ORIGINAL ARTICLEReview ofnasopharyngealcarcinomaAnita Jeyakumar, MD; Todd M. Brickman, MD; Alwin Jeyakumar, MD;Timothy Doerr, MDAbstractWe review the literature on nasopharyngeal carcinoma thathas beenpublishedwithin the past 5 years. Nasopharyngealcarcinoma is a highly morbid disease, and survival is poor.Itsmanagementremains extremely difficult, not justforotolaryngologists but for radiation oncologists andmedicaloncologists, as well. A clear understanding of its etiologyis still lacking, but nasopharyngeal carcinoma is widelysuspected to be the result of both a genetic susceptibilityand exposure to environmentalfactors orEpstein-Barrvirusinfection. With no clear cause, treatment is controversial.For example, an optimal radiation regimen has not beendetermined,reports in the literature regarding the role ofchemotherapy foradvanced diseaseare conflicting, andtreatment of local recurrences is unsettled. Still, advancesin immunologic research and chemotherapy offer hope forbetter control ofthedisease. We hope that our assessmentoftherecent literature will provide otolaryngologists witha more clear understanding oftheetiology and manage-ment of nasopharyngeal carcinoma.IntroductionNasopharyngealcarcinomais a raretumorthatarisesintheepitheliumofthenasopharynx.Itaccountsformorethan95% ofnasopharyngealmalignanciesinadultsand20 to35% ofnasopharyngealmalignanciesinchildren,'Itisoftenmisdiagnosedearlybecauseofthevaguenessofthepresentingsymptomsandthe difficultyofthena-sopharyngealexamination.AnatomyThe nasopharynx is a trapezoid chamber located posteriortothenasalchoanae;itextendsinferiorlytothelowerborderofthesoftpalate. Thesuperiorborderisformedby the basisphenoid and basiocciput. The posterior borderis made up of the prevertebral fasciaof the atlas and axis.From the Department of Otolaryngology, University of Rochester (N,Y.)School of Medicine and Dentistry (Dr, Anita Jeyakumar, Dr, Brickman,and Dr, Doerr), and the Department of Oncology, Victoria GeneralHospital, Winnipeg, Manitoba, Canada (Dr, Alwin Jeyakumar),Reprintrequests:AnitaJeyakumar,MD,DepartmentofOtolaryngol-ogy,UniversityofRochesterSchoolofMedicineandDentistry,601 Elmwood Ave,, Box 629, Rochester, NY14642, Phone: (585)275-2222; fax:(585)271-8552; e-mail:anitajeyakumar@urmc,rochestereduThe pharyngobasilarfascia,whichis the onlysoft-tissueborder, forms the lateral walls ofthe nasopharynx. The eu-stachian tubes traverse this fasciabilaterally. The eustachiantubes are coveredsuperiorlyand posteriorlybycartilage(the torustubarius). ThefossaofRosenmliller,whichislocatedsuperiorand posteriorto the torus tubarius, is animportantlandmarkbecauseitis themostcommonsiteof originfornasopharyngealcarcinoma,^HistologyAtbirth,thenasopharynxislinedwithapredominantlypseudostratifiedcolumnarepithelium.Overthefirst10yearsoflife,thisepitheliumgraduallytransformsinto apredominantlystratified,nonkeratinizingsquamousepi-thelium, exceptin a fewareas (transitionzones).EpidemiologyThe incidence of nasopharyngeal carcinoma in the UnitedStates and Europe is only about1per 100,000 population,but in Taiwan, Hong Kong, and southern China (especiallyGuangdong province), the incidence is approximately30times higher,' The risk of nasopharyngeal carcinoma in anygivenarea rises whenChinesegenes are introducedintothe area. Theincidenceamong AfricansandFilipinosisapproximately 2 to 4 per 100,000 population,' Nasopharyn-geal carcinomais more commonin males by a margin ofabout 2 to1,' Its incidence peaks at 50 to 60 years of age;a smallpeakalso occurs duringlate childhood,'Genetic analysis of endemic populations has revealed thattheassociationofHLA-A2,HLA-B17,andHLA-Bw26doubles the risk of nasopharyngeal carcinoma,' These HLAassociations are not seen in North America,Another important etiologic factor in some types of na-sopharyngeal carcinoma is the Epstein-Barr virus (EB V).The detectionof the EB V nuclear antigenand viral DNAin nasopharyngealcarcinomahas revealedthat EBV caninfectepithelialcellsandthatitisassociatedwiththeirtransformation to cancer, Clonal EBV DNAhas been foundin some preinvasivelesions, suggestinga relationshiptothe transformationprocess.Otherassociationsincludechronicnasalinfections,poorhygiene,poorventilationofthenasopharynx,andexposure to the nitrosamines and polycyclic hydrocarbonsin salt-preservedfoods.168 ENT-Ear, Nose & Throat Journal March 2006REVIEW OF NASOPHARYNGEALCARCINOMAClinicalpresentationNasopharyngealcarcinomararelycomestomedicalattentionbeforeit has spreadto regionallymphnodes.Skinneret al foundthata unilateralneckmasswas themost common presenting sign, occurring in 36% of cases."Other authors have reportedrates as high as 80%.' Otherpresenting signs and symptoms include blood-stained nasaldischarge(18% of cases), unilateralhearingloss (12%),and unilateralnasal obstruction(5%)."Cranialnerveinvolvementsubsequentto invasion ofthe skull base is seen in 25% of cases.' The two principalcranial nerve syndromes associatedwithnasopharyngealcarcinomaare retroparotid syndrome(involvingcranialnervesIX, X,XI, andXII)and petrosphenoid syndrome(involving cranial nerves III, IV, V, and VI). Occasionally,cranialnerveII becomesinvolvedthroughthe foramenlacerum.Typically,nasopharyngealcarcinomacarriesapoorprognosisbecause of its proximity to vitalstructures, itsinvasiveness, the subtlety of its symptoms, and the difficultnatureof the examination,especiallyforprimarycarephysicians. Rates of distant metastasis at presentation are3%in the UnitedStatesand up to 6%in endemicareasof the world.-'PathologyIn1979, the WorldHealthOrganization(WHO)definedthree types of nasopharyngealcarcinomaonthe basis offindings on light microscopy.*Type I.Thiskeratinizingsquamouscellcarcinoma ischaracterizedby the presence of intracellular bridges andprominentkeratinformation.Type I tumorsaccount forapproximately25% of all nasopharyngealcarcinomas inNorthAmerica butonly1% of casesin endemicareas.'Patientswithtype I disease have the worstprognosis, asthe 5-year survival rate is only 35%.^Type II.Thistumorexhibitsthe maturationsequencecharacteristic of squamouscell carcinomabut no keratinformation.'This is the leastcommonof thethree types,and it is oftenclassifiedas typeIII. The5-yearsurvivalrate is 61%. 'Type III.Thisundifferentiatedcarcinomais made upof cells of varying morphology, and it frequentlycontainsclumps of benignTcells intermixed within the tumor mass;asa result,it is alsocalleda lymphoepithelioma.^ TypeIII tumors account for 95% of all cases in endemicareasand 60% of cases in North America. The 5-year survivalrate is61%. 'Rates of distantmetastasisarehigher in patientswithtypeII or III tumorsthan in patientswithtype I tumors.On the other hand, type II and III tumors are more easilycontrolled, owing to their greater degree of radiosensitiv-ity, and thereforepatients with type II or III disease havea better prognosis.DiagnosisThediagnosisofnasopharyngealcarcinomaisbasedprimarily on the historyand physical examination. Obvi-ously, a definitive diagnosis requires a biopsy of the lesion,either in the officeor in the operating room. The preferredimaging modalities are computedtomography(CT) withcontrastand magneticresonanceimaging(MRI)withenhancement.Mostoncologytextsappear to favorMRIover CT because it provides more details on extension andintracranialinvolvement.On the other hand, CT demon-stratesmore evidence of bonyerosion. These factors areall importantin the staging of the disease.StagingApproximately20 differentstaging systems for nasopha-ryngeal carcinoma have been reported in the literature sincethe early1950s.^ John Ho, a preeminent radiation oncolo-gist, developed a staging system in the late 1960s that wasused for many years.* Ho's system, which is based on thenaturalhistoryof thediseaseand autopsyobservations,isstillusedin China, but it hasbeenreplacedby morestandardized systems elsewhere. Even so, the systems thathave replaced Ho's have various inadequacies of their own.In 1989, for example, Neel and Taylor used Cox regressionmethodstoidentifyfivedisease-relatedcharacteristicsthat were significantlyassociatedwithsurvival, but theirsystemwas not adoptedby manyinstitutions because itscriteriawere completelydifferentfromexistingsystemsthat had been used to stage nasopharyngeal cancers.' Themajordrawbackof thesystempublishedby the Ameri-can Joint Committeeon Cancer(AJCC) in 1992 was theunevennessof thepatientdistributionspecifically, toomany patients were pooled into stage IV.'" The AJCC sub-sequently improved the distribution of patients and adoptedsomeof Ho'sprognosticcriteria(e.g., the involvementofthesupraclavicularfossa),and in1997"and2002,'^it publishedupdatedguidelines thatare standard in mostinstitutions.The widespreadacceptanceofthenewestAJCC system(tables1and 2) has made it much easier tocompare outcomes in differentcenters.MolecularmarkersMosttumormarkersare proteinsfoundin plasma or se-rum thathave some degree of specificityfor a particulartumor. Proteins are used as markers partly because of theirrelativelyhighconcentrationsin serumand plasmaandbecause of the ready availability of immunologic methods(e.g., radioimmunoassayand enzyme-linkedimmunosor-bent assay) that provide rapid and accuratequantificationof markers. With a potentially superior therapeutic index,molecularmarkersrepresentanexcitingadvance in thattheycan be usedto generateimmunotherapythatwillcomplement conventionalchemotherapy."Markersfornasopharyngealcarcinomaincludep53.Volume 85, Number 3 169JEYAKUMAR, BRICKMAN, JEYAKUMAR, DOERRTable1. The2002AJCCcriteriaforstagingnasopha-ryngealcarci noma"TITumoris confinedtothenasopharynxT2Tumorextendstothesofttissueoftheoropharynxand/ornasopharynxT2aNoextension totheparapharyngealspaceispresentT2bExtensiontotheparapharyngealspaceispresentT3Tumorhasinvadedboneand/ortheparanasalsinusesT4Tumorextendsintracraniallyand/orinvolves the cra-nial nerves, hypopharynx,infratemporalfossa, ororbitNONoregionallymphnodemetastasisispresentN1Unilateralnodemetastasisispresentabovethesupraclavioularfossa; nodeis6cmorsmallerN2Bilateralnodemetastasisispresentabovethesupraclavicularfossa; nodeis 6cmorsmallerN3NodemetastasisispresentN3aNodeis largerthan6cmN3bMetastasisto thesupraclavioularfossaispresentepidermalgrowthfactorreceptor(EGFR),angiogenicfactors, EB V, proliferating cell nuclear antigen, Ki-67, andc-erbB2.''' Gene et al showed that although p53 positivitycorrelated with the presence of lymph node disease, it wasnot a significant factor in predicting outcome." Studies byChuaet al"^ and Leongetal"showedthat expressionofEGFRwas increasedin nasopharyngealcarcinoma. Thisfinding pavedthe wayfora phaseII studyofcetuximabincombinationwithcarboplatin.'* Theoverallresponseratewas17%, andtherateofpartialresponseorstabledisease was 66%. EGFR may be a viable target forfurtherclinical trials.Vascularendothelialgrowthfactor(VEGF)isanan-giogenic factor.Guang-Wu et al reported that VEGF wasexpressed in10% of subjects who had a normal nasophar-ynx,in40%ofpatientswhohada benigntumorofthenasopharynx, and in 80% of those who had nasopharyngealcarcinoma." They also reported that expression of VEGFwas even higher in patients with advanced nasopharyngealcarcinoma. Despite these findings, the role of VEGF as apotential target has yet to be explored.EB V DNA seems to show promise as a marker to monitorand predict treatment outcomes in patients with advancednasopharyngeal carcinoma. In 2003, Lin et al reported theirstudy of 99 patients withstage III or IV disease who hadbeen treated with neoadjuvantchemotherapy followed byradiation.^" At baseline, 94 of these patients, including allpatientswithmetastatic disease, haddetectablelevels ofTable2. The2002AJCC stagingsystem"NON1N2N3TIIVT2IIIIIIIIVT3IIIIIIIIIIVT4IVIVIVIVEB V DNA in plasma; none of the disease-free controls haddetectableEBV DNA. The role of immunotherapybasedon EBV latent membrane proteinsis under study.TreatmentRadiotherapy.Itwasnotuntilthe1920sthatradiationtherapy was considered for nasopharyngeal carcinoma. Theearly reluctance to irradiate the nasopharynx was attribut-able to its proximity to other radiation-sensitive structures,such as the eye and spinal cord, as well as to the poor depthof penetration of x-rays at that time. In the early1920s, thefirstintercavitary treatment with radium was performed atthe Institut Curie in Paris. This brachytherapy continues tobe used in some places today for the treatment of primaryTI andT2 tumors thinner than 10 mm, although radium hasbeenreplacedbyiridium192.''' Until1977, thestandardofcare fornasopharyngealcarcinomain NorthAmericawas standard fractionatedradiationtherapy.^'Typicalradiationfieldsencompasstheadjacentskullbase andthe nasopharynx.Fieldsare bilaterallydirectedand include the retropharyngeal drainage pathway and theanterior and posterior cervical chains." Patients with stageI or II nasopharyngealcarcinoma have a high rate of curewith radiotherapyalone, but the prognosis forthose withdistant metastasis is poor. Tumor control has beenhighlycorrelatedwiththeamountofradiationdeliveredtothetumor.Inareviewof13 randomizedtrialswithsimilardosingby AgulnikandSiu, most of the studiesinvolvedthe use of a split-fieldtechnique, with two lateral opposedfacialfieldsandananteriorfieldifnecessary.'^Inordertoachievetumorcontrol,a doseofmorethan67Gyisrequired; local controlcan be furtherimprovedby main-taining technicalaccuracyduring radiationdelivery.^'In 1998, the use of three-dimensional intensity-modulatedradiation therapy (IMRT) was initiated at Memorial Sloan-KetteringCancerCenterforthetreatmentofnasopharyngealcarcinoma.^'A 2-yearfollow-upof39ofthesepatientsrevealed a local relapse-free survival rate of 97%, comparedwith a rate of only 78% among historical controls." Similarstudies in San Francisco and Hong Kong demonstrated thelocalbenefitsofIMRT,aswellasitsfavorabletoxicityprofile.'^Ofnote,nolargerandomizedtrialcomparingIMRT with conventional two- or three-dimensionalradia-tion techniques has beencompleted.170ENT-Ear, Nose & Throat Journal March 2006JEYAKUMAR, BRICKMAN, JEYAKUMAR, DOERRTohelpusdeterminetheoptimalradiationregimen,authors must clearly report total radiation doses, doses perfraction,and target volume dose variations.Chemotherapy.Chemotherapywasfirstusedinthe1970sasacomponentofprimarycurativetreatment.'"*Chemotherapyis classifiedinto three categories based onwhen it is deliveredin relationto radiotherapy: neoadju-vant,concurrent, andadjuvant.Chemotherapyactsas aradiosensitizer,andithelpsdecreasetherateofdistantmetastasis.In1998, Intergroupstudy0099waspublishedby Al-Sarrafetal.^' Thisstudyshowedthatpatientswhoweretreated with radiation alone had a significantly lower 3-yearsurvival rate (46%) than did patients who received radia-tion with concurrent cisplatin chemotherapyfollowedbyadditional chemotherapy with cisplatin and5-fiuorouracil(76%).ThisstudychangedthestandardofcareintheUnitedStates, even though it has been criticizedbecause(1) the investigators used the1992 AJCC staging criteriaandthereforetreatedsomeearly-stagenasopharyngealcarcinomas;(2)onlyabout45%ofpatientshadWHOstageIII cancer;(3) the radiotherapytechniquesusedatdifferentinstitutionswere not uniform,whichaccountedfor the poor results seen in the radiotherapy-alone arm; and(4) compliancewith chemotherapywas poor(only55 to73%).^ Furthermore, prior to 2004,13 phase III random-ized comparisons of radiation alone with concurrent and/oradjuvant chemotherapy had been published in the literature,and Intergroup study 0099 was the only one to show thatcombinedtherapy resulted in a positive outcome.^"As a result of these criticisms, combined-modality treat-ment for advanced nasopharyngeal carcinoma has not beenacceptedtoasignificantextentinendemicsoutheasternAsia.However,someofthese13 previouslypublishedtrials had shortcomingsof their own. For example, Rossiet al included many patients who were at low risk for dis-tantmetastasiswhileusinga less-activecombinationofvincristine, cyclophosphamide, and doxorubicin.^" Chi et alused adjuvant cisplatin, 5-fiuorouracil, and leucovorin andnoted no benefit in survival, but their patients experiencedan unusuallyhighnumber of treatment-relateddeaths inthe combination arm and an intermediate risk of relapse inone of their cohorts.^' Hareyama et al foundno benefittousing neoadjuvant chemotherapy, but their study was small,they included patients with early-stagedisease, and theirchemotherapeuticdosageswere low.^'' Finally,an Asian-Oceanian Clinical Oncology Association study^' involvedarelativelylowdoseofcisplatin,andanInternationalNasopharynxCancer Study Group triaF* was markedbya significant number of patients who refusedradiotherapyand a large number of chemotherapy-relateddeaths.The first studytoshowanybenefitto concurrentche-motherapyinanendemicareawasthe2003studybyLin et al.^" The structure of this study was similar to thatof Intergroupstudy0099.^' Patientsreceivedconcurrentcisplatinandalowerdoseof5-fluorouracil.The5-yeardisease-freesurvivalratewas89%inthecombinationarm,comparedwith73%intheradiation-onlyarmastatisticallysignificantdifference.^"In summary, the conflicting results in the literature makeitdifficulttodevelopachemotherapeuticregimenoreven to determine that chemotherapyconfersanybenefitat all. The difficultyis compoundedby the use ofdiffer-entstagingsystemsandstudyprotocols.Forexample,somestudiesarenotrandomized,andsomehavesmallsample sizes. In many publishedseries, authors have notspecifiedrates of distant metastases or indicatedwhetherthemetastasiswasthefirstoronlysiteoffailure;itisimportantthatthese data be interpretedin relationto theWHOclassificationbecausetypesIIandIIIareassoci-atedwithhigherratesofdistantmetastasis.Finally,wehave not identified the optimum number of chemotherapycycles. We do know that the timing of chemotherapyap-pears to have an impacton clinical outcome and that thedose intensityis best maintainedin the inductionsetting.In the13 randomizedtrials reported by Agulnik andSiu,the disparityin dose intensities may partially explainthelack of benefitassociatedwithadjuvantchemotherapy.'^More trials on chemoradiationare requiredtodeterminethe optimumchemotherapeuticagents andschedulethatcan be used with radiation therapy to achieve better treat-ment results.Surgery.Surgeryhas a limited role in the treatment ofnasopharyngealcarcinomabecauseofthetumor'shighdegreeofradiosensitivityandtheanatomicbarrierstosurgical access. The role of the surgeon is usually limitedtoobtainingtissuefordiagnosis,occasionallyresectingresidualadenopathyafterdefinitiveradiotherapy,andprovidingsymptomaticrelief(e.g., placementoftympa-nostomy tubes).Various surgical approaches have been described in theliterature, includingtranspalatal,transmaxillary,midlinemandibulotomy,facialdegloving,infratemporalfossa,and endoscopicapproaches.^' Surgeryis associatedwithslightlybettercontrolanda lowerrateofcomplicationsthanrepeatirradiationinpatientswithlimiteddisease.Surgeryis typically contraindicatedfor patients with anyevidenceofextensionintotheparapharyngealspace,skull base, paranasalsinuses, or carotid artery because ofsurgery's high degree of morbidity and the low probabilityof effectinga cure.Feeetaldescribedacombinationtranspalatal,trans-maxillary, and transcervicalapproachin 33 patientswithrecurrentnasopharyngealcarcinoma.^"Theyachieveda5-year local control rate of 67% and an overall survival of60%. Fisch etaP'describedthe infratemporalapproach,and Panje et aP^ described the lateral temporalapproach;although both resulted in excellent tumor exposure on the172ENT-Ear, Nose & Throat Journal March 2006REVIEW OF NASOPHARYNGEALCARCINOMAipsilateralside, contralateralexposure was poor,makingcomplete excision of the tumor difficultin cases of tumorextension. Other surgical approaches have been described,but regardless of the choice, the nature of nasopharyngealcarcinomademandsthattheoperationbe tailoredtotheindividualpatient.Nasopharyngectomy is an alternative treatment for localrecurrentand residualnasopharyngealcarcinoma.'^TreatmentcomplicationsComplications of radiotherapy are fairly well documented.Xerostomia is the most common; others include pituitarydysfunction,temporalbonenecrosis,dysphagia,cranialnervepalsy,hearingloss,carotidarterystenosis,hypo-thyroidism, dry eye syndrome, myelitis, encephalopathy,hypopituitarism,andseveretrismus,tonameafew.^'-^''Repeatirradiationhasbeenassociatedwithlong-termproblemswithnecrosisofthecentralnervoussystem,bone, and softtissue.Most of the complications associated with cisplatin-basedchemotherapy are bone marrow suppression, hearing loss,andrenalimpairment.'"Experiencewithchemotherapyisstilllimited,andstudieswithlongerfollow-uparerequired.Surgical complications can be divided into two catego-ries: those associated with nasopharyngectomyand thoseassociated with neck dissection.'"* Because surgery is usuallyperformedafterradiationhasbeendelivered,complica-tionsrelatedtopoorwoundhealingarecommon;theyincludepalatal fistula, nasopharyngealwoundinfection,osteonecrosis, nonunionor malunionof osteotomysites,andfiapnecrosis.Themostseriouspotentialcomplica-tionsassociatedwithresectionofrecurrentdiseasearedeath,carotidarteryrupture,andviolationofthedura.^'Other possible complicationsarespecificto thesurgicalapproach;amongthemaremaxillarynecrosis,choanalstenosis, saddle-nose deformity,and trismus.Follow-upThe roles of directandindirectnasopharyngoscopy,CT,MRI, and molecularmarkersstill need to be fullydeter-minedwithrespecttosurvivalandcost-effectiveness.Frequent follow-up with biopsy of any suspicious residualor recurrent disease is necessary.References1.Paulino AC, GruppSA. Nasopharyngealcancer. eMedicine Aug.19, 2004. www.emedicine.coni/ped/topicl553.htni(accessed Jan.17,2006).2.WitteMC, NeelHB III. Nasopharyngealcarcinoma.In: Atlas ofHead and Neck Surgery-Otolaryngology.2nd ed. New York: Lip-pincott Williams & Wilkins, 2001:1637-54.3.Ruckenstein MJ. Nasopharyngeal carcinoma. In: Ruckenstein MJ,ed. Comprehensive Review of Otolaryngology. Philadelphia: W.B.Saunders, 2004:197-8.4.Skinner DW, Van Hasselt CA, Tsao S Y. Nasopharyngeal carcinoma:Modesofpresentation.AnnOtolRhinolLaryngol1991;100:544-51.5.Sham JS, Cheung YK, ChoyD, etal. Cranialnerveinvolvementand base of the skull erosion in nasopharyngeal carcinoma. Cancer1991;68:422-6.6.WHO Handbook for Reporting Results of Cancer Treatment. WHOOffsetPublicationNo. 48.Geneva:WorldHealthOrganization,1979.7.Lee AW, Foo W, Law SC,etal. Staging of nasopharyngeal carcinoma:From Ho's to the new UICC system. Int J Cancer1999;84:179-87.8.Ho J. Stage classificationof nasopharyngeal carcinoma: A review.IARC Sci Publ1978;(20):99-113.9.NeelHB III, Taylor WF. Newstaging system fornasopharyngealcarcinoma. Long-term outcome. Arch Otolaryngol Head Neck Surg1989;115:1293-1303.10.AmericanJointCommitteeonCancer.ManualforStagingofCancer. 4th ed. Philadelphia: J.B. Lippincott,1992.11.Fleming ID, Cooper JS, Henson DE, et al, eds. AJCC Cancer Stag-ing Manual. 5th ed. Philadelphia:Lippincott-Raven,1997.12.Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer'stagingManual. 6th ed. New York: Springer, 2002.13.AgulnikM,SiuLL.State-of-the-artmanagementofnasopharyngealcarcinoma:Currentandfuturedirections.BrJCancer2005 ;92:799-806.14.MouldRF, Tai TH.Nasopharyngealcarcinoma:Treatmentsandoutcomesin the 20th century. Br J Radiol 2002;75:307-39.15.GeneE, HosalAS, GedikogluG,etal. Prognosticvalueof p53,proliferatingcell nuclearantigen,andKi-67 expressionin undif-ferentiatednasopharyngealcarcinomas.OtolaryngolHeadNeckSurg 2000; 122:868-73.16.ChuaDT,NichollsJM,ShamJS,AuGK.Prognosticvalueofepidermalgrowthfactorreceptorexpressioninpatientswithadvancedstage nasopharyngealcarcinoma treatedwithinductionchemotherapyandradiotherapy.IntJRadiatOncolBiolPhys2004;59:11-20.17.Leong JL, Loh KS, PottiTC, et al. Epidermal growth factor receptorin undifferentiatedcarcinomaof the nasopharynx.Laryngoscope2004;114:153-7.18.Chan AT, Hsu MM, Goh BC, et al. A phase II study of cetuximab(C225) in combination with carboplatin in patients (pts) with recur-rent or metastatic nasopharyngeal carcinoma (NPC) who failed to aplatinum-based chemotherapy[abstract]. Proc Am Soc Clin Oncol2003;22:497.19.Guang-WuH,SunagawaM,Jie-EnL,etal.The relationship betweenmicrovessel density, the expression of vascular endothelial growthfactor(VEGF),andthe extensionofnasopharyngealcarcinoma.Laryngoscope2000; 110:2066-9.20.Lin JC, Jan JS, Hsu CY, et al. Phase III study of concurrent chemo-radiotherapy versus radiotherapy alone for advanced nasopharyngealcarcinoma: Positive effect on overall and progression-free survival.J Clin Oncol2003;21:631-7.21.Al-SarrafM,LeBlancM,GiriPG,etal.Chemoradiotherapyversusradiotherapyinpatientswithadvancednasopharyngealcancer: Phase III randomized Intergroup study 0099. J Clin Oncol1998;16:1310-17.22.DiazEM,SturgisEM,LaramoreGE,etal.Neoplasmsoftheheadandneck.In:KufeDW, PollockRE, WeichselbaumRR, etal.Holland-FreiCancerMedicine.Hamilton,Ont.:B.C. Decker,2003:1325-72.23.Hunt MA, ZelefskyMJ, WoldenS, et al. Treatment planning anddeliveryof intensity-modulatedradiationtherapy forprimaryna-sopharynxcancer. Int J Radiat Oncol Biol Phys 2001;49:623-32.Continued on page184Volume 85, Number 3173LEE, ELIASHAR, ELIACHAR Some extensive reconstructive proceduresfor exam-ple, laryngofissure, arytenoidectomy, vocal fold resection,and cordotomymay result in a secure airway and closureof the tracheotomysite at the expense of voice quality. Long-term treatment and close follow-up are necessaryin cases where scarringmay progress and persist.^"*Inconclusion,althoughthereissomecontroversyre-garding the management of acute laryngotrachealtrauma,treatmentinexperiencedhandswillusuallyresultinafavorableoutcome.''^References1.EliacharI. Managementofacutelaryngealtrauma. ActaOtorhi-nolaryngolBelgl996;50:151-8.2.BentJPIII,SilverJR,PorubskyES. Acutelaryngealtrauma; Areviewof77patients.OtolaryngolHeadNeckSurg1993; 109:441-9.3.SchaeferSD.Theacutemanagementofexternallaryngealtrauma. A 27-year experience. Arch OtolaryngolHeadNeck Surg1992;118:598-604.4.Gluckman JL. Laryngeal trauma: Surgical therapy in the adult. EarNose Throat J1981;60:366-72.5.RichardsonMA. Laryngealanatomyandmechanismsoftrauma.Ear Nose Throat J1981 ;60:346-51.6.Greene R, StarkP. Trauma of the larynx andtrachea. RadiolClinNorth Am1978;l6:309-20.7.MyersEM, IkoBO. Themanagementofacutelaryngealtrauma.J Traumal987;27:448-52.8.Goldenberg D, Golz A, Flax-GoldenbergR, Joachims HZ. Severelaryngeal injury caused by blunt trauma to the neck: A case report.J LaryngolOtol1997,111:1174-6.9.GanzelTM,MumfordLA.Diagnosisandmanagementofacutelaryngealtrauma. Am Surg1989;55:303-6.10.Hanft K, Posternack C, Astor F, Attarian D. Diagnosis and manage-ment of laryngealtraumain sports. South Med J1996;89:631-3.11.StanleyRB Jr., HansonDG. Manualstrangulationinjuriesofthelarynx. Arch Otolaryngol1983;IO9:344-7.12.Chagnon FP, Mulder DS. Laryngotracheal trauma. Chest Surg ClinNAm1996;6:733-48.13.SchaeferSD, CloseLG. Acutemanagementof laryngealtrauma.Update. Ann OtolRhinolLaryngol1989;98:98-104.14.Jewett BS, Shockley WW, Rutledge R. Externallaryngealtraumaanalysisof392patients.ArchOtolaryngolHeadNeckSurgI999;125:877-8O.15.Gussack GS, Jurkovich GJ, Luterman A. Laryngotracheal trauma: Aprotocolapproachto a rare injury.Laryngoscope1986;96:660-5.16.StanleyRB Jr. Value of computedtomographyinmanagement ofacute laryngealinjury.J Traumal984;24:359-62.17.Schaefer SD. Use of CT scanning in the management of the acutelyinjuredlarynx. OtolaryngolClin North Am1991 ;24:31 -6.18.SchaeferSD, BrownOE. Selective applicationof CT in the man-agementof laryngealtrauma. LaryngoscopeI983;93:1473-5.19.Eliachar I, Lewin JS. Imaging evaluation of laryngotracheal stenosis.J Otolaryngol1993;22:265-77.20.HliacharI.Unaidedspeechinlong-termtube-freetracheostomy.Laryngoscope2000; 110:749-60.2LdeMello-FilhoFV,CarrauRL.Themanagementoflaryngealfracturesusing internal fixation. Laryngoscope2000;110:2143-6.22.Kennedy KS, Harley EH. Diagnosis and treatment of acute laryngealtrauma. Ear Nose Throat JI988;67:584, 587,590-2, passim.23.Lim JW, Lerner PK, RothsteinSG. Epiglottic position after crico-thyroidotomy: A comparisonwith tracheotomy. AnnOtolRhinolLaryngol1997; 106:560-2.24.Brosch S, Johannsen HS. Clinical course of acute laryngeal traumaandassociatedeffectsonphonation.JLaryngolOtol1999; 113:58-61.JEYAKUMAR, BRICKMAN, JEYAKUMAR, DOERRContinued frompage 17324.Rossi A, Molinari R, Boracchi P, et al. Adjuvant chemotherapy withvincristine, cyclophosphamide, and doxorubicin after radiotherapyin local-regionalnasopharyngealcancer: Results of a 4-year mul-ticenterrandomizedstudy. J ClinOncol1988;6:1401-10.25.ChiKH, Chang YC, Guo WY, et al. A phaseIII study ofadjuvantchemotherapy in advanced nasopharyngeal carcinoma patients. IntJRadiat OncolBiolPhys2002;52:1238-44.26.HareyamaM, SakataK,ShiratoH, etal. A prospective,random-ized trial comparing neoadjuvantchemotherapy with radiotherapyalone in patients with advanced nasopharyngeal carcinoma. Cancer2002;94:22l7-23.27.ChuaDT,ShamJS,ChoyD,etal.PreliminaryreportoftheAsian-OceanianClinicalOncologyAssociationrandomizedtrialcomparingcisplatin and epirubicin followed by radiotherapy versusradiotherapy alone in the treatment of patients withlocoregionallyadvancednasopharyngealcarcinoma.Asian-OceanianClinicalOncology AssociationNasopharynxCancer Study Group. Cancer1998;83:2270-83.28.International Nasopharynx Cancer Study Group. Preliminary resultsofa randomizedtrial comparingneoadjuvantchemotherapy(cis-platin,epirubicin,bleomycin)plusradiotherapyvs.radiotherapyalone in stage 1V(> or = N2, MO) undifferentiatednasopharyngealcarcinoma: Apositiveeffecton progression-free survival. VUMCAI trial. Int J Radiat OncolBiolPhys1996;35:463-9.29.ShuCH, ChengH,LirnyJF, etal.Salvagesurgeryforrecurrentnasopharyngealcarcinoma.Laryngoscope2000; 110:1483-8.30.Fee WE Jr., GilmerPA, GoffinetDR, et al. Surgicalmanagementofrecurrentnasopharyngealcarcinomaafterradiationfailureatthe primarysite. LaryngoscopeI988;98:1220-6.31.FischU, FaganP, Valavanis A. The infratemporalfossaapproachforthelateralskullbase.OtolaryngolClinNorthAm1984; 17:513-52.32.PanjeWR,DohrmannGJIII,PitcockJK,etal.Thetransfacialapproachfor combinedanterior craniofacialtumor ablation. ArchOtolaryngolHeadNeckSurg1989;l 15:301-7.33.To EW, Lai EC, Cheng JH, et al. Nasopharyngectomy for recurrentnasopharyngeal carcinoma: A review of 31 patients and prognosticfactors.Laryngoscope2002; II2:1877-82.34.Lin HS, Fee WE Jr. Malignant nasopharyngealtumors. eMedicineJuly22,2005.www.emedicine.com/ent/topic269.htm(accessedJan.17,2006).184 ENT-Ear, Nose & Throat Journal March 2006