oral mucositis

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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+/PO43- 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, PO43- 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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19

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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Pathol 69, 331–338 (1990). 112. Foote RL, Loprinzi CL, Frank AR et al. Randomized trial of a chlorhexidine mouthwash for

alleviation of radiation-induced mucositis. J Clin Oncol 12, 2630–2633 (1994). 113. Spijkervet FK, Saene HKV, Saene JJV, Panders AK, Vermey A, Mehta DM. Mucositis prevention by

selective elimination of oral flora in irradiated head and neck cancer patients. J Oral Pathol Med

19, 486–489 (1990). 114. Weisdorf DJ, Bostrom B, Raether D. Oropharyngeal mucositis complicating bone marrow

transplantation: Prognostic factors and the effect of chlorhexidine mouth rinse. Bone Marrow

Transplant 4, 89–95 (1989). 115. Madan PD, Sequeira PS, Shenoy K, Shetty J. The effect of three mouthwashes on radiation-

induced oral mucositis in patients with head and neck malignancies: A randomized control trial. J Cancer Res Ther 4, 3–8 (2008).

116. Rutkauskas JS, Davis JW. Effects of chlorhexidine during immunosuppressive chemotherapy. A preliminary report. Oral Surg Oral Med Oral Pathol 76, 441–448 (1993).

117. Raether D, Walker PO, Bostrum B, Weisdorf D. Effectiveness of oral chlorhexidine for reducing stomatitis in a pediatric bone marrow transplant population. Pediatr Dent 11, 37–42 (1989).

118. Bergmann OJ, Mogensen SC, Ellermann-Eriksen S, Ellegoard J. Ayclovir prophylaxis and fever during remission-induction therapy of patients with acute myeloid leukemia: A randomized, double blind, placebo -controlled trial. J Clin Oncol 15, 2269-2274 (1997).

119. Bubley GJ, Chapman B, Chapman S. Effect of acyclovir on radiation-and chemotherapy-induced mouth lesions. Antimicrob Agents Chemother 33, 862-865 (1989).

120. Eisen D, Essell J, Broun ER, Sigmun D, Devoe M. Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy. Bone Marrow Transplantation 31, 51–55 (2003).

121. Nicolatou-Galitis O, Velegraki A, Sotiropoulou-Lontou A et al. Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy. Support

Care Cancer 14, 44–51 (2006). 122. Corvo R. Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients

undergoing radiotherapy for head and neck tumour: Results from a double-blind placebo-controlled trial. Eur J Cancer Care 17(3), 270–277 (2008).

123. Allison RR, Vongtama V, Vaughan J, Shin KH. Symptomatic acute mucositis can be minimized or prophylaxed by the combination of sucralfate and fluconazole. Cancer Invest 13, 16–22

124. Lefebvrea JL, Domenge C. A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin b oral suspension in cancer patients with mucositis. Oral Oncology

38, 337–342 (2002).

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125. Lashof AMLO, Bock RD, Herbrecht R et al. An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis. European Journal of Cancer 40, 1314–1319 (2004).

126. Epstein JB, Gorsky M, Caldwell J. Fluconazole mouthrinses for oral candidiasis in postirradiation, transplant, and other patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93, 671-675 (2002).

127. Koc M, Aktas E. Prophylactic treatment of mycotic mucositis in radiotherapy of patients with head and neck cancers. Jpn J Clin Oncol 33(2), 57–60 (2003).

128. Orvain C, Moles-Moreau MP, François S et al. Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (hdt/asct)-induced mucositis. Support

Care Cancer 23, 359–364 (2015). 129. Giles FJ, Miller CB, Hurd DD et al. A phase iii, randomized, double-blind, placebo-controlled,

multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (prompt-ct trial). Leuk Lymphoma 44(7), 1165-1172 (2003 ).

130. Giles FJ, Rodriguez R, Weisdorf D et al. A phase iii, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy. Leukemia Research 28, 559–565 (2004).

131. Yoneda S, Imai S, Hanada N et al. Effects of oral care on development of oral mucositis and microorganisms in patients with esophageal cancer. Jpn J Infect Dis 60(1), 23-28 (2007).

132. Vokurka S, Bystřická E, Koza V et al. The comparative effects of povidone-iodine and normal saline mouthwashes on oral mucositis in patients after high-dose chemotherapy and apbsct- results of a randomized multicentre study. Support Care Cancer 13, 554–558 (2005).

133. Madan-Kumar PD, Sequeira PS, Shenoy K, Shetty J. The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: A randomized control trial. journal of cancer research and theraputics 4(1), 3-8 (2008).

134. Yuen KY, Woo PC, Tai JW, Lie AK, Luk J, Liang R. Effects of clarithromycin on oral mucositis in bone marrow transplant recipients. Haematologica 86(5), 554-555 (2001).

135. Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Surg Oral Med

Oral Pathol 73, 682–689 (1992). 136. El-Sayed S, Epstein J, Minish E, Burns P, Hay J, Laukkanen E. A pilot study evaluating the safety

and microbiologic efficacy of an economically viable antimicrobial lozenge in patients with head and neck cancer receiving radiation therapy. Head Neck 24, 6–15 (2002).

137. Spijkervet FK, Saene HKV, Saene JJV. Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients. J Surg Oncol 46, 167–173 (1991).

138. Stokman MA, Spijkervet FK, Burlage FR et al. Oral mucositis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: A double-blind randomised clinical trial. Br J Cancer 88(7), 1012-1106 (2003).

139. Symonds RP, Mcilroy V, Khorrami J et al. The reduction of radiation mucositis by selective decontamination antibiotic pastilles: A placebo-controlled double-blind trial. Br J Cancer 74(2), 312-317 (1996).

140. Wijers OB, Levendag PC, Harms ER et al. Mucositis reduction by selective elimination of oral flora in irradiated cancers of the head and neck: A placebo-controlled double-blind randomized study. Int J Radiat Oncol Biol Phys 50(2), 343-352 (2001).

141. Bondi E, Baroni C, Prete A. Local antimicrobial therapy of oral mucositis in paediatric patients undergoing bone marrow transplantation. Oral Oncology 33, 322–326 (1997).

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142. Papas A, Clark R, Martuscelli G, Oloughlin K, Johansen E, Miller K. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 31, 705–712 (2003).

143. Wasko-Grabowska A, Rzepecki P, Oborska S et al. Efficiency of supersaturated calcium phosphate mouth rinse treatment in patients receiving high-dose melphalan or beam prior to autologous blood stem cell transplantation: A single-center experience. Transplantation

Proceedings 43(3111–3113), (2011). 144. Miyamoto CT, Wobb J, Micaily B, Li S, Achary MP. A retrospective match controlled study of

supersaturated calcium phosphate oral rinse vs. Supportive care for radiation induced oral mucositis. Journal of Cancer Therapy 3, 630-636 (2012).

145. Svanberg A, Ohrn K, Birgegard G. Caphosol ® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation. A pilot study. European Journal of Oncology Nursing 19, 50-53 (2015).

146. Rao NG, Trotti A, Kim J et al. Phase ii multicenter trial of caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer. Oral Oncology 50, 765–769 (2014).

147. Raphael MF, Boer AMD, W.Kollen WJ et al. Caphosol, a therapeutic option in case of cancer therapy-induced oral mucositis in children? Support Care Cancer 22, 3–6 (2014).

148. Pettit L, Sanghera P, Glaholm J, Hartley A. The use of mugard™, caphosol® and episil® in patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck. Journal of

Radiotherapy in Practice 13 (2), 218-225 (2014). 149. Graham KM, Pecoraro DA, Ventura M, Meyer CC. Reducing the incidence of stomatitis using a

quality assessment and improvement approach. Cancer Nurs 16, 117–122 (1993). 150. Soga Y, Sugiura Y, Takahashi K et al. Progress of oral care and reduction of oral -a pilot study in a

hematopoietic stem cell transplantation ward. Support Care Cancer 19, 303–307 (2011). 151. Kenny SA. Effect of two oral care protocols on the incidence of stomatitis in hematology

patients. Cancer Nurs 13, 345–353 (1990). 152. Maiya GA, Sagar MS, Fernandes D. Effect of low level helium–neon (he–ne) laser therapy in the

prevention and treatment of radiation induced mucositis in head and neck cancer patients. Indian J Med Res 124, 399–402 (2006).

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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.


[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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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


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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randomized clinical

trial

significantly reduced RT-induced

mucositis.

RT Mouthwash 51 Sheibani et al.

2015 [68]

Yes A double-blind

placebo-controlled

randomized clinical

trial

Benzydamine oral rinse may be

considered as an effective, safe

and well-tolerated medication

for the prevention of radiation-

induced oral mucositis and for

alleviating its symptoms.

RT Mouthwash 67 Kim et al. 1985

[87]

Yes A double-blind

randomized clinical

study

The effects of benzydamine in

this study might have been a

result of the anti-inflammatory

property of the drug.

RT Mouthwash 60 Putwatana et al.

2009 [88]

Yes A prospective

randomized single-

blinded study

Benzydamine was found inferior

to papaya herb for preventing and

relieving radiation-induced oral

mucositis and pain.

RT Mouthwash 67 Kim et al. 1986

[89]

Yes A double-blind

randomized clinical

study

Significantly alleviated the

symptoms of oropharyngeal

mucositis

CT/RT Mouthwash - Prada et al. 1987

[90]

Yes A double-blind

placebo study


[91]

Yes Prospective

randomized two-

period crossover

study

Their results showed a significant

difference in mean area under the

curve (AUC) of mouth pain and a

trend of a lessening of mean AUC

for difficulty in eating/chewing

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.

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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 9 Sonis et al. 1985

[94]

Yes Pilot study Palliation of pain was reported by

seven

study subjects.

CT/RT Mouthwash 44 Schubert and

Newton. 1987

[95]

Yes A multicenter

double-blind

placebo-controlled

trial

Subjects who received

benzydamine consistently

reported more effective pain

relief than those receiving

placebo.

Misoprostol

CT Tablet 15 Duenas-Gonzalez

et al. 1996 [72]

No A randomized

double-blind clinical

trial

The mucositis incidence and

severity was significantly higher

in patients who received

misoprostol.

RT Mouthwash - Hanson et al.

1997 [96]

No A placebo-controlled

double-blind clinical

trial

Data from one study site showed

a decrease in

the mean mucositis scores in the

misoprostol group at the

fourth and fifth week of RT, with

no significant decrease

observed at the sixth and seventh

weeks.

RT Tablet 83 Veness et al. 2006

[70]

No A randomized

double-blind

placebo-controlled

trial

There was a significant difference

in the incidence of severe

mucositis based on whether the

patients were allocated to

receive misoprostol or placebo.

CT Mouthwash 49 Lalla et al. 2012

[71]

No A randomized

double-blind

There was no significant

differences between the two

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placebo-controlled

trial

groups in mucositis

or pain severity.

Diphenhydramine RT Mouthwash 12 Rothwell et al.

1990 [73]

Yes A pilot double-blind

placebo-controlled

study

Diphenhydramine,

combined with hydrocortisone,

nystatin, and tetracycline, reduced

oral mucositis.

CT/RT Mouthwash 18 Carnel et al. 1990

[75]

No A prospective


Dyclone and viscous lidocaine

with 1% cocaine provided the

longest pain relief compared to

diphenhydramine.

RT Mouthwash 12 Barker et al. 1991

[74]

No A prospective

double-blind non-

controlled study

No significant difference between

the groups receiving

diphenhydramine or sucralfate

suspension

RT Mouthwash 31 Turhal et al. 2000

[97]

Yes A non-controlled

study

Diphenhydramine, combined with

lidocaine and sodium

bicarbonate, provided effective

symptomatic relief.

RT Mouthwash 200 Dodd et al. 2000

[98]

No Randomized double-

blind phase-3 trial

Given the comparable

effectiveness of the

mouthwashes, the least costly was

salt and soda mouthwash.

Celecoxib RT Tablet 40 Lalla et al. 2014

[77]


blind placebo-

controlled trial

Did not reduce the severity of

clinical OM, pain, dietary

compromise or the use of opioid

analgesics

Prostaglandin E2 CT/RT Lozenges 10 Porteder et al.

1988 [78]

Yes Double-blind

placebo-controlled

trial

(PGE2) lozenges reduced pain

and oral mucosal inflammation

when compared with controls.

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CT Lozenges Labar et al. 1993

[79]

Randomized double-

blind placebo-

controlled trial

Betamethasone RT Mouthwash 5 Abdelaal et al.

1989 [80]

Yes Not controlled Betamethasone rinse, without

swallowing, prevented

oral mucositis in a total of five

study patients.

Prednisone RT Tablet 32 Leborgne et al.

1998 [81]


blind placebo-

controlled study

Did not reduce the

intensity or duration of oral

mucositis

Indomethacin RT Tablet 18 Pillsbury et al.

1986 [99]

Yes Prospective

randomized double-

blind and placebo-

controlled study

Indomethacin significantly

delayed the

onset of grade 3 oral mucositis in

10 head and neck

cancer patients.

Azelastine CT Tablet 37 Osaki et al. 1994

[100]

Yes Prospective

randomized, and

controlled but not

blinded.

The beneficial effect of

azelastine was attributed to the

anti-oxidant action of the

agent.

Mesalazine CT Topical gel 12 Rymes et al.

1996[101]

Yes Open-label, non-

randomized

--

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nly

32x24mm (300 x 300 DPI)

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Documents

oral mucositis