
ty, mucosal damage is prevented and mucositis symptoms decrease [42].
6-1-2- Saline and sodium bicarbonate
Saline solution and sodium bicarbonate solution, or a combination of these, have been used for
many decades for oral hygiene care. These bland rinses help maintain moisture of the oral epithe-
lial barriers and decrease the risk of infection with the rise in the oral pH. Due to salty and fishy
tastes, a 0.9% saline solution and saline-sodium bicarbonate solution should be used at cool tem-
peratures. Sodium bicarbonate with the formula NaHCO3 does not have any taste and may be
easily used. Because of the reaction of HCO3 with H+
, H2CO3 is produced that then resolves into
CO2 and H2O. Although sodium bicarbonate has no antimicrobial effect, it has been used as a
cleansing agent that dissolves mucus and loosens debris that has accumulated around the teeth.
Additionally, another advantage of sodium bicarbonate is that it does not require a prescription
and patients may prepare this solution at home [43, 44]. However, a randomized controlled trial
performed by Ozden et al indicated that there was no significant difference between saline and
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sodium bicarbonate solutions on mucous membrane integrity and bacterial colonization [45].
Table 5 summarizes the basic oral care components in detail.
7- Prevention of Infection compounds
In cancer patients, the main cause of pain and bacterial colonization is oral mucositis. These in-
fections include both Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella and
Enterobacter spp.) and Gram-positive (coagulase-negative staphylococci and Enterococcus) bac-
teria and fungi. To date, several compounds have been used for the prevention and treatment of
oral mucositis-induced infections [46].
7-1- Chlorhexidine
Chlorhexidine gluconate is a compound with a hexamethylene bridge and terminal 4-
chlorophenyl groups, which is widely used in dentistry. This substance (as a mouthwash, at con-
centrations below 0.12% and 0.2%) not only produces a protective barrier against mucosal dam-
age but it also has antibacterial and fungicidal effects. The anti-bacterial mechanism of chlorhex-
idine gluconate includes the binding of the positively charged molecules to the negatively
charged bacterial cell wall, which leads to the disruption of membrane transport. However, sev-
eral investigators believed that the effectiveness of chlorhexidine solution varies from that of re-
ducing oral mucositis to no effects. Moreover, it has some disadvantages such as tooth discolora-
tion, a bitter taste, and an unpleasant sensation. Notwithstanding its potential benefits,
MASCC/ISOO suggested that chlorhexidine not be used as prophylaxis of oral mucositis in pa-
tients with solid tumors of the head and neck who are undergoing radiotherapy [44, 47].
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7-2- Antiviral agents
Acyclovir has been the first-line treatment for herpes simplex virus infections in addition to its
use for the treatment of varicella zoster (chickenpox). Within infected cells, acyclovir is phos-
phorylated by viral thymidine kinase that leads to the production of the triphosphate derivative of
acyclovir. Due to the translocation of this compound to the nucleus, the DNA polymerase of the
virus is inhibited. Compared to acyclovir, valacyclovir and famciclovir have higher bioavailabil-
ity (approximately 10-fold).
7-3- Antifungal agents
7-3-1-Polyene antifungals: Nystatin and amphotericin B are polyene antifungal agents that, after
interaction with ergosterols in the fungal cell membranes, lead to increased permeability that
leads to K+
leakage, acidification, and the death of the fungus. Although toxic when given sys-
temically, they are not absorbed from the gut and are safe for oral use, and they do not have
problems of drug interactions [48].
7-3-2-Azole antifungals: Clotrimazole exhibits fungistatic activity in addition to having anti-
staphylococcal activity. Troche or throat lozenge preparations are used for oropharyngeal candid-
iasis (oral thrush) or for prophylaxis against oral thrush in neutropenic patients. Clotrimazole
binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other
sterols required for cell membrane production. Although systemic absorption of clotrimazole is
limited, it is similar to other azoles in that it is a cytochrome P-450 inhibitor (primarily CYP3A4)
and may cause the elevation of serum levels of several medications. Fluconazole is a first-
generation triazole antifungal medication. It is a safe oral antifungal agent with a favorable spec-
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trum of activity and pharmacokinetic proﬁle. Fluconazole inhibits the fungal cytochrome P450
enzyme 14α-demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an
essential component of the fungal cytoplasmic membrane, causing the subsequent accumulation
of 14α-methyl sterols. Previous studies reported that Candida colonization in head and neck can-
cer patients receiving radiation therapy was as high as 75%. Additionally, fluconazole is a cur-
rent standard treatment for patients with oral candidiasis [49].
Chlorhexidine gluconate rinse described previously also has antifungal activity but cannot be
swallowed [48].
7-4- Iseganan (IB 367, protegrin IB 367)
Iseganan is a synthetic protegrin (a structural analog of protegrin-1) with broad-spectrum anti-
microbial activity for the treatment and prevention of oral mucositis. Its targets include Gram-
negative and -positive bacteria as well as Candida albicans. The main mechanism of action of
iseganan is through binding to the lipid membrane of the pathogen and the disruption of mem-
brane integrity. Iseganan as a cationic antimicrobial peptide has rapid microbicidal activity in
saliva. To date, several studies have been performed to evaluate its protective effects against oral
mucositis in cancer patients. Gilles et al indicated that treatment with oral iseganan mouth rinse
(9 mg/dose) six times a day failed to prevent or to reduce stomatitis, ulcerative oral mucositis, or
its clinical sequelae relative to a placebo [50]. Similar results was obtained by Trotti and col-
leagues [51] and based on these results, the development of intrabiotics for this purpose was
abandoned [52].
7-5- Povidone-iodine
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The broad antimicrobial spectrum of povidone-iodine is well documented. This compound is a
combination of molecular iodine and poly-vinyl-pyrrolidone. The bactericidal component is free
iodine, and these levels are dependent on the concentration of the povidone-iodine solution [53].
Adamietz et al indicated that povidone-iodine significantly reduced the severity and incidence of
radiotherapy-induced oral mucositis in head and neck cancer patients [54]. Similar results were
obtained by Rahn et al who showed that povidone-iodine reduced the incidence of oral mucositis
compared to rinsing with sterile water (n=20 in each group) [55].
7-6- Other agents
7-6-1-Triclosan: Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol), a xenoestrogen, is a
broad-spectrum antibacterial compound and is used extensively in cosmetics, dentifrices, soap,
and other consumer products [56]. The mechanism of triclosan is the destruction of bacterial cell
membranes. Additionally, triclosan has been indicated to work by blocking lipid synthesis in
Escherichia coli by inhibiting the enzyme enoyl-acyl carrier protein reductase from type II bacte-
rial fatty acid synthesis [57]. Unfortunately, it was recently demonstrated that triclosan may play
a role in cancer development, due to estrogenicity or its ability to inhibit fatty acid synthesis [56].
Satheeshkumar et al showed that triclosan in comparison to sodium bicarbonate was more effec-
tive in reducing oral mucositis in head and neck cancer patients who were undergoing radiother-
apy [58].
7-6-2-Kefir: Kefir is a fermented dairy beverage that is produced by the bacteria and yeast within
kefir grains. Several components have been detected in kefir. Due to kefir fermentation, the main
compounds that are produced include lactic acid, ethanol, and CO2, which are responsible for the
viscosity, acidity, and the low alcohol content of this beverage. Various studies demonstrated
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that kefir and its constituents have broad-spectrum antimicrobial activity [59]. In one study con-
ducted by Topuz and colleagues, the investigators concluded that there was no significant effect
between the kefir and the control groups in the reduction of chemotherapy-induced oral mucosi-
tis [60].
7-7- Antibiotic lozenges/pastes
7-7-1- PTA: The combination of polymyxin 2 mg, tobramycin 1.8 mg, and amphotericin B 10
mg is known as PTA. Considering the fact that the etiology of oral mucositis in cancer patients is
mostly due to Gram-negative bacteria, PTA has therefore been used for the prevention and
treatment of this side effect. Polymyxins are produced by the Gram-positive bacterium Bacillus
polymyxa and are selectively toxic for Gram-negative bacteria. Additionally, tobramycin is an
aminoglycoside antibiotic used to treat various types of bacterial infections, particularly Gram-
negative infections. Thus far, several studies were conducted to evaluate PTA in the prevention
and treatment of oral mucositis in cancer patients. Although initial pilot studies on PTA suggest-
ed the potential efficacy of this combination, subsequent larger well-controlled studies clearly
indicated that the topical use of PTA did not prevent oral mucositis or reduce its severity [61].
7-7-2- BCoG: This product is less costly than PTA and includes bacitracin 6 mg, clotrimazole 10
mg, and gentamicin 4 mg. The BCoG lozenge is active against Gram-positive cocci, Gram-
negative bacilli, and yeast micro-organisms [62].
8- Anti-inflammatory agents
As described, the second and third stages of oral mucositis involve the consequent activation of
transcription factors eventually leading to the upregulation of genes coding for inflammatory cy-
tokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, NF-κB and IL-6, which re-
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sults in increased tissue injury in all compartments of the mucosa [63]. Because cytotoxic and
radiotherapy for head and neck cancers induced prominent changes in the epithelium and muco-
sa, such use of anti-inflammatory agents could be a strategy for the amelioration of radiation-
induced oral mucositis [64, 65].
8-1- Benzydamine
Benzydamine hydrochloride is a nonsteroidal anti-inﬂammatory drug (NSAID) that has shown
topical anti-inﬂammatory, analgesic, anesthetic, and antimicrobial activities [66]. Previous stud-
ies demonstrated that this agent has anti-TNF alpha, anti-inflammatory effects in addition to act-
ing as a membrane stabilizer [67]. To date, several studies indicated that benzydamine hydro-
chloride has a prominent role in the prevention and treatment of oral mucositis. Recently,
Sheibani and colleagues demonstrated that benzydamine hydrochloride significantly decreased
oral mucositis and its complications in head and neck cancer patients [68]. However, inconsistent
results have occasionally been reported regarding its efficacy. For example, Lalla et al found that
benzydamine hydrochloride could not decrease oral mucositis in head and neck cancer patients
who received radiotherapy [69].
8-2- Misoprostol
Misoprostol is a prostaglandin E1 analog that has anti-inflammatory and mucosa-protecting ef-
fects. The protective effect of this agent against oral mucositis is derived from its cytoprotective
and radioprotective properties [70]. In a randomized double blind placebo-controlled study con-
ducted by Lalla et al, 22 patients were randomized to misoprostol rinse and 26 patients were ran-
domized to placebo rinse. Their results indicated no significant difference between the two
groups in mucositis or pain severity [71]. In another study by Duenas-Gonzalez et al, it was
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demonstrated that the incidence and severity of oral mucositis was increased in patients who
were treated with misoprostol tablets when compared with the placebo control group [72].
8-3- Other compounds
Diphenhydramine is an inverse agonist of the histamine H1 receptor. Diphenhydramine has been
evaluated in combination with a variety of mouthwashes with mixed actions. Rothwell et al indi-
cated that the combination of diphenhydramine with hydrocortisone, nystatin, and tetracycline
significantly decreased oral mucositis in head and neck cancer patients [73]. However, in other
studies by Carnel et al no significant difference between the control and diphenhydramine
groups was found [74, 75].
As noted regarding the pathophysiology of oral mucositis, the COX pathway is an important
pathway involved in mediating the inflammatory response. Arachidonic acid is converted to
prostaglandin H2 (PGH2), a process that is mediated by COX-1 and COX-2. That step is fol-
lowed by the conversion of PGH2 to PGE2 by PGE synthase and then to PGI2 by prostacyclin
synthase [76].
Lalla et al conducted a randomized double-blind placebo-controlled trial to evaluate the protec-
tive role of celecoxib on radiotherapy-induced oral mucositis in head and neck cancer patients.
Their results indicated that the daily use of celecoxib during the radiotherapy period did not re-
duce the severity of clinical oral mucositis, pain, dietary compromise or the use of opioid analge-
sics [77]. In another study, similar results were obtained by Haagen et al. who demonstrated that
a TNF-α inhibiting antibody (inﬂiximab) or a COX-2 inhibitor (celecoxib) could not reduce radi-
ation-induced oral mucositis [64]. Porteder et al demonstrated that PGE2 is capable of reducing
oral mucositis and pain in cancer patients who received chemo-radiotherapy [78]. However, the-
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se results were not confirmed in the randomized double-blind placebo-controlled study conduct-
ed by Labar et al [79].
Corticosteroids are other anti-inflammatory agents that have been used for the prevention and
treatment of oral mucositis in cancer patients. Betamethasone rinse could decrease oral mucositis
in all of the patients who received radiotherapy; however, in a prospective, randomized, and con-
trolled trial that was conducted by Leborgne et al on 32 head and neck cancer patients, predni-
sone did not reduce the intensity or duration of oral mucositis [80, 81].
In addition to the compounds mentioned, several anti-inflammatory agents are currently used for
the prevention and treatment of mucositis, as shown in detail in table 7.
Conclusion
In Part 1 of this review, oral mucositis has been comprehensively described. Additionally, three
major groups of compounds and various subgroups of substances for mucositis prevention and
treatment were reviewed. In Part 2, other major groups of compounds and their various sub-
groups that are used against oral mucositis will be discussed.
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Figure 1. The schematic description of different phases in the biologic progression of mucositis
Table 1. Incidence of oral mucositis among cancer patients [15]
Table 2. Different chemotherapeutic agents that induce oral mucositis [8]
Table 3. Different assessment Tools and grading Scales [35]
Table 4. Major groups of compounds and various subgroup substances for mucositis prevention
and treatment
Table 5. Basic oral care components for the prevention and treatment of oral mucositis in cancer
patients
Table 6. Anti-infective agents for the prophylaxis and treatment of oral mucositis
Table 7. Anti-inflammatory agents for the prophylaxis and treatment of oral mucositis
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. Incidence of oral mucositis among cancer patients [15]
Oral mucositis
Cancer patients
Incidence (%) Grade 3/4 (%)
Radiotherapy for head and neck cancer 85-100 25-45
Stem-cell transplantation 75-100 25-60
Solid tumors with myelosuppression 5-40 5-15
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Table 2. Different chemotherapeutic agents that induce oral mucositis [8]
Alkylating agents: Busulfan, Cyclophosphamide, Thiotepa, Procarbazine
Anthracyclines: Doxorubicin, Epirubicin, Daunorubicin
Antimetabolites: 5-FU, Methotrexate, Hydroxyurea
Antitumor agents: Actinomycin D, Bleomycin, Mitomycin
Taxanes: Paclitaxel
Vinca alkaloids: Vincristine, Vinblastine
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Tool or scale Components addressed Ranking approach Comment
National Cancer Institute Common
Toxicity Criteria (NCI-CTC)
Clinician assessment: areas of
anatomy not clearly indicated
0 = none; 1 = erythema of the mucosa;
2 = patchy ulcerations or
pseudomembranes; 3 = confluent
ulcerations or pseudomembranes,
bleeding with minor trauma; and 4 =
tissue necrosis, significant spontaneous
bleeding, and life-threatening
consequences
Does not include functional or
subjective assessment or pain
Oral Assessment Guide (OAG) Clinician assessment: voice,
swallow, lips, tongue, saliva,
mucous membranes, gingiva,
and teeth and dentures
Each aspect is rated on a 1–3 scale: 1 =
normal, 2 = altered but no loss of
function or barrier breakdown, and 3 =
loss of function or barrier breakdown
Clear, concise, and clinically
relevant; does not differentiate
areas of mucous membranes
Oral Mucositis Assessment Scale
(OMAS)
Clinician assessment: erythema
and ulceration in eight anatom-
ic locations of the oral cavity
Patient report: subjective out-
comes such as pain, difficulty
swallowing, and ability to eat
Erythema 0 (none) to 2 (severe);
ulceration formation 0 (no lesions) to 3
(> 3 cm2); patients reported on 100
mm visual analog scales 0 (no
problem) to 100 (worst problem);
ability to eat categorical scale-types of
food
Includes quantifiable function
and objective and subjective
measures, and focuses on mucous
membranes; does not include
other oral cavity changes, and
may require more training than
less extensive tools
Oral Mucositis Index (OMI) Clinician assessment: lips,
labial mucosa, buccal mucosa,
floor of mouth, soft palate, and
tongue; all areas assessed for
atrophy, ulcers, and/or erythema
Atrophy, ulceration, erythema, and
edema; scored from 0 (none) to 3
(severe) and are summed for a total
score
Strong dental focus; does not
include functional or subjective
assessment of pain
World Health Organization (WHO) Clinician assessment: areas of
anatomy not clearly indicated
0 = none; 1= soreness with or without
erythema; 2 = erythema, ulcers, patient
can swallow food; 3 = ulcers with
extensive erythema, patient cannot
swallow solid food; and 4 =
Swallowing and eating
addressed; pain is not explicitly
addressed.
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alimentation is not possible
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Table 4. Major groups of compounds and various subgroup substances for mucositis prevention
and treatment
Oral Care Components Oral care protocols, Normal saline, Sodium bicarbonate,
Calcium phosphate, Combination mouthwashes
Infection Prevention Chlorhexidine, Clindamycin, Acyclovir, Valacyclovir,
Famciclovir, Fluconazole, Clotrimazole, Nystatin, Triclosan,
Kefir, Iseganan, PTA (polymyxin, Tobramycin, and
Amphotericin B), Povidone–iodine
Anti-Inflammatory Agents Dinoprostone, Misoprostol, Prednisone, Pentoxifylline,
Benzydamine, Diphenhydramine, Prostaglandin E2,
Immunoglobulins, Corticosteroids, Indomethacin, Azelastine,
Mesalazine, Aspirin, Orgotein, Flurbiprofen, Histamine,
Colchicine, and Placentrex
Reactive Oxygen Species Inhibitors Amifostine, N-acetylcysteine, Manganese Superoxide
Dismutase
Coating Agents Hydroxypropylcellulose Gel, Polyvinylpyrrolidone and
Sodium Hyaluronate, Sucralfate, Gelclair
Anesthetics Tetracaine, Dyclonine, MGI-209 (with benzocaine), Cocaine,
Amethocaine
Analgesics Capsaicin, Methadone, Ketamine, PCA (patient-controlled
analgesia), Fentanyl, Morphine
Salivary Function Modifiers Propantheline, Pilocarpine
Natural and Miscellaneous Agents Glutamine, Vitamins, Honey, Zinc, Aloe vera gel, Rhodiola
algida, Manuka and Kanuka oils, Traumeel S, Wobe-Mugos
E, Azelastine
Growth Factors Epidermal Growth Factor (EGF), Granulocyte-Colony
Stimulating Factor (GCSF), Granulocyte-Macrophage
Colony-Stimulating Factor (GMCSF), Transforming Growth
Factor Beta 3 (TGFb3), Interleukin 11 (IL-11), Fibroblast
Growth Factors (FGFs)
Cryotherapy
Laser Therapy
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Compound Cause of
OM
Indication No.
patients
Author and year Effec
t
Study design Comment
Calcium phosphate HSCT Prevention 25 Bhatt et al. 2010
[108]
Yes Phase III trial Their proposed protocol decreased
the incidence, duration and
severity of mucositis.
HSCT Prevention 95 Papas et al. 2003
[142]
Yes A prospective
randomized trial
Signiﬁcant decrease in the number
of mucositis days, the peak level
of mucositis and the days
requiring morphine
CT Prevention 56 Wasko-Grabowska
et al. 2011 [143]
Yes Single-center
study
Caphosol may reduce the
incidence, severity, and duration
of oral mucositis and decrease the
number of days requiring
painkillers among patients treated
with a BEAM (carmustine,
cytarabine, etoposide, melphalan)
regimen but not with a Mel 200
regimen.
HSCT Prevention 40 Markiewicz et al.
2012 [42]
Yes A randomized
controlled trial
Significantly lower mean
measures of oral toxicity, peak
mouth pain, and disease course
duration
CT/RT Prevention 52 Stokman et al. 2012
[41]
No A prospective
randomized trial
No signiﬁcant difference was
observed between the CP mouth
rinse group and the control group.
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RT Prevention 42 Miyamoto et al.
2012 [144]
Yes A retrospective
matched-control
study
Significantly reduced the
incidence of radiation-induced oral
mucositis for WHO grade 3 and 4
mucositis and decreased the
duration of hospitalization.
HSCT Prevention 40 Svanberg et al. 2015
[145]
Yes Pilot study No additional signiﬁcant effect of
combining Caphosol with oral
cryotherapy
RT Prevention 98 Rao et al. 2014 [146] Yes Phase II
multicenter trial
Although patients reported modest
improvements in symptoms, their
study did not show a signiﬁcant
decrease in WHO grade ≥ P2
mucositis (compared with the
historic rate of 90% or higher
mucositis) below the 90% historic
rate.
HSCT/ CT Prevention 34 Raphael et al. 2014
[147]
No Prospective
multicenter
double-blind
randomized
controlled trial
The therapeutic use of Caphosol
was not beneficial in the treatment
of pediatric patients with cancer
therapy-induced oral mucositis.
CT Prevention 104 Pettit et al. 2014
[148]
No Prospective
single center
There is no evidence from this
study that Mugard™, Caphosol®
or Episil® improves mucositis and
dysphagia toxicity or the level of
analgesia prescribed compared
with their standard mouth care
regimen (aspirin, glycerin and
sucralfate).
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Saline (0.9%) CT Prevention 225 Sorenson et al. 2008
[102]
No Double-blind,
placebo-
controlled
randomized
study
In comparison with chlorhexidine
or cryotherapy, normal saline
failed to reduce oral mucositis.
CT/RT Prevention 212 Graham et al. 1993
[149]
No Placebo-
controlled
double-blind
phase 3 trial
Compared to palifermine, normal
saline could not decrease oral
mucositis in cancer patients.
HSCT Prevention 53 Soga et al. 2011
[150]
Yes Pilot study,
single center
They concluded that oral mucositis
in HSCT patients may be
alleviated by simple strategies
aimed at maintaining the oral
cavity clean and moist.
CT/RT Prevention 18 Kenny 1990 [151] Yes Pilot study,
single center
They suggested that the
maintenance of oral cavity hygiene
may have reduced oral mucositis.
CT/BMT Prevention 86 Epstein et al. 1992
[135]
No Randomized
study, phase 3
trial
None of the rinses including
chlorhexidine, nystatin and saline
decreased oral mucositis.
CT Prevention 132 Vokurka et al. 2005
[132]
No Randomized
multicenter
study
Compared to povidone-iodine, the
normal saline mouthwashes used
for oral cavity prophylactic care in
patients after high-dose
chemotherapy did not result in any
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significant impairment of the
course of OM.
HSCT Prevention 25 Bhatt et al. 2010
[108]
Yes Pilot study,
single center
Implementation of a standardized
oral care protocol for mucositis
management resulted in the
decreased incidence, duration and
severity of mucositis, and also
reduced the global negative impact
of mucositis.
RT Prevention 50 Maiya et al. 2006
[152]
No Randomized,
single center
Their results indicated that low-
level He-Ne laser therapy was
more effective compared to
normal saline in the prevention
and treatment of the mucositis in
head and neck cancer patients.
Sodium bicarbonate RT Prevention 200 Dodd et al. 2000
[98]
No Randomized
double-blind
phase 3 trial
Given the comparable
effectiveness of the mouthwashes,
the least costly was the salt and
soda mouthwash.
HSCT Treatment 31 Turhal et al. 2000
[97]
Yes Phase 4 clinical
trial
Their results suggested that this
three-drug mouthwash (lidocaine,
diphenhydramine, and sodium
bicarbonate in normal saline)
provided effective symptomatic
relief in patients with
chemotherapy-induced mucositis.
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RT Prevention 80 Madan et al. 2008
[115]
Yes Randomized
clinical trial
Their result demonstrated that the
use of povidone-iodine
mouthwash might reduce the
severity and delay the onset of oral
mucositis due to antineoplastic
radiotherapy compared to soda and
chlorohexidine.
CT Prevention 48 Choi et al. 2012 [44] Yes Randomized
clinical trial
Their results indicated that oral
care by sodium bicarbonate
solution for acute leukemia
patients undergoing chemotherapy
was an effective intervention to
improve oral health in comparison
to chlorohexidine.
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Compound Cause of
OM
Route of
administratio
n
No.
patients
Author and year Effect Study design Comment
Chlorhexidine CT Mouthwash 206 Sorenson et al. 2008
[102]
Yes Double-blind placebo-
controlled randomized
study
The frequency and duration of OM
were significantly improved by
prophylactic chlorhexidine and by
cryotherapy.
CT Mouthwash 34 Cheng 2004 [92] Yes Prospective
randomized crossover
study
Chlorhexidine and benzydamine were
acceptable and well tolerated by
children over the age of 6 years.
CT Mouthwash 40 Cheng et al. 2004
[93]
Yes Prospective
randomized non-
blinded two-period
crossover study
Chlorhexidine together with oral care
might be helpful in alleviating
mucositis when given prophylactically
to children on chemotherapy.
CT Mouthwash 47 Pitten et al.
2003[103]
No Double-blind
randomized controlled
study
Chlorhexidine could not decrease oral
mucositis and conversely, the risk of
mucositis and clinical sequelae
appeared to be
enhanced.
CT Mouthwash 30 Mehdipour et al.
2011[104]
No Double-blind
randomized study
Zinc sulfate compared to
chlorhexidine is more effective in the
reduction of oral mucositis.
RT Mouthwash 100 Roopashri et al.
2011[105]
Yes A drug trial Povidone-iodine, chlorhexidine and
benzydamine hydrochloride helped in
controlling pain and mucositis
although benzydamine
hydrochloride was more effective.
CT Mouthwash 17 Soares et al. Yes - The prophylactic use of 0.12%
chlorhexidine gluconate
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2011[46] reduced the frequency of oral
mucositis and oral pathogens in
children with ALL.
CT Mouthwash 14 de Brito Costa et al.
2003 [106]
Yes - Only one (14.3%) of the seven
children who used chlorhexidine
experienced oral mucositis.
CT Mouthwash 40 Cheng et al. 2003
[91]
Yes Prospective
randomized 2-period
crossover study
Their results showed a significant
difference in the mean area under the
curve (AUC) for mouth pain and a
trend of a lessening of the mean AUC
for difficulty in eating/chewing.
HSCT Mouthwash 73 Antunes et al. 2010
[107]
No A retrospective study No significant difference for
streptococcal bacteremia between the
chlorhexidine gluconate and control
groups.
HSCT Mouthwash 25 Bhatt et al. 2010
[108]
Yes A pilot study Implementation of a standardized oral
care protocol for mucositis
management resulted in a decreased
incidence, duration and severity of
mucositis, and also reduced the global
negative impact of mucositis.
BMT Mouthwash 51 Ferretti et al. 1988
[109]
Yes A prospective double-
blind trial
Chlorhexidine significantly reduced
the incidence and severity of oral
mucositis, oral streptococcus and
candidiasis.
BMT Mouthwash 35 Ferretti et al. 1987
[110]
Yes - Significantly reduced the incidence
and severity of oral mucositis
RT Mouthwash 25 Samaranayake et al.
1988 [83]
No - Although the individual patient
acceptance of chlorhexidine was
better than for benzydamine, there
was little difference between the two
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mouthwashes both in controlling pain
and mucositis or in the oral carriage of
the micro-organisms studied.
CT/RT Mouthwash 40 Ferretti et al. 1990
[111]
No A randomized double-
blind trial
Although generally not significant,
some increase in Gram-negative
bacilli was noted in the chlorhexidine-
treated patients in both the
chemotherapy and radiotherapy
groups.
RT Mouthwash 14 Cheng & Yuen 2006
[85]
No A prospective
randomized and
double-blinded study
Benzydamine compared to
chlorhexidine was more effective in
the reduction of oral mucositis.
RT Mouthwash 52 Foote et al. 1994
[112]
No A randomized trial Slightly more OM in the
chlorhexidine arm with no difference
in the duration of OM and weight loss.
RT Mouthwash 30 Spijkervet et al.
1990 [113]
No A prospective
randomized placebo-
controlled double-
blind study
Colonization patterns of Candida
species, Streptococcus fecalis,
staphylococci, and
Enterobacteriaceae,
Pseudomonadaceae, and
Acinetobacter species were not
influenced by 5 weeks of use of
chlorhexidine rinses when compared
with the placebo.
BMT Mouthwash 100 Weisdorf et al. 1989
[114]
No A randomized
placebo-controlled
double-blind trial
There was no advantage in reducing
the mucositis, controlling oral pain,
facilitating oral nutrition, shortening
hospital stay, or reducing oral
infection with herpes simplex virus.
RT Mouthwash 76 Madan et al. 2008
[115]
Yes A randomized control
trial
The povidone-iodine group had
significantly lower mucositis scores
when compared to the chlorhexidine
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group.
BMT Mouthwash 13 Rutkauskas et al.
1993 [116]
Yes A double-blind
randomized study
BMT patients
on chlorhexidine had improved
OM scores by week 2.
BMT Mouthwash 47 Raether et al. 1989
[117]
No A double-blind study No difference in ulceration, LOS,
Gram-negative or -positive bacteremia
Acyclovir CT PO 74 Bergmann et al.
1997 [118]
Yes A randomized double
blind placebo-
controlled trial.
Prophylaxis with acyclovir should be
considered for patients with acute
myeloid leukemia during remission
induction therapy.
CT/ RT PO Bubley et al. 1989
[119]
No A randomized study No differences in the frequency or the
types of mouth lesions between
acyclovir or placebo
BMT PO Acyclovi
r 60
Valacycl
ovir 60
Eisen et al. 2003
[120]
Yes A drug trial Oral valacyclovir and acyclovir were
comparably effective and safe in
preventing reactivation of HSV
infections in autologous BMT and
stem cell recipients.
Fluconazole CT/RT PO 63 Nicolatou-Galitis et
al. 2006 [121]
Yes A randomized
controlled trial
Fluconazole prophylaxis showed a
significant beneficial impact on the
severity of mucositis and on
radiotherapy interruptions in this
group of patients.
CT/RT PO 270 Corvo et al. 2008
[122]
Yes A double-blind
placebo-controlled
trial
Their results indicated that
fluconazole in irradiated patients with
head and neck tumors significantly
reduced the rate and the time to
development of oropharyngeal
candidiasis.
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CT/RT PO 40 Allison et al. 1995
[123]
Yes A comparative study The combination of fluconazole and
sucralfate decreased oral mucositis in
patients with solid cancer.
CT/RT PO 268 Lefebvre et al. 2002
[124]
Yes An open-label
randomized
multicenter study
Fluconazole suspension was a useful
therapeutic alternative
for treating mucositis in cancer
patients.
Cancer
patients
PO 279 Oude Lashof et al.
2004 [125]
Yes An open multicenter
comparative study
Their results demonstrated that in
patients with cancer and
oropharyngeal candidiasis,
fluconazole had a significantly better
clinical and mycological cure rate
compared with itraconazole.
CT/RT PO 131 Rao et al. 2013 [49] Yes A retrospective study Twice weekly during CRT for head
and neck cancer reduced the incidence
of mucositis and thrush.
Topical
steroids
/BMT/RT
Mouthwash 19 Epstein et al. 2002
[126]
Yes A preliminary study Oral rinses with fluconazole
suspension may be useful
in managing patients with dry mouth
or those who have difficulties in
swallowing caused by oral
candidiasis.
RT PO 18 Koc et al. 2002
[127]
Yes A randomized
prospective double-
blind trial
Fluconazole may be used to reduce
the frequency
of mycotic infections.
Miconazole HDT/AS
CT
PO 104 Orvain et al. 2015
[128]
Yes A retrospective study Their results indicated that
miconazole mucoadhesive buccal
tablets provided a valid alternative to
oral amphotericin B suspensions in
regard to mucositis-related
complications.
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Iseganan CT Mouthwash,
Swallow,
Topical and
Systemic
323 Giles et al. 2003
[129]
Yes A randomized double-
blind placebo-
controlled study
Their results showed that iseganan is
safe and may be effective in reducing
mucositis and its clinical sequelae.
HSCT/CT Mouthwash,
Swallow,
Topical and
Systemic
502 Giles et al. 2004
[130]
No A randomized double-
blind placebo-
controlled study
There was no significant difference
between the iseganan and control
groups.
RT/CT Mouthwash,
Swallow,
Topical and
Systemic
545 Trotti et al. 2004
[51]
No A multinational
randomized phase 3
trial
Iseganan did not reduce the risk for
developing ulcerative OM relative to
placebo.
Povidone–
iodine
RT/CT Mouthwash 40 Adamietz et al. 1998
[54]
Yes A randomized
prospective
comparative trial
The incidence, severity and duration
of radiochemotherapy-
induced mucositis may be
significantly reduced by oral rinsing
with povidone-iodine.
RT/CT Mouthwash 40 Rahn et al. 1998
[55]
Yes A randomized
controlled trial
They concluded that rinsing with
povidone-iodine reduced the
incidence, severity and duration of
oral mucositis during antineoplastic
radiochemotherapy.
RT/CT Mouthwash 40 Yoneda et al. 2007
[131]
Yes A randomized
retrospective
comparative trial
A special oral care regimen enabled
the prevention of mucositis
development.
CT Mouthwash 132 Vokurka et al. 2005
[132]
Yes A randomized
multicenter study
Compared to normal saline, povidone-
iodine mouthwashes used for oral
cavity prophylactic care in patients
after high-dose chemotherapy resulted
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in significant impairment of the course
of oral mucositis.
RT Mouthwash 80 Kumar Madan et al.
2008 [133]
Yes A randomized control
trial
This study demonstrated that the use
of alcohol-free povidone-iodine
mouthwash may reduce the severity
and delay the onset
of oral mucositis due to antineoplastic
radiotherapy.
RT Mouthwash 100 Roopashri et al.
2011 [105]
Yes A drug trial Povidone-iodine helped in controlling
pain and mucositis, although
benzydamine
hydrochloride was more effective.
RT Mouthwash 80 Madan et al. 2008
[115]
Yes A randomized clinical
trial
Their results demonstrated that the use
of povidone-iodine mouthwash might
reduce the severity and delay the onset
of oral mucositis due to antineoplastic
radiotherapy compared to soda and
chlorohexidine.
Clarithromyci
n
HSCT PO 70 Yuen et al. 2001
[134]
Yes An open-label
prospective study
Antimicrobial and healing effects
Nystatin CT/HSCT Mouthwash 86 Epstein et al. 1992
[135]
No Randomized study,
phase 3 trial
Their results showed that nystatin did
not reduce the severity of
oral mucositis compared to a saline
rinse.
Triclosan RT Mouthwash 24 Satheeshkumar et al.
2010 [58]
Yes A randomized phase 3
clinical trial
Less weight loss and faster healing of
grade 3 mucositis occurred in the
triclosan group compared to the
control group.
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Kefir CT/ RT Mouthwash,
Swallow,
Topical and
Systemic
37 Topuz et al. 2008
[60]
No A randomized phase 3
clinical trial
The incidence or severity of mucositis
and the serum levels of pro-
inflammatory cytokines between the
kefir and control groups did not differ.
BCoG RT Antimicrobia
l lozenges
137 El-Sayed et al. 2002
[136]
No A double-blind phase
III randomized
controlled trial
No effect on severity of oral mucositis
compared to the control group
PTA RT Antimicrobia
l lozenges
30 Spijkervet et al.
1990 [137]
Yes A prospective
randomized placebo-
controlled double-
blind study
RT Antimicrobia
l lozenges
65 Stokman et al. 2003
[138]
No A double-blind
randomized placebo-
controlled trial.
Selective oral flora elimination in
head and neck irradiation patients did
not prevent the development of severe
mucositis.
RT Antimicrobia
l lozenges
275 Symonds et al. 1996
[139]
Yes A placebo-controlled
double-blind trial
Significantly less dysphagia and
weight loss in PTA
RT Antimicrobia
l lozenges
77 Wijers et al. 2001
[140]
No A placebo-controlled
double-blind
randomized study
Their results indicated no difference
between the case and control groups.
HSCT PO 27 Bondi et al. 1997
[141]
No - Decreased incidence, severity and
duration of oral mucositis compared to
the control group
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For Review
Only
Compound Cause of
OM
Route of
administration
No.
patients
Author and year Effect Study design Comment
Benzydamine RT Mouthwash 29 Epstein et al.
1986 [82]
Yes A randomized and
placebo-controlled
clinical trial
All patients using benzydamine
tolerated the rinse well and
continued with regular rinsing
throughout the course of radiation
therapy.
RT Mouthwash 25 Samaranayake et
al. 1988 [83]
No - Although the individual patient
acceptance of chlorhexidine was
better than with benzydamine,
there was little difference
between the two mouthwashes
both in controlling pain and
mucositis or in the oral carriage
of the microorganisms studied.
RT Mouthwash 43 Epstein et al.
1989 [84]
Yes A randomized and
placebo-controlled
clinical trial
Benzydamine reduced oral
mucositis and its complications.
RT Mouthwash 145 Epstein et al.
2001 [66]
Yes A multicenter ran-
domized double-
blind, placebo-
controlled clinical
trial
Benzydamine oral rinse was
effective, safe, and well tolerated
for the prophylactic treatment of
radiation-induced oral mucositis.
RT Mouthwash 14 Cheng and Yuen.
2006 [85]
No A prospective
randomized and
double-blinded study
Benzydamine compared to
chlorhexidine was more effective
in reducing oral mucositis.
RT Mouthwash 81 Kazemian et al.
2009 [86]
Yes A double-blind
placebo-controlled
Benzydamine 0.15% oral rinse
was safe, well tolerated and
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Compounds Preventing Oral Mucositis <40

Compounds Preventing Oral Mucositis <40

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