Management of oral mucositis induced bychemotherapy and radiotherapy: An updateInés Vêlez, DDS, MSVLuis A. Tamara, MD, CNMTVSheldon Mintz, DDS, MS^

Oral mucositis is a frequently occurring and debilitating complication of cancer therapy. Many treatmentshave already been discussed regarding the management of this condition, but some reports show little evi-dence supporting the effectiveness of some of these interventions. The role of the general practitioner inthe prevention and management of chemotherapy- and radiotherapy-induced mucosifis is critical. The gên-erai practitioner must collaborate with the oncologist, and the oncologist must consult with the patient'sgeneral practitioner fo ensure comprehensive treatment ot this condition. Working knowledge ot the vastnumber ot substances used for the treatment of orai mucositis is mandatory for heaith care providers. Thisarticle presents a concise and updated review of the types of therapies used for cancer treatmenl-inducedoral mucositis, providing clearly defined guidelines for the general practitioner (Quintessence Int 2004-35-129-136)

Key words: chemotherapy, mucositis, oral, radiotherapy

CLINICAL RELEVANCE: Cancer therapy-induced oralmucositis compromises personal and social lifestyles aswell as cancer treatment and nutritional status. The roieof the general practitioner in the prevention and manage-ment of cancer therapy-induced mucositis is critical.

'T'he optimal care of many patients with maiignant tu-X mors is a muitidisciplinary effort that combines

surgery, radiation therapy, and chemotherapy. Mostcancer therapies are designed to act on rapidly repro-ducing ceils. The celis that line the gastrointestinal tractfrom the mouth to the rectitm are especially vitlnerable.

The following are the bases for prescription of can-cer treatment:

1. Pathologic characteristics of the tumor (type, differ-entiation)

2. Staging of the tumor {tumor size, metastasis)3. Evaluation of the patient's general condition4. Periodic assessment of tolerance to treatment and

tumor response

CHEMOTHERAPY

Response to chemotherapy is different for each tissue.Kinetics of cellular growth define the characteristics ofthe tumor and the effective use of chemotherapy.Inherent to cytokinetic principles is the concept of thecell cycle. This cycle is composed of four phases:

'Associate Protessor and Director, Department of Oral and MaxillotaciaiPathology, Nova Southeastern University, College of Dental Medicine. FortLauderdale. Florida

^Resident Physician, Departrnent of Interral tifledicine. New HanoverMedical Center. Wilmington. North Carolina.

'Professor, DepartmenI of Orai and Maxil lotacial Surgery. NevaSoutheastern University, College of Dentai fifledicine. Fort Lauderdale,Flonda. Protessor. Department ct Oral and Manillofacial Surgery.Universily ot Michigan, Ann Arbor. Michigan; Distm guis tied Professer, Oraland Maxillofaciai Surgery, University of Tei Aviv, Tel Aviv. Israel.

Reprint requests: Dr Inés Véiez. Neva Southeastern University, College clDental Medicine, 3200 Soutti University Drive, Fort Lauderdale, FL 33326-20t8. E-mail: iveleE@nova.edu

1. Gl (or GO) phase: Preliminary preparation of thefunctional "adult" cell for division

2. S phase: DNA synthesis3. G2 phase: DNA repair and cytoplasm quantity in-

crease to provide "support" for two daughter cells4. M phase: Condensation and separation of chromo-

somes and division of the cell

Most of the chemotherapeutic agents act in a spe-cific phase of the ceil cycle.

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TABLE 1 Chemotherapeutic agents classified by mechanism of action

Type Actionfwiost commonlyknown agents

Alkyiating Impairs ceil function by forming bonds withagents biologically important molecules (ie, cyclo-

phosphamide, ciioranibucil, cyspiatin]Antimetabolites Competes or substitules normal metabo-

lites involved in DNA and RNA synthesis(ie, fluorouracil)

Natural products Produces DNA strand breakage{ie, bleomycin], impairs mitotio activity{ie, paclitaxel, etoposide, camptcsar]

Nitrogen mustrads,nitrosoureas, piatinumagentsFoi ate analogs, purineanalogs, adenosin analogs,pyrimidine analogsAnti-tumor antibiotics,antfiracyclines, taxanes,epipodophyliotoxins,camptothecin

It is also important to have in mind that there arethree subpopulations of cells:

1, Nondividing and terminally differentiated cells2, Continually proliferating cells3, Resting cells that may be recruited into the cell

cycle

Tumors may have all three populations simultane-ously, but (1) tbe rate of tumor growth and (2) tbe ef-fectiveness and toxicity of cbemotberapy are botb a re-flection of tbe proportion of dividing cells, the lengthof the cell cycle, and the rate of cell loss,

Chemotherapeutic agents singly or in combination,bave been used in tbe treatment of different tumorswitb increased frequency during the past years. How-ever, the toxicity of cancer chemotherapy exceeds thatof any other pharmacologie group. In contrast viith theeffect of radiotherapy, chemotherapy-induced toxicity isnot confined to the tissues of the area being treated,

Tbe most common manifestations of clinical toxic-ity due to cbemotberapy are emesis, myelotoxicity, in-fection, anemia, anorexia, cacbexia, asthenia, fatigue,mucositis, gastrointestinal (GI) tract ulcérations, anddiarrhea,^

Tbe anticancer agents most commoniy associatedwitb oral mucositis include bleomycin, doxorubicin,fluorouracil, and methotrexate^ (Table 1),

RADIOTHERAPY

Tbe most common form of radiation used for cancertreatment today is tbe high-energy photon. Photonsare released from the nucleus of a radioactive atom,and they interact with the tissue electrons, giving themenergy to ionize. Ionizing radiation is energy suffi-ciently strong to remove an orbital electron from anatotn and alter molecules and tissues.

The aim of radiotherapy is to deliver a preciselymeasured dose of irradiation to a deflned tumor vol-ume with minimal damage to the surrounding tissue,

Different radiotherapy modalities

Brachytherapy. Localized radiation is delivered di-rectly into the target tissue of the tumor area usingsmall fragments of radioactive sources. The radioac-tive seeds are placed under local or general anesthesia.This method is useful for superficial lesions. Once theradioactivity disappears, the seeds remain within thetissue as inert fragments. Low toxicity is associatedwith this treatment,^

Radioimmunotherapy, This is a modality for thecare of cancer patients that is able to deliver, by sys-temic administration, a tumor-targeted radiation manytimes higher than the highest radiation dose permittedfor normal tissue, Radioimmunotherapy uses aradio-labeled antibody tbat reacts with a tumor-spe-cific antigen target. Mild to moderate clinical toxicityrelated to this type of treatment has been reported,*especially neutropenia and tbrombocytopenia, Tbis isdue to marrow radiation that results from radio-la-beled antibodies circulating wben the therapy is ad-ministered intravenously. It is likely that more sys-temic and tumor-targeted radiation will be used forcancer therapy in the coming years. However, moreresearch in this area is required.^

Radioactive iridium implant. This technique is use-ful for invasive lesions of oral squamous cell carci-noma. Under general anesthesia, catheters are placedinto the tumor, and radioactive iridium 192 (IR 192) isdelivered into the area,

Megavoitage externai beam radiation. In the headand neck, this modality is used with extensive lesions,salivary gland tumors, and lymph node métastases.Different radiation doses are required depending ontumor type and tumor volume, Toxicity is related tothe kinetic properties of the cells, fraction size, inter-val between fractions, quality and type of radiation,dose given, and tissue sensitivity. Fractionation of ra-diation spares acute oral reactions because of a com-pensatory proliferation of the epitbelium of the mu-cosa, whicb accelerates at 2 to 3 weeks after initiationof therapy.^

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TABLE 2 Radiotherapy modalities

Type

Brachytherapy

Delivery system

Implantation of radioactive seedsRadioimmunotherapy Injection of tumor-targeted radio-labeled antibodyIridium implan!Extemal beamradiotherapy

Implantation of iridium 192Tumor application of ionising radiation producedby an externai source

Toxicity

LowMild to moderateModerateModerate tosevere (manyvariables related)

Radiation therapy witb curative intent and postop-erafive radiafion usually involves daily treatment for 6to 7 weeks, Tbe total dose is typically 60 to 70 Gy,Preoperative treatment involves 45 to 50 Gy in 4 to 5weeks. Combining this with brachytherapy providesexcellent control for early tumors,^ The minimal toler-ance dose (TD5/5) is different for each case and de-fined as tbe dose of radiation that should not causemore than 5% severe complication rate within 5 yearsafter treatment' (Tahle 2).

Radiafion injuries may present different phases: (a)Early effects are very common and are usually seenduring treatment They may present within a constella-don of symptoms, and residual damage is often noted;(bj intermediate effects occur several weeks or montbsafter the radiation treatment is completed; and (cj lateeffects are rare and may appear months to years afterthe treatment, Oncogenesis is a late effect of radiationtherapy.'

The radiation-induced damage of the oral mucosais usually produced by extemal beam radiation utilizedin treatment of a bead and neck tumor (ie, squamouscell carcinoma, adenocarcinoma), or because of totalbody or hemi-body radiation that includes the headand neck area. These last modalities have heen usedfor diseases such as leukemia, lymphoma, and aplasticanemia as well as bone marrow transplantation,

Dysphagia, mucositis, hoarseness, ulcération, andnecrosis of the tissues are ail reported sequelae.Fibrosis, xerostomia, dysgeusia, dysphonia, and de-layed wound heaEng also occur as a result of the dam-age to the oral tissues and the salivary glands duringradiation treatment. These effects are usually confinedto the area in the radiation field.

Mucosifis is an early effect of radiafion and resultsfrom mitofic death of the basal cells of the oral ep-ithelium. It usually appears 2 weeks after initiation ofradiotherapy.

Clinicaîly, oral mucositis usually presents with ery-thema accompanied hy dryness, pain, and burningsymptoms. Severe uJcerafion' and the inability to toler-ate even fiquids may occur. It can be a very debilitafingcomplication of cancer treatment and may occur sec-ondary to the systemic effects of cytotoxic ehemother-apeufic medications, the local effect of radiation on

TABLE 3 World Health Organization grading ofmucositis

Grade Signs and symptoms

No symptomsSore mouth; no uicersSore mouth with ulcersbut able to eat normallyLiquid diet onlyUnable to eat or drink

the oral mucosa, or both. The damaged oral mucosaand the reduced immunity resulfing from cancer ther-apy also may give rise to opportunistic infections.Complications of salivary gland dysfunction* andtrauma also can modify the evolution of mucosifis.

Personal and social lifestyles, as well as cancertreatment and nutritional status are compromised bythese noxious eftects, Tbere are different grades of mu-cositis, some of which are so prohlematic tbat systemjctreatment is required (Tahle 3), The findings berelnmandate a tborougb collaboration among generalpractitioners, oncologists, and other health careproviders.

THERAPIES

The following have been used in the treatment of radi-afion-induced and chemotherapy-induced mucositis,though some reports demonstrate little evidence sup-porting the effectiveness of the corresponding inter-ventions.

Antioxidants

Anfioxidants may he particularly important since can-cer treatment is an oxidative process. Radiotherapyand chemotherapy generate free radical species, whichrequire anfioxidants to be neutralized. Inflammationalso causes free radical reactioti by respiratory burstreaction. Thus, it is necessary to enhance the body'santioxidant stores in order to prevent mucositis and tomaintain healthy oral tissues.

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TABLE 4 Recommendations singly or in combination

Therapeutic approach

Cryotherapy

Low-intensity laser(20 J/cni= he i i um-neon)

Mouthwash {lidocaine,aiuminum hydrox, tópicavitamin E, chamomile)Benzydaminehyd roc hlo rideGlutamine

Sucralfate

Fentanyi transderrnalsystemAmifostine

Dose and frequency

Administered 30 minutes followingcancer therapy and periodicaliythroughout every day during cancertreatmeni820 nm/200 mW continuous wavedaily

Administered singiy or in combinationas frequently as needed

0.15% oral rinse 15 mL every 2 hwith expectoration4 g of powder dissoived in liquid to swishand swallow twice dailySwish and swallow four times daily

One patch every 2 to 3 days

Intravenous/subcutaneous 300 mg/m=15 to 30 minutes before radiation therapy

Mechanism of action

Vasoconstriction diminishes distributionof the toxic agent to the oral mucosa andreduces inflammation

Activates epitheliai heaiing

Improved mucosal healing; relieves painon a temporary basis; reduces[nfiammationLoca i anti-inflammatory antimicrobiai andanaigesic actionImmunomoduiator antioxidant, ceilregeneration, ceii fuelTopical protectant, stimulates prostaglandinproductionAnesthetic action

Radio-protection aniioxrdart effect, DNAprotection repair acceleration, xerostomiaprevention

Secondary effects

None

Epiieptic patient cansustain a seizure pro-voked by the laser beamNone

None

None known

None

Dry mouth

Ailergy, hypotension.hypocaicemia, nausea

Beta-carotene, This has been proven to be useful inchemotherapy-induced mucositis. In one trial,chemotherapy patients were given 400,000 IU per dayfor 3 weeks and then 125,000 IU for an additional 4weeks. In these patients, mucositis developed laterand tended to be less severe than mucositis that ap-peared in control patients.^

Vitamin E in combination with vitamin C. Both acton a cellular level by protecting the cell membraneand preventing peroxidation.'" Studies have found thetocopherol form of vitamin E to be effective when it isapplied topically twice per day (Table 4),^"

Glutamine. A precursor of glutathione, this is veryimportant for stress periods. It is the most abundantamino acid in the human body, and it is now consid-ered a conditionally essential amino acid during peri-ods of cataboiism (see Tabie 4).

It has been suggested that during stress, supplemen-tal giutamine may be needed to maintain gastrointesti-nal system integrity and provide fuel for cells withrapid turnover.'^ Glutamine also seems to play the roleof an immunomoduiator and mucosal barrier in pa-tients with advanced esophageal cancer.'^

Glutamine has successfully reduced radiotherapy-and chemotherapy-induced mucositis," Early studiesshow that glutamine has a positive effect throughthree mechanisms: (1) as a cellular fuel; (2) as a pre-cursor for nucleotides needed for cell regeneration;and (3) as a source of glutathione, which is a potentantioxidant's The use of 4 grams of powdered giuta-mine in oral rinse in a swish and swallow suspension,twice per day, decreases the intensity and duration of

the mucositis'^ and is cost-effective. Topical actionalso has been proven to be beneficial.

Glutathione. This is the body's main antioxidanfthat protects cells from free radical damage. Gluta-thione may enhance the body transportation of drugs,Blood levels of glutathione are reduced by radiother-apy and by severe inflammation, which occurs in mu-cositis. For these reasons, glutathione may be used byintraoral spray or oral dissolvable tablets.

Lysofylline. A protectant tbat reduces lipid peroxi-dation also decreases oxidative injury. It is presentlybeing tested in chemoradiation trials of head and neckcancer,

All of these synergistic partners enhance the body's en-dogenous antioxidants and neutralize toxic free radicals.

Mucosal barriers

Sucralfate. This is a sucrose aluminum hydroxidecompound that forms a gel-like webbing over tissues,serving as a type of bandage, acting through a topicalprotectant effect in patients at risk for developing mu-eositis. In addition, local produetion of prostaglandinE2 is stimulated (see Table 4).^ Sucralfate must begiven four times daily (swish and swallow) in order toprovide a continuous protective layer over the ulcers.Its use has been successful in treating esophagitis andgastric ulcération,''*'^ Clinical and histopathologic ev-idence of oral mucositis reduction in cancer patientstreated with sucralfate has been demonstrated.^"

Clobetasol (0.05% ointment 1:1 with Orábase). Asa topical corticosteroid, it plays a role in inflammation

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and immunosuppression.'' It is contraindicated in in-fection. Clobctasol must be applied as a tbin film, andtbe patient must not bave anytbing by moutb for one-balf hour.

iVIouthwashes

Benzydamine hydrochloride. As an oral rinse, tbishas been sbown to be effective, safe, artd well toler-ated in ameliorating tbe symptoms of cancer treat-ment-induced mucositis (see Table 4). Rinsing tbenexpectorating 15 mL of 0.15''/o solution every 2 bourswill belp witb tbe painful inflammation of tbe moutband throat. Benzydamine bas local analgesic, antimi-crobial, and anti-inflammatory properties. It preventstbe release of the arachidonic acid cycle, wbicb is aninitiator of tbe inflammatory process. ^

Coriicosteroid mouthwashes. Tbese may be bene-ficial and are contraindicated if tbe patient bas a bacte-rial or viral infection. ' Triamcinolone acetonide 0.2%aqueous suspension can be used as a rinse for 1 minutetwice a day and expectorated. Limited evidence basbeen demonstrated in some studies to support its useas a treatment for stomatitis.**

Chamomile mouthwashes. Tbese bave been usedto improve mucosal bealing. with controversialresults.^ However, rinsing witb 15 drops in 10 mL ofwarm water, tbree times a day, bas reduced the inci-dence and severity of mucositis in cancer patients.'^ Itis said to have anti-inflammatory and healing effects.

Glycerin-containing mouthwashes. Tbese are noteffective. Glycerin can produce drj/ness of tbe mouthwitb prolonged usage.

Local anesthetic mouthwashes. These may belp torelieve pain on a temporary basis.

Analgesics

Capsaicin. This is found in cbili peppers and actsupon nerve endings to provide temporary pain relief.The exact mechanism of action is unknown,^'

Morphine. A central nervous system analgesic, itdepresses pain impulse transmission. It is effective formanaging mucositis pain in cancer patients, but drymouth is one of its adverse reactions." It does not im-prove the health of the mucosa.

Cannabinofds. Even tbougb cannabinoids bave beentouted to be good analgesics, more work is needed to es-tablisb a clinical utility of these substances. Tbe thera-peutic potential of cannabinoids remains an importanttopic for future investigations. *"

Fentanyl {transdermal patch). A very potent short-acting opioid, it is used primarily as an anesthetic. It isavailable in a sustained-release transdermal deliverysystem (duragesic) witb a balf-life of 22 hours. It is es-

pecially useful in patients unable to take oral medica-tions.' Tbe patcb must be cbanged every tbree days.There is a 12-bour latent period before the drug be-comes effective when the first patch is placed.^^Duragesic helps with the management of chronic pain,but dry mouth is an adverse side effect. '

Anti-inflammatories

Prostaglandins El and E2. Tbese are known to bavemany properties including tbe ability to protect tbe gas-tric mucosa from injuries. However, tbe present studydid not find evidence to support its use to prevent orameliorate cancer treatment-induced mucositis."

Growth factors

Recombrnant keratinocyte growth factor. It is knownto influence tbe growth, development, and repair ofepidermal tissues. It also accelerates wound beabng,"increases the number of stem cells tbat survive a doseof radiation tberapy. ' and reduces tbe incidence andduration of oral mucositis due to cancer treatment.Tbis therapy, b owe ver, requires furtber studies.

Fibrobiastic growth factor (renifermin). It isknown to be able to stimulate salivary gland byperpla-sia and salivary gland output.- Maintaining a moistoral mucosa may help reduce the severity of mucositis.

Epidermal growth factor (EGF). This is present inbiologic fluids including saliva. Its level decreases inpatients receiving radiation tberapy to tbe bead andneck. * EGF plays a role in healing damaged mucosa.In recent studies it was demonstrated tbat less tissuedamage was associated witb a bigber EGF level in

Immunomoduiators

Thalidomide. An immunomodulatory and antiangio-genic agent, it inbibits tumor necrosis factor-alpba(TNF-o;), whicb is associated witb oropharyngeal ul-cers. In multiple studies,^" ' tbe efficacy of tbis med-ication against oral and esophageal ulcers bas beendemonstrated. In one trial,'' 92% of patients had com-plete bealing after 4 weeks by taking 200 mg by moutbat bedtime.

To prescribe tbalidomide, bowever, general practi-tioners must register witb tbe System for TbalidomideEducation and Prescribing Safety (STEPS) to mini-mize the substantial risks of teratogenicity."

Pentoxiphyltine (trental). This also is an inhibitor oftumor necrosis-alpha (one tablet tbree times daily withfood). However, the studies regarding prevention ofmucositis with this medication are contradictory. "' ^

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Granulocyte colony stimulating factor (GCSF).This has heen reported to shorten the white blood cellrecovery time and decrease the incidence of infectionand mucositis in bone marrow transplantation pa-tients. {Filgrastim, 10 pg/kg per day for 7 days, fol-lowed by 5 mcg/lcg per day for 4 days). In a recentstudy,'•' a modest reduction of the severity of radiation-induced oral/oropharyngeal mucositis, in patients re-ceiving radiotherapy/chemotherapy for head and neckmalignancies, was reported. The beneficial effect ofgranulocyte-macrophage colony stimulating factormouthwash also was reported in another recentstudy.'' However, other trials failed to demonstrate itsprotective effect on mucositis,'* and the substantialcosts of GCSF limit its use. Overall, there is insuffi-cient evidence to strongly recommend its use.

Radioprotectants

Amifostine (ethyol). This is a radioprotectant able to en-hance the tolerance of normal tissues to a given dose ofradiation and decrease treatment morbidity. Amifostine'scytoprotective mechanism involves DNA protection, re-pair acceleration, and antioxidant function.*'

it has been reported to prevent salivary gland injuryinduced by radiation, reducing xerostomia and mu-cositis, and hématologie abnormalities.^ Amifostine isapproved by the Food and Drug Administration(FDA) for the prevention of xerostomia in head andneck cancer patients receiving radiotherapy when ad-ministered intravenously. However, subcutaneous ad-ministration of amifostine gives radioprotection com-parable to IV ad mini strati on.'' In a controlled trial,^' asignificant degree of cytoprotection was found in pa-tients experiencing xerostomia, fibrosis, loss of taste,mucositis, and dysphagia.''''''"

The American Society of Clinical Oncology (ASCO)recommends the consideration of amifostine to de-crease the incidence of xerostomia in patients who un-dergo radiation therapy in the head and neck region.However, the ASCO states that data is not sufficient torecommend amifostine to prevent mucositis associatedwith radiation therapy''-''^ Life-threatening anaphylac-toid reaction, nausea, vomiting, hypotension, andhypocalcemia associated with amifostine treatmenthave all been reported.*' The real benefit of amifostinein the overall management of cancer patients requiresadditional studies to determine whether its use mightmaintain the dose intensity of anticancer therapies.''''

Nonpharmacologic approach

Cryotherapy. This produces vasoconstriction, whichreduces hlood flow and diminishes the distribution ofthe chemotherapeutic agent to the oral mucosa. It re-

suits in the reduction of mucositis intensity caused bylocal cytotoxic activity. Ice swishing for 30 minutesfollowing cancer therapy has been shown to be beneu-cia! for these patients (see Table 4). '''

Low-intensity iaser therapy. Tbis may improvewound bealing and accelerate replication of the cells.Low-energy helium-neon (He-Ne) laser seems to be asafe, simple, atraumatic, and efficient method for theprevention and treatment of chemotherapy/radiother-apy-induced mucositis.«••'s-'' Activation of epithelialhealing theoretically should reduce the severity andduration of mucositis of various origins.

CONCLUSiON

A review of the literature delineated a vast number ofagents that have been identified as effective in the pre-vention and treatment of mucositis in cancer patients.However, no single agent is universally effective. It istherefore extremely important to prevent mucositis orat least to reduce its severity and complications. Thefollowing recommendations are based on the availablepublished work as discussed herein:

1. Before cancer therapy, the patient must receive acomprehensive denta) treatment. The aim of thisapproach is to achieve and maintain an infection-free oral environment. It is beneficial to educate thepatient regarding the importance of oral hygiene.

2. Patients undergoing chemotherapy and/or oral ra-diotherapy shouid follow a routine of gently brush-ing the teeth, tongue, and gingiva at least threetimes per day with a fluoride dentifrice. Daily use ofdental floss also should be encouraged. Regularrinsing of the orai cavity with bicarbonate of sodaaids oral hygiene and restores oral pH. Denturesshould be removed when sleeping and cleaned be-fore reinsertion. Scrupulous hygiene is essential.

3. Cryotlierapy-Instructing the patient to melt icechips in the oral cavity for 30 minutes immediatelyfoilowing cancer therapy and then periodicallythroughout the day during the entire treatment pe-riod reduces the severity of mucositis.

4. Pilocarpine (salagen 5 mg four times daily), artificialsaliva when necessary, and antifungal, antiviral, orantibiotic medications for oral and pharyngeal super-imposed infection can be prescrihed in order to pre-vent and/or improve the mucosal condition. Thesemay include chlorhexidine (10- to 15-mL rinse threetimes daily), Acyclovir (250-mg IV every 8 hours, onday 3 to day 12 in herpes simplex virus (HSV)seropositive patients), and Nystatin (5 to 10 mLswish and expectorate every 4 hours) to reduce therisk of mueotoxicity from bacteria, viruses, and fimgi.

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5, Drinks containing caffeine or alcohol, alcohol-con-taining mouthwashes, and tobacco products mustbe avoided, as well as spicy and acidic food, Tbesesubstances can dry tbe mucosa and may cause pain.

In the current review, all of the procedures detailedin Table 4 have been consistently reported to be harm-less and beneficial for the relief of this condition. Anyof these procedures used singly or in combinafion ishighly recommended.

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