Oral mucositis in patients with leukaemia following high-dose chemotherapy and autologous haematopoietic stem cells transplantation

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Review/Praca poglądowa

Oral mucositis in patients with leukaemia following high-dose chemotherapy and autologous

haematopoietic stem cells transplantation

Jolanta Wojciechowicz

^1,

*, Magdalena Kostyra

¹

, Justyna Kozińska

²

, Marek Hus

²

, Tomasz Tomaszewski

¹

1DepartmentofMaxillofacialSurgery,MedicalUniversityofLublin,Poland

2DepartmentofHematooncologyandBoneMarrowTransplantation,MedicalUniversityofLublin,Poland

Introduction

Haematopoietic stem cell transplantation (HSCT) involves the intravenous infusion of allogeneic or autologous stem cells collected from bone marrow, peripheral blood or umbilical cord blood in patients whose bone marrow or immune system has been damaged. After administered them into the body, their objective is to re-establish

haematopoietic function. In allogeneic transplant, a donor ofthesamespeciesisthesourceofcells,andinautologous transplant, haematopoietic cells come from the recipient himself or herself. There are also syngeneic transplants (geneticallyidenticaltwins).Indicationsfor thistherapeutic treatment include primarily haematopoietic malignancies, suchasleukaemias, lymphomas,myelomas,myelodysplas- tic syndromes, advanced lung, ovarian, breast, testicular cancers, as well as benign diseases, such as aplastic

*Correspondingauthorat:KlinikaChirurgiiSzczękowo-TwarzowejUM,ul.Karmelicka7,20-081Lublin,Poland.Tel.:+48815323851;

fax:+48815323851.

E-mailaddress:lanyfztk@wp.pl(J.Wojciechowicz).

article info

Articlehistory:

Received:23.09.2013 Accepted:12.02.2014 Availableonline:22.02.2014

Keywords:

Haematopoieticstemcell transplantation

Stemcells

Oralmucositis

abstract

Historically,oralmucositis(OM)hasbeenidentiﬁedasasymptomdevelopinginpatients undergoingirradiationduetoheadandneckcancers,thoseundergoingtherapyinpre- parationforastemcelltransplant,orreceivingspecialtherapeuticprotocolsduetoacute myeloidleukaemia. Itresultsfromdirecttoxicinjurytothemucosalepithelialcellsby theimmunosuppressiveregimen.Inthisarticlewewanttodescribepathogenesis,diag- nostic and actual possibility of treatment ofOM. The literature reports several rating scale for OM that have been used for patients undergoing cancer therapy. The most usefulofthemareOralToxicityScaleandOralMucositisAssessmentScale.Inthepre- ventionandtreatmentofOMassociatedwithstandardchemotherapyvariousdrugsand agentsactinglocallyandsystemicallyareused.Manyofthemarestillremaininginthe courseofresearch.

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journal homepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2014.02.001

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anaemia. Conditioning treatment is required in a patient prior tothe HSCT, whichinvolves administeringhigh-dose chemotherapy,oftenincombinationwithradiationtherapy.

Such therapy leads to myeloablation and destruction not onlyof cancercells, but alsoof recipient'shaematopoietic system.Non-myeloablativetransplantswithreduced-inten- sity conditioningare also used,which involve the application of lower doses of chemotherapy in combination with strongimmunosuppressivetreatment.Suchtherapy canbe used in olderpatients over 65 years of age on account of lowertoxicity.Negativeeffectsoftoxicconditioningtherapy includeintensiﬁedinﬂammationsofthemucousmembrane ofthe mouth,nasopharynxandintestines,socalled mucositis[1,2].Somegroupsofanticancerdrugswhichareused aloneorincombination,aschemotherapybeforeautologous HSCT are particularly often responsible for mucositis. The mostrecordedmucotoxic agentsare:thymidinesynthetase inhibitors,suchasmethotrexate,topoisomeraseIIinhibitors (etoposide, irinotecan); pyrmidine analogues (cytarabine);

purine analogues (6-mercaptopurine and 6-thioguanine);

alkylating agents at high doses (busulfan, melphalan and cyclophosphamide);andintercalatingdrugs(idarubicin,doxorubicin, daunorubicin). When these agents are administered in multiple cycles the risk of mucositis increases at eachcourse[3](TablesIandII).

Pathomechanism and clinical symptoms of mucositis

Inﬂammation of the mucous membrane lining the oral cavity and other parts of the gastrointestinal tract and nasopharynx is a serious complication of the above men- tionedconditioningtherapy,andaffects80–100%ofpatients [4].Thecourseisoftensoseverethatpatientsrequirestrong analgesics andparenteralnutrition [5]. In view of patients'

subjective opinions, it is also one of the most intolerable side effects of the therapy. It is a pathological process common for cancer patients receiving radiation therapy, chemotherapy or both of these treatments, and patients requiringautogenicstemcelltransplantation.Mucosalinju- ries affectthe entire gastrointestinaltract,from oralcavity to anus [6]. Resulting lesions occurring in epithelium and tunica submucosa are characterisedin ﬁveclinical phases:

(a)initiation,(b)primarydamageresponse,(c)signalampli- ﬁcation,(d)ulceration,and(e)healing[7–10](Tab.III).

Primary mucosal cell injuries resulting from oxidative stress lead to the expression of early response genes and activationof DNAtranscriptionfactor.Thepathophysiology ofmucositisinvolvesvariousfactors,suchasnuclearfactor kappaB (NF-kappaB) protein complexplayinganessential role in the immune response to an infectious agent, cyclooxygenase-2(COX-2)activatedbyagentsrelatedtothe inflammation, pro-inflammatory cytokines – in particular interleukin (IL)-1b (IL)-6, and tumour necrosis factor (TNF) [7,8]. Clinically,it beginswithnon-specific oraldiscomfort preceded byredness,burningsensation,increasedsensitiv- itytosourandhotfoods,thenerosionandulcersoccurthat makeitdifficulttotakeandswallowfoods,accompaniedby aseriesofothersymptomsthatmake patient'sfunctioning difficult, of which the following should be listed: pain, swelling, fever, mycosis, bacteraemia and sepsis [4, 6, 11, 12]. Then, viral infection symptoms dominate with increasedmucosal temperatureonhard palate,gingiveand dorsum of tongue combined with necrosis and extensive lichenoid lesions. Quantitative and qualitative salivary changesleadingtoadecreaseinsalivaryIgG,IgA,IgMlevels and toxerostomiaaddtoit [6,9,12,13].Asaconsequence

TableII–Groupsofanticancerdrugsresponsiblefor mucositis

Thymidinesynthetaseinhibitors Methotrexate TopoisomeraseIIinhibitors Etoposide

Pyrmidineanalogues Cytarabine

Purineanalogues 6-Mercaptopurine,

6-thioguanine Intercalatingdrugs Idarubicin,doxorubicin,

daunorubicin TableI–ConditioningregimensinPBSCT

BEAM BCNU,etoposide,cytarabine,melphalan BuMel Busulfan,melphalaninhighdoses BorMel Botezomib,melphalaninhighdoses Melphalan Highdoses140–200mg/m²

TableIII–Thepathobiologyofmucositis-fivephases

PhaseI PhaseII PhaseIII PhaseIV PhaseV

Initiation Primarydamageresponse Signalampliﬁcation Ulceration Healing DNAandnon

DNAdamage

Activationoftranscription factorssuchasNF-kappaB

Positivefeedbackloops increasecytokine production

Bacteriacoloniseulcer surface

Migrationandproliferation ofregenerativeepithelial cells

Reactiveoxygen speciesdamage basalepithelialcells

Increasedproductionof TNF-a,IL-1,IL-2,IL-6

Clinicallyminimalsigns andsymptoms

Increasetheactivityof macrophagesandproduction ofadditionalproinﬂammatory cytokines

Mucosaappearsclinically normal

Clinicallyobserved tissuedestruction

Activationof sphingomyelinase andceramide

Clinicallyevidenterosions

Apoptosisofbasalepithelial cellsandmucosaldamage

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of the above lesions, microbes appear in the oral cavity which are not present in normal ﬂora in this area, e.g.

Gram-negative – Escherichia coli, Klebsiella pneumoniae, Enter- obactercloacae,Pseudomonas aeruginosa, Gram-positive: Strep- tococcus mitis, Streptococcus oralis, Streptococcus sanguis, capnophylesandfusobacteria, fungiof thegenusCandida – CandidaalbicansandCandidatropicalis,leadingtomulti-organ systemic mycosis [12, 13]. Bacterial cell walls produce lipopolysaccharides which stimulate macrophages to pro- ducedamagingcytokines(Fig.1).

Diagnosis and estimate of changes

FortheevaluationofOM,twoscalestoassesslesionswithin themucosaareusedthathavebeendevelopedbytheWorld HealthOrganisation: OralToxicityScaleand OralMucositis Assessment Scale (OMAS). As regards the interpretationof symbolsapplied inthesescales, 0representsnopathologic lesions, 1 – erythema requiring no clinical treatment, 2 – presence of pain requiring no analgesics and difﬁculty in swallowing. In grade 3 – mucosal ulcers, pain requiring painkillers(analgesics)arepresent,feedingistotallyimpos- sible, and ﬁnally grade 4 – necrosis and necessity of parenteralnutrition.Formoredetailedevaluationoflesions inaform of erythemaand ulceration, OMASscale isused:

a severityof ulcerationsis characterisedby 3groups. This evaluationrelatestovermilionontherightandontheleft, lipmucosa,jugalmucosa,palate,ﬂoorofthemouth,lateral tongue surface on both sides, and dorsal surface of the tongue(TablesIVandV).

The incidence and clinical severity of OM depend on a typeand a dose of irradiation, combination of radiation therapy with the chemotherapy, a type and dose of a chemotherapeutic. In the last case, high toxicity of preparations such as 5-FU, cisplatin, etoposide, melphalan wasreported,andslightlylowertoxicityinthecaseofdrugs suchas: doxorubicin,vinblastine,taxan, methotrexate, and ﬁnally very rare toxicity if asparaginase and carmustine wereadministered[8,9]. Combinationtherapywithseveral chemotherapeuticsincreasestheincidenceofOMfrom 40%

to 70% compared to standard chemotherapy. In those patients who receive conditioning treatment prior to the HSCT–inparticularifitconsistsofTBI(ionisingirradiation –totalbody irradiation)incombinationwithchemotherapy – the incidence of OMis75–99%[9]. Other factorsthat are not associated with a type of therapy also play a role in etiopathogenesis,namelypatient'sage,gender,race,general condition,systemicdisease.Theresultsfromstudiescarried out to investigate risk factors are inconclusive; however, they suggest that oral inﬂammation affects more women than men.Peopleovertheageof50yearsandchildrenare athigherriskofOM[9].OMismorecommoninolderpeople due to the decreased effectiveness of regenerative and immunesystemprocesses,and inchildrenduetoagreater rateofbasalepitheliumcells'division[8,9,14].

Fig.1–Clinicalsymptomsofmucositis

TableIV–WHO'sOralToxicityScale OralToxicityScale

Grade1 Sorenesserythema

Grade2 Erythema,ulcers;patientcanswallowsolidfood Grade3 Ulcerswithextensiveerythemapatientcannot

swallowfood

Grade4 Mucositistotheextentalimentationisnot possible

TableV–OMASOralAssessmentScaleinmucositis OralMucositisAssessmentScale(OMAS)

Erythema

08 Noerythema

18 Mildtomoderateerythema

28 Severeerythema

Ulceration

08 Noclinicallesion

18 Anulcer<1cm²

28 Anulcerof1–3cm²

38 Anulcer>3cm²

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Therapeutic procedure

Apart from the general medical approach, dental manage- mentisalsoanimportantaspectofcomprehensiveprepara- tionof apatientbothforauto- andallo-HSCT.Itshouldbe carried out at least two months prior to the planned transplant,andshouldincludedetailedintra-andextra-oral examinationssupportedbyexaminationssuchasanOrtho- pantomogram(OPG),X-raysofindividualteethofwhichthe state raises doubts, or an X-ray of the paranasal sinuses.

Not onlyteeth should beevaluated, but alsooral mucosa, parodontium, parotid glands and their orifices, namely all measures shouldbetakentoidentifyand eliminatepoten- tialfoci of infection, andconsequently,complications after thetransplant.Alltherapeuticproceduresshouldbecarried out in consultation with a treating haematologist on the basisofcurrentbloodtestresults.Ifinvasiveproceduresare planned,suchasextractionsofteeth,dentalplaqueremoval orendodontictreatment,localproceduresshouldbesupple- mentedwith antibioticprophylaxis. Teethdamageddue to decayprocess requiring sophisticatedand long-term endodontic procedures, teeth following endodontic treatmentif root canals are filled carelessly or periapical lesions are present, totally and partially retained teeth affected by pathologicalprocessesinsurroundingtissuesnoworinthe future,teethaffectedbyadvancedparadentosisarequalified forextraction[15].

Therearenostandardsforthepreventionandtreatment ofOM[4].All currentlyusedmeasuresarestillinvestigated in clinical studies. Certainly, daily oral care is extremely important.Forthispurpose,toothbrushing2–3timesaday or after every meal using ultra-soft toothbrush, ideally changed every day, are recommended in patients. Special dentalpasteswithaperoxidasesystem(e.g.Biotene)should be used. If the symptoms of xerostomia are present, this systemhelpstorestoreprotective functionof salivaand to preventprimaryandsecondaryoralinfections[8,16, 17].It is inadvisable to use toothpicks and dental floss due to additional soft tissuetrauma [8]. Supplementaryrinsing of the mouth 3times a day isrecommended using solutions withadditivessuchaschlorhexidineandxylitol[17].Atthe Haematooncology and Bone Marrow Transplantation Department of the Medical University of Lublin, it is used in a concentration of 0.2%, in a preparation Corsodyl, in combination with antifungal agent – amphotericin B (Fungizone)asa suspension.Chlorhexidineisthoughtto playamajorroleinregulatingtheamountofdentalplaque, reducestheriskoftoothdecayandgingivitis,and prevents fungal infectionsas well.Itdoes notdirectlyinfluencethe treatment of OM [9]. One of the first symptoms of OM is very nagging pain. Local anaesthetics (diphenhydramine, lidocaine,dyclonine)aswellasnonsteroidalanti-inflammatory drugs such as paracetamol are used in the manage- mentofit.Inseveremucositiswhenthepainisverystrong, opioids are given: morphine and derivatives and fentanyl, withtherouteofadministrationtailoredindividuallytothe needsofeachpatient(orally,intravenously,subcutaneously or sublingually) [8, 18]. The local use of the preparation called Caphosol is added to the above therapy. Caphosol

mouth rinse contains calcium and phosphate ions, and helpstomaintainproperhygieneoftheoralcavity,keepit moist, and prevent oral mucositis (OM), if used regularly.

Caphosol canbeusedincombinationwithothertreatment options as it has no known interactions with other thera- pies. The studies have shown its high efﬁcacy in the treatmentofOMinpatientsreceivinghigh-dosemelphalan [19].

New methods of therapy

At the University Hospital of the School of Medicine of Ribeirao Preto, University of Sao Paulo (UHSMRP/USP), mouthwashwasdevelopedcalled‘‘MucositisFormula’’.Itis used to treat the clinical symptoms of OM. ‘‘Mucositis Formula’’ is a combination of anti-inﬂammatory (benzida- mine) and antifungal (nystatin) substances, anaesthetics (neututocain),anddistilledwater[5].

Pharmacological approaches to managing or alleviating the symptoms of OM are well supported by physiotherapy treatment,suchascryotherapyorlasertreatment.Thelocal application of cold results in the constriction of blood vessels, reduced ﬂow of blood with high concentration of cytostaticagents,andthus,lowerstheirmucotoxicaction.

Ithasbeenprovedthattheuseofcryotherapyinpatients treatedwith5-fluorouracildecreasestheriskoforalmucosa inflammation by 50%. Such results can be obtained when patientsstarttosuckicecubes5minbeforetheadministra- tion ofthedrug,and continuetodosoforthenext30min of the therapy period. The benefits accruing from such approach are also observed in patients treated with high dosesof drugssuchasmelphalan,metotrexate,edatrexate, etidronate, and in patients following the bone marrow transplant[8,9,18].

The studies have alsoconfirmed the positive impact of helium–neon(He–Ne)laserinthepreventionandtreatment of OM in HSCT patients. Low-power laser therapy acceler- atestheepithelializationoflesions,decreasesinflammation, is effective in fighting the pain, and stimulates salivary glandfunction[4,17,18].

A regards the prevention and treatment of mucositis, manyhopesarepinneduponcytokinesastheyinfluencethe course of inflammatory processes andimmuneresponse of thebody[18,20].Pro-inflammatorycytokines,includingIL-1, IL-2 as well as TNF, are thought to play a key role in the pathogenesis ofOM. Currently,granulocyte-colonystimulat- ingfactor(G-CSF)andgranulocyte–monocytecolonystimulat- ingfactor(GM-CSF)areusedfortherapeuticpurposes.G-CSF is aglycoproteinthat regulatesthe proliferation anddiffer- entiation of haematopoietic cellsby increasingthe number and stimulating the activity of neutrophils in peripheral blood, whichshortensthedurationofinfection andneutro- penia in persons undergoing myeloablative therapy before the autoHSCT [11]. There is no clinical evidence on the efficacy of the local use of the above preparations [20].

However,GM-CSF-synonym:CSF2,GMCSF,MGCadministered by subcutaneous injection over 5–14 days during the chemotherapy,inparticularif5-FU,cisplatin,cyclophosphamide, doxorubicin and etoposide, methotrexate, vinblastine and

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adriamycinareused,iseffectiveinreducingthesymptomsof mucosalinﬂammation[9].Thedrugisdiscontinuedafterthe whitebloodcellcountisincreasedupto1.010[8].

Keratinocyte growth factor (KGF) is an important sub- stance usedsystemically for the preventionand treatment of mucositis. Palifermin (Kepivance) is a human KGF pro- duced in E. coli [18]. It inﬂuences the proliferation and reduces the apoptosis of epithelial cells, stimulates keratinocyte migration, and thus participates in the wound healingprocess. Paliferminat adoseof60mg/kgper dayis recommended before the auto-HSCT. The drug should be started3daysbeforetheplannedconditioningregimen,and continued for the subsequent 3 days following the transplant[20].

For the prevention and treatment of accompanying fungalinfections,substancesthatreduceclinicalsymptoms of candidiasis in the oral cavity and gastrointestinal tract are used. These include nystatine, clotrimazole,amphoter- icinB,ﬂuconazole[18].

Itisthoughtthattheprophylaxisforbacterial infections is extremely important in HSCT patients, as they are a common cause of complications and treatment failures.

Suggested antibiotics include new-generation quinolones, levofloxacin and ciprofloxacin. These drugs show high activity and efficacy against Gram-positive bacteria and P.

aeruginosa, and are of particular importance in the fight against infections in auto-HSCT patients [21]. Moreover, intravenous b-lactam antibiotics – third-generation cepha- losporin (Biotum), aminoglycoside antibiotics – amikacin (Biodacyna),andfluoroquinolonechemotherapeitics–cipro- flozacin (Ciprofloksacin Kabi) are administered to treat infections at the Haemato-oncology and Bone Marrow TransplantationClinicoftheMedicalUniversityofLublin.

Gastrointestinal symptoms accompanying high-dose therapy:nausea,vomiting,diarrhoea,requirethatthenutri- tionalprotocolbedevelopedtobeusedinextremecasesof parenteralnutritionandineverycasewithantiemeticdrugs (Torekan).

Preventive treatment

‘‘In agreeing with the rule, that prevention is better than cure’’, the comprehensive dental management should include the prophylaxis in a broad sense. It covers oral hygiene instructions, selecting appropriate dental pastes, brushesandmouthwashsolutions,andfrequentpreventive exams. It isimportant toensure long-term dental careon a regular basis to a patient after the transplantation, to make it possible to diagnose and prevent inﬂammationof theoralcavitythatcausesimmunesystemdisorders.

Summary

In general, mucositis should be treated conservatively to avoidfurther tissueirritation and damaging theremaining cells from which the epithelium will regenerate [9]. The effectsof severemucositis are so adverse, causing serious discomfort, lengthened hospital stays, additional hospital

cost,and increasedriskforinfectionandmortality.Further establishmentofamethodologyfororalhealthcareinHSCT will be needed, and further research should focus on strategies directedat the prevention and treatment of OM [22].

Authors' contributions/Wkład autorów

Accordingtoorder.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

The work described in this article hasbeen carried out in accordance withThe Code of Ethics of the World Medical Association (Declarationof Helsinki)for experiments invol- ving humans; EU Directive 2010/63/EU for animal experiments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

references/pi smiennictwo

[1] DeptałaA,AsendrychA.Rolaallotransplantacji

krwiotwórczychkomórekmacierzystychwleczeniuguzów litych.Współczesnaonkologia2006;10:13–17.

[2] ZauchaR,ZauchaJM,WalewskiJ,JassemJ.Aktualne wskazaniadochemioterapiiwwysokichdawkach wspomaganejprzeszczepieniemautologicznychkomórek układukrwiotwórczegouchorychnanowotwory.

OnkologiawPraktyceKlinicznej2007;3:59–69.

[3] NiscolaP,RomaniC,CupelliL,etal.Mucositisinpatients withhematologicmalignancies:anoverview.

Haematologica2007;92:222–231.

[4] KhouriVY,StracieriABPL,RodriguesMC,etal.Useof therapeuticlaserforpreventionandtreatmentoforal mucositis.BrazDentJ2009;20:215–220.

[5] SonisST,OsterG,FuchsH,etal.Oralmucositis

andtheclinicalandeconomicoutcomesofhematopoietic stem-celltransplantation.JClinOncol2001;19:

2201–2205.

[6] RapoportAP,MillerWateletLF,LinderT,etal.Analysisof factorsthatcorrelatewithmucositisinrecipientsof autologousandallogeneicstem-celltransplants.JClin Oncol1999;17:2446–2453.

[7] Ramírez-AmadorV,Anaya-SaavedraG,Crespo-SolísE,etal.

Prospectiveevaluationoforalmucositisinacuteleukemia patientsreceivingchemotherapy.SupportCareCancer 2010;18:639–646.

[8] SvanbergA.Mucositispreventionforpatientsreceiving highdosechemotherapyandstemcelltransplantation.

ActaUniversitatisUpsaliensis2012;11:171–183.

(6)

[9] ScullyC,SonisS,DizPD.Mucosaldiseasesseries,oral mucositis.OralDis2006;12:229–241.

[10] EttingerDS.Supportivecareincancertherapy,1.NJ:

HumanaPress;2009.p.193–210.

[11] Grzegorczyk-JaźwińskaA,Dwilewicz-TrojaczekJ,KozakI, etal.OcenadziałaniastosowanegomiejscowoG-CSFu pacjentówpoautologicznymprzeszczepieniu

krwiotwórczychkomórekmacierzystychobserwacje wstępne.DentMedProbl2004;41:695–701.

[12] KarolewskaE,KonopkaT,PupekM,ChaberR.Mucositisin childrenwithleukemiaandsalivarydefensefactors.Dent MedProbl2007;44:30–36.

[13] HamerlakZ,BanachJ.Wynikileczeniaciężkichzapaleń jamyustnejudziecichorychnaostrebiałaczkiichłoniaki złośliwe.DentMedProbl2004;41:687–694.

[14] BaraschA,PetersonDE.Riskfactorsforulcerativeoral mucositisincancerpatients:unansweredquestions.Oral Oncol2003;39:91–100.

[15] KarolewskaE,KonopkaT.Algorytmstomatologicznego postępowaniaproﬁlaktyczno-leczniczegoudzieciz białaczkami.CzasStomatol2006;4:245–252.

[16] KirstiläV,Lenander-LumikariM,TenovuoJ.Effectsofa lactoperoxidase-system-containingtoothpasteondental plaqueandwholesalivainvivo.ActaOdontolScand 1994;52:346–353.

[17] AntunesHS,MellodeAzevedoAM,daSilvaBouzasLF,etal.

Low-powerlaserinthepreventionofinducedoral mucositisinbonemarrowtransplantationpatients:a randomizedtrial.Blood2007;109:2250–2255.

[18] ŁagockaR,Bendyk-SzefferM,Buczkowska-RadlińskaJ.

Managementoforalmucositisassociatedwithstandard chemotherapy-reviewofliterature.JStoma2011;64:

394–410.

[19] vanGroningenL,PottingC,vanderVeldenW,etal.

Caphosolinpreventionoforalmucositisinautologous stemcelltransplantrecipientsafterhigh-dosemelphalan (CASH).JClinOncol2008;26:1519–1525.

[20] Raber-DurlacherJE,vonBültzingslöwenI,LoganRM,etal.

Systematicreviewofcytokinesandgrowthfactorsforthe managementoforalmucositisincancerpatients.Support CareCancer2013;21:343–355.

[21] GilL,StyczyńskiJ,KomarnickiM.Infectiouscomplicationin 314patientsafterhigh-dosetherapyandautologous hematopoieticstemcelltransplantation:riskfactors analysisandoutcome.ClinEpidemiolStudyInfect 2007;35:421–427.

[22] KashiwazakiH,MatsushitaT,SugitaJ.Professionaloral healthcarereducesoralmucositisandfebrileneutropenia inpatientstreatedwithallogenicbonemarrow

transplantation.SupportCareCancer2012;20:367–373.