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nasopharyngeal carcinoma

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Seminar Introduction Nasopharyngeal carcinoma is a non-lymphomatous, squamous-cell carcinoma that occurs in the epithelial lining of the nasopharynx. This neoplasm shows varying degrees of differentiation and is frequently seen at the pharyngeal recess (Rosenmüller’s fossa) posteromedial to the medial crura of the eustachian tube opening in the nasopharynx. 1 The first report on a group of 14 patients who had this type of tumour was published in 1901. 2 A further clinical study of 79 patients was published in 1922. 3 The first comprehensive study of nasopharyngeal carcinoma was done in 1941, and described clinicopathological features in 114 patients. 4 This neoplasm is an uncommon disease in most countries, and its age-adjusted incidence for both sexes is less than one per 100 000 population. 5 However, the disease occurs with much greater frequency in southern China, northern Africa, and Alaska. The Inuits of Alaska 6 and ethnic Chinese people living in the province of Guangdong are especially prone to the disease. The reported incidence of nasopharyngeal carcinoma among men and women in Hong Kong (geographically adjacent to Guangdong province) is 20–30 per 100 000 and 15–20 per 100 000, respectively. 5 That the incidence of nasopharyngeal carcinoma remains high among Chinese people who have immigrated to southeast Asia or North America, but is lower among Chinese people born in North America than in those born in southern China, is noteworthy. 7,8 This finding suggests that genetic, ethnic, and environmental factors could have a role in the cause of the disease. Pathology The malignant epithelial cells of the nasopharynx are large polygonal cells with a syncytial composition. Their nuclei are round or oval with scanty chromatin and distinct nucleoli. The cells show no parakeratosis or cornification and are frequently intermingled with lymphoid cells in the nasopharynx, giving rise to the introduction of the term lymphoepithelioma. 9 Electronmicroscopy studies have established that these tumour cells are of squamous origin and that the undifferentiated carcinoma is a form of squamous-cell carcinoma. 10,11 Epstein-Barr virus (EBV) is consistently detected in patients with nasopharyngeal carcinoma from regions of high and low incidence. EBV-encoded RNA signal has been shown, by in-situ hybridisation, to be present in nearly all tumour cells, whereas EBV-encoded RNA is absent from the adjacent normal tissue, except perhaps for a few scattered lymphoid cells. Premalignant lesions of the nasopharyngeal epithelium have also been shown to harbour EBV, which suggests that the infection occurs in the early phases of carcinogenesis. 12 Detection of a single form of viral DNA suggests that the tumours are clonal proliferations of a single cell that was initially infected with EBV. Specific EBV latent genes are consistently expressed in nasopharyngeal carcinomas and in early, dysplastic lesions. The corresponding latent viral proteins (latent membrane protein 1 and 2) have substantial effects on cellular gene expression and cellular growth, resulting in the highly invasive, malignant growth of the carcinoma. 13,14 The histological classification of nasopharyngeal carcinoma proposed by WHO in 1978, categorised tumours into three groups: type I included typical keratinising squamous-cell carcinomas, similar to those Lancet 2005; 365: 2041–54 Department of Surgery (Prof W I Wei FRCS) and Department of Clinical Oncology (Prof J S T Sham FRCR), University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, China Correspondence to: Professor William I Wei [email protected] www.thelancet.com Vol 365 June 11, 2005 2041 Nasopharyngeal carcinoma William I Wei, Jonathan S T Sham Incidence of nasopharyngeal carcinoma has remained high in endemic regions. Diagnosing the disease in the early stages requires a high index of clinical acumen and, although most cross-sectional imaging investigations show the tumour with precision, confirmation is dependent on histology. Epstein-Barr virus (EBV)-encoded RNA signal is present in all nasopharyngeal carcinoma cells, and early diagnosis of the disease is possible through the detection of raised antibodies against EBV. The quantity of EBV DNA detected in blood indicates the stage and prognosis of the disease. Radiotherapy with concomitant chemotherapy has increased survival, and improved techniques (such as intensity-modulated radiotherapy), early detection of recurrence, and application of appropriate surgical salvage procedures have contributed to improved therapeutic results. Screening of high-risk individuals in endemic regions together with developments in gene therapy and immunotherapy might further improve outcome. Search strategy and selection criteria We did an extensive search of published work about nasopharyngeal carcinoma through the Pubmed/MEDLINE database from 2004 back to the mid-60’s, and this search included the OLDMEDLINE. We also searched The Cochrane Library for review articles published between 1990 and 2003. Search terms included: “nasopharyngeal carcinoma”, “nasopharynx cancer”, “radiotherapy”, “chemotherapy”, “salvage therapy”, “nasopharyngectomy”, “combined treatment modality”, “clinical trials”, “randomized controlled trials”, and “meta-analysis”. The searches included reports of studies on human beings and were those published in English. Priority of selection was large contemporary clinical trials or studies. Abstracts of recent pertinent medical conferences were also included for information about latest developments. Most of the publications used were from work published within the past 15 years, although we have also included a few highly regarded old articles.

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SeminarIntroductionNasopharyngealcarcinomaisanon-lymphomatous,squamous-cellcarcinomathatoccursintheepitheliallining of the nasopharynx. This neoplasm shows varyingdegreesofdifferentiationandisfrequentlyseenatthepharyngealrecess(Rosenmllersfossa)posteromedialto the medial crura of the eustachian tube opening in thenasopharynx.1The rst report on a group of 14 patients who had thistype of tumour was published in 1901.2A further clinicalstudyof79patientswaspublishedin1922.3Therstcomprehensivestudyofnasopharyngealcarcinomawasdone in 1941, and described clinicopathological featuresin 114 patients.4This neoplasm is an uncommon diseasein most countries, and its age-adjusted incidence for bothsexes is less than one per 100 000 population.5However,thediseaseoccurswithmuchgreaterfrequencyinsouthern China, northern Africa, and Alaska. The InuitsofAlaska6andethnicChinesepeoplelivingintheprovinceofGuangdongareespeciallypronetothedisease.ThereportedincidenceofnasopharyngealcarcinomaamongmenandwomeninHongKong(geographicallyadjacenttoGuangdongprovince)is2030per100 000and1520per100 000,respectively.5That the incidence of nasopharyngeal carcinoma remainshighamongChinesepeoplewhohaveimmigratedtosoutheastAsiaorNorthAmerica,butisloweramongChinesepeopleborninNorthAmericathaninthoseborninsouthernChina,isnoteworthy.7,8Thisndingsuggests that genetic, ethnic, and environmental factorscould have a role in the cause of the disease. Pathology The malignant epithelial cells of the nasopharynx are largepolygonal cells with a syncytial composition. Their nucleiareroundorovalwithscantychromatinanddistinctnucleoli. The cells show no parakeratosis or cornicationand are frequently intermingled with lymphoid cells in thenasopharynx,givingrisetotheintroductionofthetermlymphoepithelioma.9Electronmicroscopystudieshaveestablished that these tumour cells are of squamous originandthattheundifferentiatedcarcinomaisaformofsquamous-cell carcinoma.10,11Epstein-Barrvirus(EBV)isconsistentlydetectedinpatients with nasopharyngeal carcinoma from regions ofhighandlowincidence.EBV-encodedRNAsignalhasbeenshown,byin-situ hybridisation,tobepresentinnearlyalltumourcells,whereasEBV-encodedRNAisabsent from the adjacent normal tissue, except perhaps fora few scattered lymphoid cells. Premalignant lesions of thenasopharyngealepitheliumhavealsobeenshowntoharbour EBV, which suggests that the infection occurs inthe early phases of carcinogenesis.12 Detection of a singleformofviralDNAsuggeststhatthetumoursareclonalproliferations of a single cell that was initially infected withEBV. Specic EBV latent genes are consistently expressedinnasopharyngealcarcinomasandinearly,dysplasticlesions.Thecorrespondinglatentviralproteins(latentmembraneprotein1and2)havesubstantialeffectsoncellular gene expression and cellular growth, resulting inthe highly invasive, malignant growth of the carcinoma.13,14ThehistologicalclassicationofnasopharyngealcarcinomaproposedbyWHOin1978,categorisedtumoursintothreegroups:typeIincludedtypicalkeratinising squamous-cell carcinomas, similar to thoseLancet 2005; 365: 204154Department of Surgery(Prof WI Wei FRCS) andDepartment of ClinicalOncology(Prof J S T ShamFRCR),University of Hong KongMedical Centre, Queen MaryHospital, Hong Kong SAR,ChinaCorrespondence to: Professor William I [email protected] Vol 365 June 11, 20052041Nasopharyngeal carcinomaWilliam I Wei, Jonathan S T ShamIncidence of nasopharyngeal carcinoma has remained high in endemic regions. Diagnosing the disease in the earlystages requires a high index of clinical acumen and, although most cross-sectional imaging investigations show thetumourwithprecision,conrmationisdependentonhistology.Epstein-Barrvirus(EBV)-encodedRNAsignalispresent in all nasopharyngeal carcinoma cells, and early diagnosis of the disease is possible through the detection ofraised antibodies against EBV. The quantity of EBV DNA detected in blood indicates the stage and prognosis of thedisease.Radiotherapywithconcomitantchemotherapyhasincreasedsurvival,andimprovedtechniques(suchasintensity-modulatedradiotherapy),earlydetectionofrecurrence,andapplicationofappropriatesurgicalsalvageprocedures have contributed to improved therapeutic results. Screening of high-risk individuals in endemic regionstogether with developments in gene therapy and immunotherapy might further improve outcome.Search strategy and selection criteriaWe did an extensive search of published work aboutnasopharyngeal carcinoma through the Pubmed/MEDLINEdatabase from 2004 back to the mid-60s, and this searchincluded the OLDMEDLINE. We also searched The CochraneLibrary for review articles published between 1990 and 2003.Search terms included: nasopharyngeal carcinoma,nasopharynx cancer, radiotherapy, chemotherapy,salvage therapy, nasopharyngectomy, combinedtreatment modality, clinical trials, randomized controlledtrials, and meta-analysis. The searches included reports ofstudies on human beings and were those published inEnglish. Priority of selection was large contemporary clinicaltrials or studies. Abstracts of recent pertinent medicalconferences were also included for information about latestdevelopments. Most of the publications used were from workpublished within the past 15 years, although we have alsoincluded a few highly regarded old articles. Seminarfound in the rest of the upper aerodigestive tract; type IIincludednon-keratinisingsquamouscarcinomas;andtypeIIIincludedundifferentiatedcarcinomas(panel).15Analternativeclassicationhasdividedtumoursintotwo histological types, namely squamous-cell carcinomasandundifferentiatedcarcinomasofthenasopharyngealtype.16ThesecondclassicationiscorrelatedwithEBVserology: patients with squamous-cell carcinomas have areducedEBVtitre,whereasthosewithundifferentiatedcarcinomas of the nasopharyngeal type have raised titres.In North America, around 25% of tumour patients havetype I histology, 12% have type II, and 63% have type III.ThehistologicaldistributioninsouthernChinesepatients is 2%, 3%, and 95%, respectively.17Biopsiesobtainedfromnasopharyngealcarcinomassometimesshowamixedhistologicalpattern,andthispatternvariesamongdifferentpartsofthetumour.ThemostrecentWHOclassicationhastakenthismixedpattern into account as well as the association of EBV withtypeIIandtypeIIItumours.Thehistologicaltypesofnasopharyngealcarcinomaarenowdenedeitherassquamous-cellcarcinomasornon-keratinisingcarcinomas,andthesecondgroupissubdividedintodifferentiatedandundifferentiatedcarcinomas.18Thisclassicationismoreapplicableforepidemiologicalresearchandhasalsobeenshowntohaveaprognosticbearing. Undifferentiated carcinomas have a higher localtumour control rate with treatment and a higher incidenceof distant metastasis than do differentiated carcinomas.19,20Symptoms and serological diagnosisPatientswithnasopharyngealcarcinomacanpresentwith symptoms from one or more of four categories. Thecategories consist of (1) presence of tumour mass in thenasopharynx(epistaxis,nasalobstruction,anddischarge);(2)dysfunctionoftheeustachiantube,associatedwiththelateroposteriorextensionofthetumourtotheparanasopharyngealspace(tinnitusanddeafness);(3)skull-baseerosionandpalsyofthefthandsixthcranialnerves,associatedwiththesuperiorextension of the tumour (headache, diplopia, facial painand numbness); and (4) neck masses, usually appearingrst in the upper neck. Symptoms such as anorexia andweightlossareuncommoninpatientswithnasopharyngealcarcinomasanddistantspreadshouldbesuspectedwhensuchsymptomsarepresent.Unfortunately, because of the non-specic nature of thenasal and aural symptoms and the difculty of making aclinicalexaminationofthenasopharynx,mostpatientswiththediseasearediagnosedonlywhenthetumourhas reached an advanced stage (stages III and IV).Aretrospectiveanalysisof4768patientsidentiedsymptoms of nasopharyngeal carcinoma at presentationasneckmass(76%),nasaldysfunction(73%),auraldysfunction(62%),headache(35%),diplopia(11%),facialnumbness(8%),weightloss(7%),andtrismus(3%).Thephysicalsignspresentatdiagnosiswereenlarged neck node (75%) and cranial nerve palsy (20%).Thecranialnervesmostcommonlyaffectedwerethethird,fth,sixth,and12thnerves.21,22Thepresentingsymptomsinyoungpatientswereingeneralsimilartothose reported in adults.23Patientswhopresentwithsymptomsofnasopharyngealcarcinomashouldbeclinicallyassessedfor physical signs of the disease. A positive EBV serologytestwillgivefurthergroundsforsuspicionandwouldjustify an endoscopic examination and a biopsy from thenasopharynx. If the clinical suspicion for nasopharyngealcarcinomaishigh,evenifthesuspectedtumourisnotvisualisedwithendoscopicexamination,cross-sectionalimaging by CT or MRI should be undertaken. A denitivediagnosisofnasopharyngealcarcinomaneedsapositivebiopsytakenfromthetumourinthenasopharynx,supportedeitherbyitsvisualisationinthenasopharynxor (in the case of predominantly submucosal tumours) itsvisualisation with cross-sectional imaging. Population screeningIn southern China, where nasopharyngeal carcinoma isendemic,EBVserologyhasbeenusedforpopulationscreening.InastudyundertakeninWuzhou(Guangxiprovince,China)24intheearly1980s,1136individualsidentied as positive for immunoglobulin A against viralcapsid antigen received regular clinical examinations ofthenasopharynxandneckfor4 years.Duringthisfollow-up period, 35 cases of nasopharyngeal carcinomaweredetected,mostofwhich(92%)werediagnosedearlyateitherstageIorstageII.Theannualdetectionrateofnasopharyngealcarcinomaforthisgroupwas317 times higher than for the population as a whole. 2042 www.thelancet.com Vol 365 June 11, 2005 Panel: WHO histological classication of nasopharyngealcarcinoma15Keratinising squamous-cell carcinoma (WHO type I)This type of nasopharyngeal carcinoma shows squamousdifferentiation with the presence of intercellular bridgesand/or keratinisation over most of its extent.Non-keratinising carcinomaThis group comprises a differentiated type of non-keratinisingcarcinoma and an undifferentiated type. These tumours aregenerally more radiosensitive than squamous cell carcinomaand have stronger relationships with the Epstein-Barr virus.1. Differentiated non-keratinising carcinoma (WHO type II)The tumour cells show differentiation with a maturationsequence that results in cells in which squamousdifferentiation is not evident on light microscopy.2. Undifferentiated carcinoma (WHO type III)The tumour cells have oval or round vesicular nuclei andprominent nucleoli. The cell margins are indistinct, and thetumour exhibits a syncytial rather than pavementedappearance.SeminarSimilar results were reported from another study doneinZhongshan(Guangdongprovince,China).25Thesensitivity and predictive value of serology in populationscreeningwasproposedtobeimprovedbytestingagainst a panel of EBV antibodies.26The predictive valueof EBV serology for nasopharyngeal carcinoma was lentsupportbyamorerecentreportfromTaiwan.27Inthisstudy, the initial EBV serology of 9699 study participantswas cross-checked against the cancer registry and deathregistryintheensuing15-yearperiod.Thedurationoffollow-upwascorrelatedwiththedifferenceinthecumulativeincidenceofnasopharyngealcarcinomabetweenseropositiveandseronegativepatients.Prospectivestudiesarenowneededtoassesstheeffectofsuchpopulation-basedscreening,intermsofthereductioninmortalityrelatedtonasopharyngealcarcinomainthescreenedpopulation;therisk-benetratio (risks from endoscopic examination and biopsies);and cost-effectiveness. Imaging studiesBefore the introduction of cross-sectional imaging, littlewasknownaboutthenaturalbehaviourandroutesofextensionofnasopharyngealcarcinomasintheearlystagesofdevelopment.Surgerywasnotaprimarytreatment,andpost-mortemexaminationsofpatientswho died from nasopharyngeal carcinoma were of littleimportancesincethetumourswereusuallyveryadvancedbythetimeofdeathandhadundergonesignicantsecondarychangesasaresultoftreatment.The best that could be done was to use plain radiographsto assess bone destruction and soft tissue mass abuttingontheupperairway,butthesetechniqueswereoflowsensitivityandspecicityandaddedlittletoourknowledge of invasion and extension of the disease.Clinicalexamination(includingendoscopicexamination)canprovidevaluableinformationaboutmucosalinvolvementandtumourextensionintothenasalfossaeandoropharynx,butcannotascertaindeepextension,skull-baseerosion,orintracranialspread,exceptwheretherearetell-talesymptomsandsignsofgrossextensionalongtheseroutes.Cross-sectionalimaginghasrevolutionisedandimprovedtheeffectiveness of treatment for nasopharyngeal carcinoma.Intermsofcontributiontostaging,CThasidentiedparanasopharyngealextensionasoneofthemostcommonmodesofextensionofnasopharyngealcarcinoma28andhasshownperineuralspreadthroughthe foramen ovale to be an important route of intracranialextension. Perineural spread through the foramen ovalealsoaccountsfortheCTevidenceofcavernoussinusinvolvement without skull-base erosion.29MRIisbetterthanCTfordisplayingbothsupercialanddeepnasopharyngealsofttissueandfordifferentiatingtumourfromsofttissue.MRIisalsomoresensitiveforassessmentofretropharyngealanddeepcervicalnodalmetastases.30However,thetechniqueisoflimitedeffectivenessforassessingbonedetails and CT should be undertaken when the status ofthe base of the skull cannot be satisfactorily establishedwithMRI.31Intermsofstaging,MRIisabletodetectmarrowinltrationbytumours,whereasCTcannotdetect this kind of inltration unless there is associatedbone erosion. This kind of marrow inltration has beensuggestedtobeassociatedwithanincreasedriskofdistant metastases.32Detectionofdistantmetastasesatdiagnosiswithconventionalradiographs,CT,andMRIisnotusuallysuccessful.Severalreportshaveconcludedthatbonescans,33liver scintigraphy,34 abdominal ultrasonography,35and marrow biopsy36are of little value in routine stagingandhaverecommendedthattheyneednotbeused.Astudyconcludedthattherewasnoevidencetolendsupporttodistantimagingforlow-risk(N0orstageI)disease,butrecommendedthathigh-risk(N3)diseaseshould be fully staged with chest radiography, bone scan,andliverultrasonography.37Theroleofpositronemissiontomography(PET)inthedetectionofdistantmetastases in other malignancies has been established,38butitsapplicationinthestagingofnasopharyngealcarcinoma has not been ascertained. Cross-sectionalimagingdisplaystheextentoftheprimarytumourwithunprecedentedprecision.Thisaccuracy enables radiotherapy treatment to be designedand administered more accurately, effectively improvingtheoutcomesforthisformoftreatment.39Evenbetterresultshavebecomepossiblewithintensitymodulatedradiotherapy,whichmakesuseofcompositeCT-MRItargets40enabling radiotherapy to be targeted even moreaccurately onto tumours, sparing adjacent tissues.Whenusedtomonitorapatientsconditionaftertreatment,bothCTandMRIhavelowsensitivityandmoderatespecicityinthedetectionoftumourrecurrence;41although, in general, MRI is better than CTinshowingtumourrecurrenceandpostradiationcomplications.42Recurrentnasopharyngealcarcinomascanexhibitavarietyofsignalintensitiesandcontours,and these can be difcult to interpret.43However, CT canshow bone regeneration after treatment, which could bean indication of the complete eradication of the tumourintheaffectedarea44suggestingafavourableprognosiswith related clinical ndings.45PET has been reported tobe more sensitive than CT and MRI at detecting residualand recurrent tumours in the nasopharynx.46Staging systemTherearevariouswaysofclassifyingnasopharyngealcarcinomas.AtpresenttheAmericanJointCommitteeonCancerStagingandEndResultReporting/InternationalUnionAgainstCancer(AJC/UICC)systemispreferredinEuropeandAmerica,47whereasHossystemisfrequentlyusedinAsia.48,49ThenodalclassicationinHossystemhasincorporatedprognosticsignicance,butthestraticationofthewww.thelancet.com Vol 365 June 11, 2005 2043SeminarT stagesintovesectorsdiffersfrommoststagingsystems.Thedevelopmentofarevisedstagingsysteminthepastdecadewasmotivatedbythedesiretoincorporateexperiencesgainedfromvariouscentresaroundthe world,takingintoaccountmanyprognosticfactors, includingskull-baseerosion,involvementof cranial nerves,50primarytumourextensiontoparanasopharyngeal space,51and the level and size of thecervicalnodes.52ArevisedAJC/UICCstagingsystemwas published in 1997;53in this new staging system theT1 stage included tumours classied as both T1 and T2undertheoldsystem.ThenewT2stagecoveredtumoursthathadextendedtothenasalfossa,oropharynx,orparanasopharyngealspace.ThenewT3stagecoveredtumoursthathadextendedtotheskullbaseorotherparanasalsinuses.ThenewT4stagecoveredtumoursthathadextendedintotheinfratemporalfossa,orbit,hypopharynx,andcranium,ortothecranialnerves.Forcervicalnodalstaging,N1underthenewsystemreferredtounilateralnodalinvolvement;N2tobilateralnodaldiseasethathadnotreachedN3designation,irrespectiveofthesize,number, and anatomical location of the nodes; and N3 tolymphnodeslargerthan6cm(N3a),ornodesthathadextendedtothesupraclavicularfossa(N3b).54Thenewstagingsystemhasenabledpatientstobestagedmoresensitivelyandisabetterpredictorofsurvivalthantheold system (table 1).55,56PrognosisAswithmostothertumours,theextentofanasopharyngealcarcinomaasembodiedintheTMNstaging system (table 1) is the most important prognosticfactor. Indeed, most other known prognostic factors aredirectlyorindirectlyrelatedtotheextentorbulkofthetumour.Thechangesinprognosticfactorsidentiedandreportedatdifferenttimesinthepastprobablyrepresented adoption of these known adverse factors inthenewstagingsystems,ortheuseoftreatmentstrategiestoaddresstheseknownadverseprognosticfactors and to nullify their adverse effects.Areportin199057showedthat,besidestheTandN stages,otherprognosticfactorsincludedsizeanddegree of xation of neck nodes, sex, age, the presence ofcranialnervepalsy,andearsymptomsatpresentation.ThefactorsofsizeoflymphnodeandearsymptomsprobablysuggestthelackofrecognitionofnodalsizeandparanasopharyngealextensionintheTandN staging system used at that time. A study reported in199258showedthatthetumourshistologicaltypeandthe radiotherapy dose and coverage were also signicantindependent prognostic factors. The adverse prognosticfactor of histological type is shown in this report, whichincluded mainly the white population with WHO type Ihistology.Paranasopharyngealextensionwasanindependentprognosticfactorcorrelatedwithadverselocal tumour control and increased distant spread.59 Evenafter paranasopharyngeal extension of tumour had beenincorporatedintothe1997AJC/UICCstageclassications,theadverseprognosticeffectremainsvalid despite the use of concurrent chemoradiotherapy.60AlargevariationoftumourvolumeispresentinT stagesofdifferentstagingsystems,andprimarytumourvolumerepresentsanindependentprognosticfactoroflocalcontrolandismorepredictivewiththeAJC/UICCstagingsystemthanwithHosTstageclassication.61ValidityoftumourvolumehasbeenconrmedinpatientswithT3andT4tumours,62andthere is an estimated 1% increase in risk of local failurefor every 1 cm3increase in primary tumour volume.63Inadditiontodirectmeasurementoftumourvolume,quantitativeanalysisofcirculatingEBVDNAinnasopharyngealcarcinomahasshownapositivecorrelation with disease stage and a strong relation withclinicalevents,aswellasexhibitingprognosticimportance.64Basedonthedifferenceinfailurepatterns,differentprognosticcategoriescanbedenedacrossstages.Theseare(1)T12N01(relativelygoodtreatmentoutcome);(2)T34N01(mainlylocalfailure);(3) T12N23 (mainly regional and distant failure); and(4) T34N23 (local, regional and distant failure). Theseprognosticgroupingswillhaveimportantimplicationsfor the selection of appropriate treatment strategies andthedesignoffutureclinicaltrialstoaddressdifferentfailurepatterns.65Thereisearlyevidencethatforadvanceddiseases,addingchemotherapytoradiotherapywillimprovetreatmentoutcome,bothinterms of locoregional control and distant metastases.66,67Treatment RadiotherapyRadiotherapyisthestandardtreatmentfornasopharyngealcarcinoma.Unfortunately,itcanproduceundesirablecomplicationsaftertreatmentbecause of the location of the tumour at the base of skull,closely surrounded by and in close proximity to radiationdose-limitingorgans,includingthebrainstem,spinalcord,pituitary-hypothalamicaxis,temporallobes,eyes,middleandinnerears,andparotidglands.Sincenasopharyngeal carcinomas tend to inltrate and spreadtowards these dose-limiting organs, they are even moredifcult to protect.One of the most common radiotherapy approaches fornasopharyngealcarcinomaistostartphaseItreatmentwith large lateral opposing faciocervical elds that covertheprimarytumourandtheuppernecklymphaticsinone volume, with matching lower anterior cervical eldforlowernecklymphatics.Whenthespinalcorddosereaches4045Gy,therearetwooptionsforphaseIItreatment.Treatmentcaneitherbechangedtolateralopposingfacialeldswithanteriorfacialeldfortheprimarytumour,withmatchinganteriorcervicaleld2044 www.thelancet.com Vol 365 June 11, 2005 Seminarforthenecklymphatics. Alternatively,treatmentcanbecontinuedwiththelateralopposingfaciocervicaleldsbut with shrinkage of elds to avoid the spinal cord, andbytreatingthesuperior-posteriorlymphaticwithelectronelds.68,69Themajorobjectiontotreatingtheprimary tumour and the neck lymphatic in two separatevolumes (both of these phase II treatment techniques) isthatthereisadangerofunderdosingtheparanasopharyngealextensionofthetumourandtheuppernecknodesatthejunctionbetweentheprimarytumour and neck lymphatic target volumes.In radiotherapy a dose of 6575 Gy is normally given tothe primary tumour and 6570 Gy to the involved necknodes, whereas the dose for prophylactic treatment for anode-negativeneckis5060Gy.Thistreatmenthassuccessfully controlled T1 and T2 tumours in 7590% ofcasesandT3andT4tumoursin5075%ofcases.65,6871Nodal control is achieved in 90% of N0 and N1 cases, butthe control rate drops to 70% for N2 and N3 cases.65Asinterrupted or prolonged treatment reduces the benetsof radiotherapy, every effort should be made to maintainthe treatment schedule.72Because of the high incidencewww.thelancet.com Vol 365 June 11, 2005 2045The American Joint Committee on Cancer Staging53Ho Staging49Tumour in nasopharynx (T) Primary tumour (T)T1 Tumour conned to the nasopharynx T1 Tumour conned to nasopharynx (space behind choanal orices and nasal septum and aboveposterior margin of soft palate in resting position)T2 Tumour extends to soft tissues of oropharynx and/or nasal fossa T2 Tumour extended to nasal fossa, oropharynx, or adjacent muscles or nerves below base of skullT2a without parapharyngeal extensionT2b with parapharyngeal extensionT3 Tumour invades bony structures and/or paranasal sinuses T3 Tumour extended beyond T2 limits and subclassied as follows:T3a Bone involvement below base of skull (oor of sphenoid sinus is included in this category)T3b Involvement of base of skullT3c Involvement of cranial nerve(s)T3d Involvement of orbits, laryngopharynx (hypopharynx), or infratemporal fossaT4 Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, or orbitRegional lymph nodes (N) Regional lymph nodes (N)The distribution and the prognostic effect of regional lymph node spread from nasopharynx cancer, especially of the undifferentiated type, is different from that of other head and neck mucosal cancers and justies use of a different N classication scheme.NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasis N0 Node palpable or thought to be benignN1 Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above theN1 Node(s) wholly in upper cervical level, bounded below by the skin crease extending laterally and supraclavicular fossa backward from or just below thyroid notch (laryngeal eminence) N2 Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above theN2 Node(s) palpable between crease and supraclavicular fossa, the upper limit being a line joining the supraclavicular fossa upper margin of the sternal end of the clavicle and the angle formed by the lateral surface of the neck and the superior margin of the trapeziusN3 Metastasis in a lymph node(s) N3 Node(s) palpable in the supraclavicular fossa and/or skin involvement in the form of carcinoma en N3a greater than 6 cm in dimension cuirasse or satellite nodules above the claviclesN3b extension to the supraclavicular fossaDistant metastasis (M) Metastases (M)MX Distant metastasis cannot be assessedM0 No distant metastasis M0 No haematogenous metastasesM1 Distant metastasis M1 Haematogenous metastases present, and/or lymph nodal metastases below the clavicleStage grouping Stage groupingStage 0 T1s N0 M0Stage I T1 N0 M0 Stage I T1,N0Stage IIA T2a N0 M0 Stage II T2 and/or N1Stage IIB T1 N1 M0T2 N1 M0T2a N1 M0T2b N0 M0T2b N1 M0Stage IIIT1 N2 M0 Stage III T3 and/or N2T2a N2 M0T2b N2 M0T3 N0 M0 T3 N1 M0T3 N2 M0Stage IVAT4 N0 M0Stage IV N3 (any T)T4 N1 M0T4 N2 M0Stage IVBAny TN3 M0 Stage IVCAny TAny NM1Stage V M1Table 1: Staging systems for nasopharyngeal carcinomaSeminarofoccultnecknodeinvolvement,prophylacticneckradiationisusuallyrecommended.73Goodlocoregionalcontrol should be the prime objective of treatment sincelocoregionalrelapsesrepresentasignicantriskfactorfor the development of distant metastases.74For T1 andT2tumours,aboosterdosebyuseofintracavitarybrachytherapyimprovedtumourcontrolby16%.75Althoughstereotacticradiosurgeryhasalsobeenusedfortheboosterdose,76itisprobablybetterreservedforthetreatmentofpersistentandrecurrentnasopharyngealcarcinomasbecauseoftheundesirableside-effects associated with hypofractionated treatment.77Themajorlimitationsof2Dplanningfornasopharyngealcarcinomacannowbeovercomewith3Dconformalradiotherapyandintensity-modulatedradiotherapy.78,79Whenappliedalone,3Dconformalboost is not effective,80thus conformal radiotherapy andintensity-modulatedradiotherapyshouldbeadoptedthroughoutthetreatment.Inthecaseofextensivetumours, and when the tumour extension is close to thedose-limitingorgans,intensity-modulatedradiotherapyisdistinctlypreferableto3Dconformalplanningbecauseitfurtherimprovesthedosedifferentialbetweenthetumourandthedose-limitingorgans.81,82Intensity-modulatedradiotherapyalsoresolvestheproblem of dose uncertainty at the junction between theprimary tumour and neck lymphatic target volumes as itenablestheprimarytumourandtheuppernecknodestobetreatedinonevolumethroughout.Althoughthistechnique theoretically allows very good dose differentialbetweenthetumourandthesensitiveadjacentnormaltissuestructures,theoptimumsafetymarginneededbetween gross tumour and adjacent tissues has still notbeenestablished.Untilthisdosedifferentialinformation is available, the clinical target volume of theprimarytumourshouldbedenedcautiouslyinplanning.Randomisedprospectivetrialsshouldenablethe clinical target volume to be more accurately dened. Intensity-modulatedradiotherapyhasachievedexcellentlocoregionalcontrolofnasopharyngealcarcinomas.83A study that prospectively assessed salivaryfunctionsconrmedthegradualrecoveryofparotidfunctionwithin2yearsaftercompletionofintensity-modulatedradiotherapy.84Satisfactorydosimetricresultswerealsoachievedwiththistreatmentforrecurrentnasopharyngeal carcinomas, and the degree of short-termcontrol was encouraging.85 Other attempts to enhance thebiologicaleffectsofradiotherapyhavebeenreported.Theseattemptsincludeacceleratedfractionation,86acceleratedhyperfractionation,87andacombinationofoneorotherofthesetreatmentswithchemotherapy.88,89However,hyperfractionationradiotherapyfornasopharyngealcarcinomashouldbeusedwithcare,becauseastudyofacceleratedhyperfractionationby2DradiotherapyplanninghasreportedanincreaseinradiationdamagetotheCNSwithoutimprovementintumour control.90ChemotherapySeveral studies in the past two decades have reported theresults of the use of chemotherapy in combination withradiotherapyforthemanagementoflocoregionaladvancedcasesofnasopharyngealcarcinoma.Twelverandomisedcontrolledtrialshavereportedonneoadjuvant,concurrent,andadjuvanttherapy,oronacombination of these approaches. Nine of these studieswerereportedbefore2004andincludedfourneo-adjuvantchemotherapystudies,9194 threeconcurrentchemotherapy studies,66,67,95and two adjuvant studies.96,97Oneoftheconcurrentstudies95hasrecentlybeenupdated,98andtwooftheneoadjuvantstudies92,93havebeenupdatedandpooledformeta-analysis.99ThreemoreconcurrentchemotherapystudieshavebeenreportedfromHongKongandSingapore.100102 Resultsdifferedbetweenstudiesthatusedneoadjuvant,thosethatusedconcurrent,andthosethatusedadjuvantchemotherapyincombinationwithradiotherapy.Inadditiontothedifferenceinchemotherapyschedules,the effect of staging classication and of stage migrationforstudiesreportedatdifferenttimescouldexplainthese reported differences in results (table 2).The Intergroup 1997 study66was the rst study to showthatuseofchemotherapyalongsideradiotherapyimprovedoverallsurvivalcomparedwithradiotherapyalone.Becausethisstudyincludedcasesofwell-differentiated carcinomas, there were initial doubts as towhethertheresultswereapplicabletonasopharyngealcarcinomainendemicareas.However,asubsequentreport from Taiwan67lent support to the benets of thisapproach.Infact,thesestudiesweretheonlytwotoshow an improvement in both relapse-free survival andoverall survival. As far as the other concurrent studies were concerned,one study102reported an improvement in overall survival,and another study100reported a borderline improvementinoverallsurvival.However,neitherstudyshowedanyevidenceofimprovedrelapse-freesurvival,andthedisparitybetweenoverallsurvivalandrelapse-freesurvivalwasapparentlyexplainedbyimprovementincontrol of distant metastases in the absence of improvedlocoregionalcontrol.Theupdatedconcurrentstudy98also reported an improvement in overall survival but noimprovementinrelapse-freesurvival.Afurtherstudy101reportedanimprovementinactuarialloco-regionalcontrolat3 years,butnoimprovementinrelapse-freesurvival or overall survival, and a signicant increase inototoxicity in the treatment group. The long-term follow-up reports from these more recent studies are expectedto provide more denitive results than at present.Twoofthefourneoadjuvantstudies91,93reportedimprovementinrelapse-freesurvivalbutnoimprovement in overall survival. The others92,94reportednoimprovementgenerally.Ameta-analysis99notedimprovementsinrelapse-freesurvivalanddisease-specicsurvival.However,overallsurvivalwasnot2046 www.thelancet.com Vol 365 June 11, 2005 Seminarimproved because of the increase in intercurrent deathsin the treatment group. Promising results have also beenreportedfromphaseIIstudiesofadvancednasopharyngealcarcinomatreatedwithalternatingweeklychemotherapywithcisplatinand5-uorouracil/folinicacid.103Thetwoadjuvantchemotherapystudies96,97reportednoimprovementeither in relapse-free survival or overall survival.Studiestryingtoimproveontheuseofconcurrentchemotherapyplusadjuvantchemotherapyhavebeenreportedwithobjectivesvaryingfromimprovementoftolerance and side-effects to improvement of efcacy forthemoreadvancedcases.Thepoorcompliancewithadjuvantchemotherapyafterconcurrentchemo-radiotherapy can be overcome by the use of neoadjuvantchemotherapy.Astudyonneoadjuvantchemotherapyfollowedbyconcomitantchemoradiotherapyhasreportedexcellentoverallsurvivalandacceptabletoxicity.104Replacementofcisplatinwithotherchemotherapeutic agents in part of the treatment couldovercomeorreducetheototoxicityassociatedwithsixcourses of cisplatin. A study using cisplatin concurrentlywithradiotherapy,followedbyadjuvantifosfamide, 5-uorouracil,andleucovorin,forpatientswithstageIVbnasopharyngealcarcinomahasbeenreported.105Althoughthepatientsconcernedhaddiseaseatamoreadvancedstage,theoutcomesofthisgroupwerecomparablewiththosereportedinotherseriesofpatients with less advanced disease for whom platinum-basedadjuvantchemotherapywasused.Thechemotherapy regime also has an acceptable compliancerate.AlthoughthestageIandIIcasesweregenerallyconsidered to have resulted in relatively good treatmentoutcomes,analysishasshownthattheAmericanJointCommitteeonCancerScreening1997systemhasallowedmorepatientswithapoorprognosistobegrouped under stage II.106With such stage migration ofthe more advanced cases to stage II, and early evidencethatdisease-freesurvivalismuchthesameforstageIIpatientswitharaisedtumourburdenaftertreatmentwithconcurrentchemoradiotherapyandforstageIpatientstreatedwithradiotherapyalone,theroleofconcurrentchemoradiotherapyshouldbeexploredforstageIIpatients.107Aninternationaleffortisnowunderwaytoundertakeameta-analysisofupdateddatafrommanyofthesereportedrandomisedcontrolledtrials, with more than 1700 patients. The results of thismeta-analysis are eagerly awaited.ThereisnowgeneralagreementthatthepositiveresultsreportedintheIntergroup1997study66areapplicabletonasopharyngealcarcinomainendemicareas,buttheconictingevidenceofchemotherapyonlocalcontrolanddistantmetastaseshavegenerateddiscussion. The conclusion seems to be that of the threebasicapproachestestedinthesestudies(neoadjuvant,concurrent,andadjuvantchemotherapy),concurrentchemoradiotherapy is the most efcacious. Nevertheless,theclassicprinciplesofchemoradiotherapytiming(namely,thatconcurrentchemoradiotherapyprovidesmoreeffectivelocalcontrol,whereassequentialuseofchemotherapyandradiotherapyismoreeffectivewithdistant metastases) have not been borne out by the studyresults.108Despitetheuseofconcurrentchemoradiotherapy,distantmetastasesremainthemajorcauseoftreatmentfailure,32andtheoutlookforstage IV patients remains poor.109Follow-upClinicalDocumentationofcompleteremissioninthenasopharynxandnecklymphatics,withtheapplicationof clinical examination, endoscopic examination with orwithoutbiopsy,andimagingstudies,isimportant.Forassessmentofcompleteremissioninthenasopharynx,the decision about where to draw the line between a slowregressingtumourandaresidualtumourremainswww.thelancet.com Vol 365 June 11, 2005 2047Number ofTiming of chemotherapy % disease-free% overall patients survival (years) survival (years)RT RT/CT RT RT/CTInstitute Nationale229 Adjuvant: vincristine, doxorubicin,56 (4) 58 (4) 67 (4) 59 (4)Tumori, Italy94cyclophosphamide 6 cyclesInternational NPC339 Neoadjuvant: bleomycin,30 (5)* 39 (5)* 46 (5) 40 (5)Study Group89epirubicin, cisplatin 3 cyclesIntergroup 009964147 Concurrent: cisplatin 3 cycles, then 24 (3)* 69 (3)* 47 (3)* 78 (3)*adjuvant: cisplatin, 5-FU for 3 cyclesAsian Oceanian Clinical334 Neoadjuvant: epirubicin,42 (3) 48 (3) 71 (3) 78 (3)Oncology Association90cisplatin 23 cyclesSun Yat-sen University,456 Neoadjuvant: bleomycin,49 (5)* 59 (5)* 56 (5) 63 (5)Guangzhou91cisplatin, 5-FU 23 cyclesSun Yat-sen University,784 Neoadjuvant: bleomycin, cisplatin,43 (5)* 51 (5)* 58 (5)* 64 (5)*Guangzhou + Asian5-FU 23 cyclesOceanian ClinicalOROncology AssociationNeoadjuvant: epirubicin, (pooled updated)97cisplatin 23 cyclesPrince of Wales Hospital,350 Concurrent: cisplatin 69 (2) 76 (2)Hong Kong 938 cycles weeklyPrince of Wales Hospital,350 Concurrent: cisplatin52 (5) 62 (5) 59 (5)* 72 (5)*Hong Kong (updated)968 cycles weeklySapporo Medical80 Neoadjuvant: cisplatin,43 (5) 55 (5) 48 (5) 60 (5)University, Japan925-FU 2 cyclesNational Yang-Ming157 Adjuvant: cisplatin,50 (5) 54 (5) 61 (5) 55 (5)University, Taiwan955-FU 9 cycles weeklyTaichung Veterans284 Concurrent: cisplatin,53 (5)* 72 (5)* 54 (5)* 72 (5)*General Hospital, Taiwan1015-FU for 2 cyclesQueen Mary Hospital,219 Concurrent: uracil, then adjuvant:58 (3) 69 (3) 77 (3) 87 (3)Hong Kong98cisplatin, 5-FU alternating with vincristine, bleomycin, methotrexate 6 cycles overallNational Cancer Centre,220 Concurrent: cisplatin 3 cycles,62 (2) 76 (2) 77 (2)*85 (2)*Singapore100then adjuvant cisplatin, 5-FU for 3 cyclesHong Kong NPC348 Concurrent: cisplatin 3 cycles,61 (3) 69 (3) 79 (3) 78 (3)Study Group99then adjuvant: cisplatin, 5-FU for 3 cycles* p005; disease-specic survival; p=006; RT=radiotherapy alone; RT/CT=combined radiotherapy and chemotherapy arm; 5FU=5-uorouracil.Table 2: Results of randomised prospective studies on application of chemotherapy and radiotherapy inthe management of nasopharyngeal carcinoma Seminarproblematic, but in most cases salvage treatment shouldnotbedelayedforlongerthanabout10weeks.110Residualtumoursinthenasopharynxcanbetreatedwitheitherconedownelds111orbrachytherapy112withgoodresults,andresidualnecknodediseaseisamenable to radical neck dissection. Clinicalandimagingfollow-upofpatientsisrecommended because locoregional relapses, if detectedearly,areamenabletoradicalsalvagetreatment.113Therecommendedfollow-upproceduresincludeclinicalexaminationofthenasopharynx(includinganendoscopic examination) and neck, and regular imagingevery46monthsduringtheinitial35yearsaftertreatment.114,115Endoscopicexaminationshouldbeusedto detect supercial tumours, and cross-section imagingshouldbeusedtodetectdeepinltratingtumoursnotassociatedwithmucosallesion.31AnimagingstudycomparingPETwithMRIfordetectionofresidualandrecurrenttumourhasreportedPETasthesuperiormodality.46Forthedetectionofdistantmetastases,theuseofserumEBVDNAhasbeenshowntobemoresensitive and reliable than other options.116EBV geneCirculating free EBV DNA has been reported in patientswithnasopharyngealcarcinoma,117andtheincreasednumberofcopiesofEBVDNAinthebloodduringtheinitialphaseofradiotherapysuggeststhattheviralDNAwasreleasedintothecirculationaftercelldeath.118ThequantityoffreeplasmaEBVDNA,asmeasuredbyreal-timequantitativePCR,isrelatedtothestageofthedisease.ThequantitiesofEBVDNAcopiesbeforeandaftertreatmentaresignicantlyrelatedtotheratesofoverallanddisease-freesurvival.119Astudyhasreportedthat the levels of post-treatment EBV DNA compared withpretreatmentEBVDNAareagoodpredictorofprogression-freesurvival.120WhenEBVDNAwasusedtogether with immunoglobulin A against the viral capsidantigenofEBV,thesensitivityofearlydiagnosisofnasopharyngealcarcinomaincreased.121RaisedlevelsofEBVDNAwereonlydetectedin67%ofpatientswithlocoregional recurrence,116,122 although in those with distantmetastasislevelsofEBVDNAcopieswereheightenedbefore the appearance of clinical abnormality.116Sequelae of therapySurvivorsofnasopharyngealcarcinomahaveimpairedhealth-related quality of life.123,124Patients who survive thediseasecanhaveseverallatecomplications,manyofwhichresultfromtheeffectsofradiationonthedose-limitingorgansadjacenttothenasopharynxandnecknodes. The use of chemotherapy in more advanced casesaddstotheside-effects,whichincludeototoxicityassociatedwithcisplatin.100Asmallproportionofthelong-termsequelaerepresenttheeffectsofunhealedresidual damage by the tumour, such as residual cranialnervepalsiesandserousotitismediaresultingfrompersistentdisturbanceoftheeustachian-tubefunction.Thesesequelaeincludeneuro-endocrine125andauditory126complications,drymouth,poororalanddentalhygiene,127,128radiation-inducedsofttissuebrosis,129andcarotidarterystenosis.130Themostdebilitatingsequelaeareneurologicalcomplications.Thesecanincludeseriousdisorderssuchastemporallobe necrosis,131cranial nerve palsies132and dysphagia,133andalsolessobviouseffectssuchasmemoryloss,134cognitivedysfunction,135andneuropsychologicaldysfunction136(table 3).Aseriesofcasesinwhichhypofractionatedradiotherapy was used in combination with 2D planningproduced a 60% actuarial risk of complication and a 28%riskofneurologicalcomplications.137Cuttingdownlatecomplicationsoftreatmentshouldbeoneofthemainobjectivesoffutureclinicaltrials.Shieldingofthepituitary-hypothalamicaxisin2Dplanningandtreatmenthasbeenshowntosignicantlyreduceneuroendocrinecomplications.138Useofintensity-modulatedradiotherapyhasbeenshowntoimprovesalivaryfunction,84butotherbenetsneedalongerfollow-up period to conrm. 2048 www.thelancet.com Vol 365 June 11, 2005 Time of assessment Risk and details of sequelaeSide-effects associated with hypofractionated10 years 31% of patients developed one or more late irradiation sequelae. Most were mild soft-tissue damages. Neurological damage thatradiotherapy135occurred in 10% of patients constituted the major morbidity and accounted for most of the treatment mortalities (1%)Hypothalamic-pituitary function1235 years With life table analysis, the cumulative probability of endocrine dysfunction was estimated to be 62% after 5 years. These includedisturbances of growth hormone, gonadotropins, corticotropin, and/or thyrotropin. The progressive impairment in hypothalamic pituitary function leading to endocrine dysfunction that requires treatment occurs in 50% of patients at 5 years after cranial irradiationLong-term sensorineural hearing decit1242 years Within 3 months after radiotherapy, deterioration of bone conduction threshold at 4 kHz was noted in 31% of ears. In 40% of these ears, recovery was evident at 2 yearsDental and oral hygiene12714 years Xerostomia (92%), trismus (29%), higher prevalence of clinical candidosis (24%)Carotid artery stenosis1285 years15 times increase in risk of developing signicant carotid stenosis Temporal lobe necrosis1295 years 5-year actuarial incidence ranged from 0% to 14% (dependent on fractional and total dose)Cranial nerve palsy130120 years Hypoglossal palsy, vagus palsy, recurrent laryngeal nerve palsy, and accessory palsies. Often associated with marked neck brosisDysphagia131Not stated Swallowing function continues to deteriorate over time, even many years after radiation therapyMemory loss1322 years Visual memory performance deteriorated with time, while verbal memory remained more stableCognitive function associated with temporal1 year For patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functionslobe necrosis133were signicantly impaired, although their general intelligence remained relatively intactTable 3: Late complications of radiotherapy for the treatment of nasopharyngeal carcinomaSeminarManagement of residual or recurrent diseaseDespite the effectiveness of radiation and chemotherapyin the management of nasopharyngeal carcinoma, localfailureorregionalfailurepresentingaspersistentorrecurrenttumourstilloccurs.Toattainahighsalvagerate,earlydetectionandtreatmentisessential.18FDG-PETisbetterthanCTindetectingresidualorrecurrentdiseaseinthenasopharynx,139anditsresultscanusuallybeconrmedwithbiopsythroughendoscopicexamination.Residualorrecurrenttumourintheneckafterradiotherapyisnotoriouslydifculttoconrmbecauseinsomelymphnodesonlyclustersoftumourcellsarepresent.140Aggressivetreatmentforlocallyrecurrentnasopharyngealcarcinomaiswarranted,especiallyincaseswherethediseaseisconned to the nasopharynx. Survival after retreatmentformoreextensivediseaseremainspoor,butisstillhigherthaninpatientsreceivingsupportivetreatmentonly.113Even for patients with synchronous locoregionalfailures,aggressivetreatmentshouldbeconsideredforselected patients141(table 4).Disease in the neck Aftercombinedchemoradiationfornasopharyngealcarcinoma, isolated failure in the neck is less than 5%.146If cancer persists or recurs in the cervical lymph nodes,as evidenced by imaging studies or clinical progressionofthelymphnodes,salvagetherapyisneeded.Whenmanagedwithanothercourseofexternalradiotherapy,the overall 5-year survival rate is around 20%.147Radicalneckdissectionasaformofsurgicalsalvagehasachieved a 5-year tumour control rate of 66% in the neckand a 5-year actuarial survival of 38%.142When tumour inthe neck node extends beyond the connes of the lymphnode,brachytherapyshouldbeappliedtothetumourbedinadditiontoradicalneckdissection.Withthisadjuvant therapy, a similar tumour control rate has beenachieved as for radical neck dissection for less extensiveneck disease.148Disease in the nasopharynxResidual or recurrent disease in the nasopharynx can bemanaged with a second course of external radiotherapy.Thedosageshouldbegreaterthantheinitialradiationdose. Although a salvage rate of 32% has been achieved,thecumulativeincidenceoflatesequelaeafterre-irradiationis24%withtreatmentmortalityof18%.149Toavoidthehighincidenceofcomplicationsresultingfromre-irradiation,stereotacticradiotherapy,brachytherapy, and surgical resection have been used forpatientswithsmalllocalisedtumoursinthenasopharynx.Stereotacticradiotherapy,whenusedforthemanagementofresidualorrecurrenttumour,isassociatedwitha2-yearlocaltumourcontrolrateof72%.77However,onlyafewpatientshavebeentreatedwith this method, and long-term follow-up informationis not available.150BrachytherapyWith brachytherapy, the radiation dose decreases rapidlyfromtheradiationsource,enablingahighdoseofirradiationtobedeliveredtotheresidualorrecurrenttumour in the nasopharynx but a much smaller dose tothesurroundingtissue.Brachytherapyalsodeliversradiation at a continuous low dose rate, which gives it afurtherradiobiologicaladvantageoverfractionatedexternal radiation. Intracavitary brachytherapy has beenusedfornasopharyngealcarcinomas.151Theradiationsourcewasplacedeitherinatubeoramouldbeforeinsertion into the nasopharynx. In view of the irregularcontourofthenasopharynx,accurateapplicationoftheradiationsourcetoprovideatumoricidaldoseisdifcult.Tocircumventthisproblem,radioactiveinterstitialimplantshavebeenusedtotreatsmalllocalisedresidualorrecurrenttumoursinthenasopharynx.152Radioactive gold grains (198Au) are the most frequentlyusedradiationsourceforthispurpose.Goldgrainscanbeimplantedeithertransnasallyorwiththesplit-palateapproach.143The split-palate approach gives the surgeon adirect view of the tumour site and enables him or her toimplantthegoldgrainspermanentlyintothetumourwithgreatprecision.Fortumourslocalisedinthenasopharynx,withoutboneinvasion,thismethodhasprovidedeffectivesalvagewithminimummorbidity.153Where gold grain implants were used to treat persistentand recurrent tumours after radiotherapy, the 5-year localtumourcontrolrateswere87%and63%,respectively,andthecorresponding5-yeardisease-freesurvivalrateswere68%and60%.154Otherstudiesusingintracavitarybrachytherapy have also reported success.155,156NasopharyngectomyIf the residual or recurrent tumour in the nasopharynx istooextensiveforbrachytherapyorhasextendedtotheparanasopharyngealspace,nasopharyngectomycanachievesalvageinselectedpatientswithlocalisedwww.thelancet.com Vol 365 June 11, 2005 2049Number ofStage ofLocal control/survival rate Complications Treatment- patients recurrence related mortality Reirradiation706 T1 to T3 5-year survival rate 14%;Late sequelae18%(conventional)14210-year survival rate 9% 24%Stereotactic18 T1 and T2 2-year local control rate 72% 56% 0radiosurgery75Re-irradiation (IMRT)7749 T1 to T4 9-month local control 100% 0 0Brachytherapy 106 T1 5-year local control, residual19% 0(Gold grain)14387%, recurrent 62%; 5-year disease-free survival, residual 68%, recurrent 60%Nasopharyngectomy 109 T1 5-year local control rate 68%,25% 0(Maxillary swing)1445-year disease-free survival 54%Nasopharyngectomy 37 T1 to T3 5-year local control rate 67%,54% 3%(transpalatal)1455-year disease-free survival 52%IMRT= intensity-modulated radiation therapy.Table 4: Results of different types of salvage therapy for residual or recurrent tumour in thenasopharynx after radical external radiotherapySeminardisease.Becauseoftheawkwardpositionofthenasopharynxinthemiddleofthehead,exposureforoncologicalextirpationofthetumourhaspresentedadifculttechnicalchallenge.Variousapproacheshavebeenreported,includinganinfratemporalapproachfromthelateralaspect;157transpalatal,transmaxillary,andtranscervicalapproachesfromtheinferioraspect;145,158 andanantereolateralapproach.144Themortalitiesassociatedwiththesesalvagesurgicalprocedureshavebeenlow,andsinceallthepatientsconcernedhadpreviouslyundergoneradicalradiotherapy,theassociatedmorbiditiesinsomepatients,suchastrismusandpalatalstula,wereacceptable. As long as the residual or recurrent tumourcanberemovedadequately,thelong-termresultshavebeensatisfactory.The5-yearactuarialcontroloftumours in the nasopharynx is about 65% and the 5-yeardisease-free survival rate is around 54%.159,160External radiotherapyFormoreadvancedorinltrativetumours,asecondcourseofexternalradiotherapyisneeded.161Asecondcourse of external radiotherapy given concurrently withchemotherapy has been tried; this approach was built ontheexperiencegainedfromtheuseofconcurrentchemoradiotherapyinprimarytreatment.Thistreatmenthasbeenreportedtogivea5-yearactuarialoverallsurvivalrateof26%,althoughtheriskofmajorlatetoxicitieswassignicant.162Theuseofprecisionradiotherapysuchasintensity-modulatedradiotherapycouldimprovethetherapeuticratioforlocalcontrol;promisinginitialresultshavebeenreported,85butdistant metastases will remain a major issue for patientswith local relapse.Distant metastasisCisplatin-basedcombinationchemotherapyisthemosteffectivetreatmentformetastaticnasopharyngealcarcinoma.Cisplatinandinfusional5-uorouracilhasbecome the standard treatment with a 6676% responserate.163Several phase II studies of the newer agents havebeenreported.164167Moreintensivecombinationsgiveahigher response rate, but are also usually associated withincreased toxicities.168170None of these combinations hasyet been compared with the combination of cisplatin andinfusional 5-uorouracil.Treatmentofmetastaticnasopharyngealcarcinomas,mainlywithchemotherapy,isessentiallypalliative,althoughlong-termdisease-freesurvivorshavebeenreported.171Forselectedpatientswithfewmetastases,additionallocoregionaltreatmentcangiveextendeddisease control. Resection of lung metastases can resultin longer control for patients in whom the spread of thecarcinoma to the lung has been limited.172In cases wherethere has been little spread to the mediastinal nodes, theadditionofradiotherapytochemotherapycouldalsoresult in protracted tumour control.173Recent developmentsInadditiontothenoveltreatmentapproachesthataregenerallyapplicabletocancersatothersites,thecloseassociation between EBV and nasopharyngeal carcinomagivesfurtheropportunitiesfornoveltreatment.StrategiestargetedatEBVincludegenetherapyandimmunetherapy,andtheproof-of-principlesstudieshavebeendoneinlaboratories.Genetherapywithanovelreplication-decientadenovirusvectorinwhichtransgeneexpressionisunderthetranscriptionalregulation of oriP of EBV has been reported.174Immunetherapyapproacheshaveincludedtherapeuticaugmentation of cytotoxic T-lymphocyte responses175andadoptivetransferofautologousEBV-speciccytotoxicT-cells.176FuturestudiesontherolesofthevirusintransformationandfunctionsofEBVlatentproteinscould help to identify other novel treatment targets.177Conict of interest statementWe declare that we have no conict of interest.References1 Sham JS, Choy D, Wei WI, et al. 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Berberine Inhibits Metastasis of Nasopharyngeal Carcinoma ... · Berberina inibe metástases do carcinoma nasofaringeal Berberine Inhibits Metastasis of Nasopharyngeal Carcinoma 5-8F

ADENOVIRUSlp53 GENE THERAPY NASOPHARYNGEAL CARCINOMA … · 2020. 4. 8. · ADENOVIRUS-p53 GENE THERAPY IN NASOPHARYNGEAL CARCINOMA XENOGRAITS M.Sc. Degree, 2000 Stuart Ailen Lax

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21 Nasopharyngeal Carcinoma in Children - JK Science

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Nasopharyngeal carcinoma and hearing loss

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Nasopharyngeal undifferentiated carcinoma with sarcomatoid ... · Nasopharyngeal carcinoma (NPC) is a carcinoma arising in the nasopharyngeal mucosa that shows light microscopic or

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Nasopharyngeal Carcinoma FPON CME Webcast€¦ · Nasopharyngeal Carcinoma FPON CME Webcast Dr. Sarah Hamilton Radiation Oncologist – Vancouver Centre. November 21, 2019. Disclosures

From Juvenile Nasopharyngeal Angiofibroma to ...beat.sums.ac.ir/article_45819_dabc10201c9f4cb79b8b8bf3312b3ad… · From Juvenile Nasopharyngeal Angiofibroma to Nasopharyngeal Carcinoma;

An Incidental Nasopharyngeal Carcinoma 2 1 Coexistent With Primary Nasopharyngeal ... · 2015-11-27 · because nasopharyngeal carcinoma may harbor foci of granulomatous reactions.5

Cancer Stem Cells in Nasopharyngeal Carcinoma

Noninvasive detection of nasopharyngeal carcinoma based on

Clin Nasopharyngeal carcinoma in situ in nasopharyngeal ... · Nasopharyngeal carcinoma in situ in nasopharyngeal carcinoma of koilocytic changes in biopsy material,'4 other authors

Chemical Carcinogenesis and Nasopharyngeal Carcinoma

Research Paper OVOL2 links stemness and metastasis via ...for cancer patients. Key words: OVOL2, metastasis, EMT, stemness, nasopharyngeal carcinoma Introduction Nasopharyngeal carcinoma

Sinonasal or nasopharyngeal undifferentiated Carcinoma

The genomic landscape of nasopharyngeal carcinoma€¦ · Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic

Palliative Treatment In Nasopharyngeal Carcinoma

Clin Nasopharyngeal carcinoma in situ in nasopharyngeal ...jcp.bmj.com/content/jclinpath/45/10/898.full.pdf · Nasopharyngeal carcinoma in situ in ... Thereare manytypes ofneoplasmwhichmay