青少年鼻咽癌治疗

Multimodal Treatment,Including Interferon Beta,of Nasopharyngeal Carcinoma in Children and Young Adults Preliminary Results From the Prospective,Multicenter Study NPC-2003-GPOH/DCOGMartina Buehrlen,MD1;Christian Michel Zwaan,MD,PhD2,3;Bernd Granzen,MD3,4;Lisa Lassay,MD1;Peter Deutz,MD1;Peter Vorwerk,MD,PhD5;Gundula Staatz,MD,PhD6;Gu¨nther Gademann,MD,PhD7;Hans Christiansen,MD,PhD8;Foppe Oldenburger,MD3,9;Miriam T amm,MSc10;and Rolf Mertens,MD,PhS1BACKGROUND:The authors report preliminary results from a prospective multicenter study(Nasopharyngeal Carcinoma[NPC]2003 German Society of Pediatric Oncology and Hematology/German Children’s Oncology Group[NPC-2003-GPOH/DCOG]).METHODS: From2003to2010,45patients(ages8-20years),including1patient with stage II NPC and44patients with stage III/IV NPC,were recruited to the study.The patient with stage II disease received radiotherapy(59.4grays[Gy]).The patients with stage III/IV disease received3courses of neoadjuvant chemotherapy with cisplatin,5-fluorouracil,and folinic acid.The cumulative irradiation dose was 54Gy in5patients,who achieved complete remission after neoadjuvant chemotherapy,and59.4Gy in the remaining40patients.All patients received concomitant cisplatin during the first week and last week of irradiation.After irradiation,all patients received inter-feron beta for6months.Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans.RESULTS:After the completion of treatment,43of45patients were in complete remission.In2patients,only a partial response was achieved,followed by distant metastases(1patient)or local progression and distant metastases(1patient),6months and10months after diagnosis,respectively.Another patient developed a solitary pelvic bone metastasis21months after diagnosis.After a median follow-up of30months(range,6-95months),the event-free survival rate was92.4%,and the overall survival was97.1%.Acute toxicity consisted mainly of leucopenia,mucositis,and nausea;and late toxicity consisted of hearing loss and hypothyr-oidism.CONCLUSIONS:Combined therapy with neoadjuvant chemotherapy,radiochemotherapy,and interferon beta was well toler-ated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.Cancer2012;000:000–000.V C2012American Cancer Society.KEYWORDS:nasopharyngeal carcinoma,children,interferon beta,chemotherapy,positron emission tomography scan. INTRODUCTIONNasopharyngeal carcinoma(NPC)is a rare malignant tumor in childhood that arises from the epithelial cells that cover the nasopharynx.The incidence varies with age,geographic factors,and ethnic factors,indicating that both genetic and environmental factors contribute to tumor development.NPC is relatively common in China,South-East Asia,Alaska, North Africa,and parts of the Mediterranean basin.In Europe and the United States,it represents only approximately 1%of all childhood cancers.1The World Health Organization(WHO)recognizes3NPC subtypes:type1,squamous cell carcinoma;type2,non-keratinizing carcinoma;and type3,undifferentiated carcinoma.The most common subtype in children is type3,and few patients have type2.2Because of their localization,small tumors usually are asymptomatic,and early symptoms are unspe-cific;therefore,most patients present with advanced locoregional disease.Distant metastases occur in bones,lungs,bone-marrow,mediastinum,and liver.3NPC is strongly associated with Epstein-Barr virus(EBV)infection.4It is a very radiosensitive and chemosensitive tumor.For adults with early stage NPC,radiation therapy remains the mainstay of treatment.5-7For patients with advanced disease,the benefit of additional chemotherapy has been demonstrated.1,8,9Children and adolescents usually Corresponding author:Martina Buehrlen,MD,Universita¨tsklinikum Aachen,Klinik fu¨r Kinder-und Jugendmedizin,Pauwelsstrasse30,52074Aachen,Germany; Fax:(011)0049-241-8082481;mbuehrlen@ukaachen.de1Department of Pediatric and Adolescent Medicine,University Hospital Aachen,Aachen,Germany;2Department of Pediatric Oncology,Erasmus Medical Center/ Sophia Children’s Hospital,Rotterdam,Netherlands;3Dutch Childhood Oncology Group,Den Haag,Netherlands;4Department of Pediatrics,University Hospital Maastricht,Maastricht,Netherlands;5Department of Pediatric Oncology,University Hospital Magdeburg,Magdeburg,Germany;6Department of Diagnostic and Interventional Radiology,University Medical Center Mainz,Mainz,Germany;7Radiotherapy Department,University of Magdeburg,Magdeburg,Germany;8Depart-ment of Radiotherapy and Radio-Oncology,University Hospital Goettingen,Goettingen,Germany;9Department of Radiation Oncology,Academic Medical Center, Amsterdam,Netherlands;10Department of Medical Statistics,University Hospital Aachen,Aachen,GermanyFax:(011)0049-241-8082481DOI:10.1002/cncr.27395,Received:August26,2011;Revised:November10,2011;Accepted:November18,2011,Published online in WileyOnline Library()present with advanced stage disease.10-12In recent years, most pediatric patients with NPC have received a combi-nation of chemotherapy and radiotherapy with various regimens worldwide,usually containing cisplatin and of-ten5-fluorouracil.Reported survival rates vary between 55%and90%for overall survival(OS)and between 60.6%and77%for disease-free survival(DFS)and event-free survival(EFS).10,12-23From1992to2002,the first prospective NPC trial by the German Society of Pedi-atric Oncology and Hematology(NPC-91-GPOH),in which chemotherapy,radiotherapy,and interferon beta (IFN-b)were combined,was conducted within the GPOH.After a median follow-up of48months,an OS rate of95%and an EFS rate of91%were achieved,and the level of toxicity was acceptable.11Encouraged by these promising results,the next prospective trial,NPC-2003-GPOH,was started pared with the NPC-91-GPOH study,chemotherapy was reduced in NPC-2003-GPOH by omitting methotrexate in the induction chemo-therapy courses with the intention of reducing the rate of severe mucositis.The irradiation dose was reduced in the patients who achieved a complete response after neoadju-vant chemotherapy to reduce late effects.To compensate for these reductions,additional cisplatin was applied con-comitantly with irradiation.Moreover,the preparation of IFN-b was changed during the course of the studies.In NPC-1991,the patients received CHO-beta(Rentschler, Laupheim,Germany)or Fiblaferon(Biosyn,Fellbach, Germany).In NPC-2003,the patients received Fiblaferon or Rebif(Merck Serono,Geneva,Switzerland). MATERIALS AND METHODSPatientsFrom2003to2010,after approval of the protocol was obtained from the Ethical Committee of the University of Aachen and local ethical approval was obtained from the participating sites,53patients from27centers in Germany (n¼45),Austria(n¼2),and the Netherlands(n¼6) were recruited for the current study.Forty-five of those patients fulfilled the inclusion criteria(histologically proven NPC and age25years)without having any exclusion cri-teria(keratinizing squamous cell carcinoma,distant metas-tases,NPC as secondary malignoma,cytostatic treatment before entering the study,and pregnancy).Eight patients had to be excluded for the following reasons:Two patients had a primary mediastinal tumor with distant metastases and no nasopharyngeal tumor but a histologic diagnosis of NPC.One patient had typical NPC but with evidence of distant metastases.Four patients received treatment with major deviations from the study protocol,and1patient had NPC as a secondary malignoma after receiving therapy for Hodgkin’s disease. StagingStaging was performed according to the American Joint Committee of Cancer(AJCC)Cancer Staging Manual, fourth edition(1993).24The low-risk group was defined as stage I(T1N0M0)or stage II(T2N0M0),and the high-risk group included stage III(T3N0M0or T1-T3N1M0) and stage IV(T4N0-N3M0and T1-T4N2-N3M0). Diagnostic ImagingPretreatment evaluations included computed tomography (CT)scans or magnetic resonance imaging(MRI)studies of head and neck,CT scans of the chest,abdominal ultra-sound studies(or,if any doubt,CT scans of the abdo-men),bone scans,and positron emission tomography (PET)scans(when available).Tumor response was eval-uated on CT/MRI studies obtained after3cycles of neo-adjuvant chemotherapy,6weeks after the end of radiochemotherapy,and at the end of IFN treatment. PET scans were obtained from30patients,20patients, and14patients at those respective time points. Response CriteriaResponse criteria were defined as follows(according to WHO guidelines from197925):A complete response (CR)was defined as no evidence of disease;a partial response(PR)was defined as a decrease!50%in the sum of the greatest dimensions of target lesions,no evidence of new lesions,or progression of any lesion;stable disease (SD)was defined as small changes that did not meet criteria for PR or progressive disease(PD);PD was defined as an increase!25%in the sum of the greatest diameters of tar-get lesions or the appearance of new lesions.In addition to these criteria,a very good PR(VGPR)was defined as no evidence of measurable disease but asymmetry of the tumor region or contrast medium enhancement.Monitoring of ToxicityBefore treatment,a complete history and physical exami-nation were performed along with full blood counts and serum biochemistry tests,endocrine evaluation,an audio-gram,and electrocardiography and echocardiography. These evaluations were recommended after each cycle of chemotherapy for monitoring toxicity.TherapyTreatment was started after informed consent was obtained from the patient and/or the parents.The low-risk group included patients with stage I or II disease. These patients received no neoadjuvant chemotherapy but did receive radiotherapy with concomitant cisplatin.The high-risk group included all patients with stage III and IV disease.Treatment for the high-risk group included 3cycles of neoadjuvant chemotherapy and radiotherapy with concomitant cisplatin.After the com-pletion of radiotherapy,all patients received IFN-b for 6months.The treatment protocol is provided in Figure 1.ChemotherapyPatients received neoadjuvant chemotherapy in 3cycles at intervals of 3weeks (chemotherapy A (ChA)).Each cycle contained cisplatin 100mg/m 2given as an infusion over 6hours.Immediately after the cisplatin infusion,leucovorin 25mg/m 2was given as an intravenous bolus infusion ev-ery 6hours for 6doses.Thirty minutes after the first leu-covorin bolus,5-fluorouracil (5-FU)1000mg/m 2per day as a continuous infusion over 5days was started.Support-ive therapy included adequate hydration and mannitol before,during,and after cisplatin.In case of ototoxicity grade !2according to Common Toxicity Criteria or nephrotoxicity with a creatinine clearance <50mL/mi-nute/1.73m 2,cisplatin was replaced by carboplatin 500mg/m 2intravenously over 1hour.Patients with severe mucositis (grade 4)received a reduced 5-FU dose in the subsequent courses (1000mg/m 2per day over 4days).RadiotherapyThe clinical target volume included the primary tumor region and all visible,macroscopic lymph node metastases with a 1-cm safety margin,the whole nasopharynx,the parapharyngeal lymph nodes,and the level II cervical lymph nodes;in addition,for patients with stage III and IV disease,the clinical target volume also included lymph node levels III,IV,and V as well as the supraclavicular regions.Patients with stage I and II disease received irradi-ation to the nasopharynx and respective cervical lymph nodes with a total dose of 45grays (Gy)in single daily doses of 1.8Gy followed by a 14.4-Gy boost of irradiation to the tumor.Patients with stage III and IV disease received irradiation to the nasopharynx and respective re-gional lymph nodes,including the whole jugular group and the supraclavicular region,with the same total dose of 45Gy and single daily doses of 1.8Gy.The prescribed boost dose to the primary tumor and lymph nodes metas-tases was 14.4Gy,and this was reduced to 9Gy in patients who were in complete remission after neoadju-vant chemotherapy.Concomitant cisplatin 20mg/m 2/day on 3consecutive days was given during the first and last week of irradiation (chemotherapy B(ChB)).Figure 1.The treatment protocol for the study 2003German Society of Pediatric Oncology and Hematology/German Children’s Oncology Group nasopharyngeal carcinoma study (NPC-2003-GPOH/DCOG)is illustrated.RT indicates radiotherapy;Gy,grays;IFN-b ,interferon beta;Ch B,chemotherapy B;CR þ,patients in complete remission;CR À,patients not in complete remission;Ch A,chemotherapy A;5-FU,5-fluorouracil;MTX,methotrexate.NPC-2003-GPOH/DCOG—Preliminary Results/Buehrlen et alInterferon TreatmentAfter they completed chemotherapy and radiochemother-apy,all patients received IFN-b.Up to2010,the GPOH patients received the natural INF-b Fiblaferon,whereas the Dutch patients received the recombinant Rebif.Fibla-feron is no longer available;thus,since2010,all patients have received Rebif.Like in the study NPC-1991-GPOH,11patients received Fiblaferon at a dose of 100,000IU/kg intravenously over30minutes3days per week,usually Monday,Wednesday,and Friday,and the maximum single dose was5million IU for patients with abody weight>50kg.This regimen originally was derived from dose-finding studies by Treuner et al.26Patients received Rebif at the same dose and regimen subcutane-ously with a maximum single dose of6million IU.In most patients,injection of Rebif was performed by the patients themselves or their parents.Statistical AnalysisNPC-2003-GPOH is a prospective,multicenter cohort study.The primary objective is EFS,which we defined as the time from diagnosis to the first progression at any site, relapse,or death from any cause(this was referred to as DFS in our previous article11but was defined in the same way).Patients who remained alive without disease pro-gression or relapse were censored at the date of their last follow-up.OS,toxicity,and the response rate to neoadju-vant chemotherapy are secondary endpoints to the study. For OS,the time from diagnosis to death was calculated. All deaths were counted regardless of cause,and the patients who remained alive were censored at the date of their last follow-up.EFS and OS were estimated according to the Kaplan-Meier method.27We determined95%con-fidence intervals(CIs)for EFS and OS at a median follow-up time based on log-log transformation,as suggested by Kalbfleisch and Prentice.28The calculation of the median follow-up was based on the patients who were without relapse,disease progression,or death.Statistical analyses were performed using the software package SAS(version 9.2;SAS Institute,Inc.,Cary,NC).29The figures were cre-ated by using the software package R(version2.12.1;R Foundation for Statistical Computing,Vienna,Austria).30 RESULTSPatient CharacteristicsThere were45patients enrolled in the study,and there was a predominance of males(31males[69%],14females [31%]).The median age at diagnosis was15years(range, 8-20years).Of the45patients,only1patient had stage I disease and could be assigned to the low-risk group.The remaining44patients had stage III or IV disease and were assigned to the high-risk group.TNM staging of the patients is summarized in Table1.Tumor histology was NPC WHO type3in42 patients and type2in3patients.The presence of EBV antigen or DNA in tumor tissue was positive in28 patients,negative in5patients,and no information was available about EBV in tumor tissue for12patients.An initial PET scan was performed in36patients, and35patients had abnormal uptake of fluorine-18fluo-rodeoxyglucose(18F-FDG).One patient had his NPC diagnosed by adenotomy,the tumor was subtotally resected,and the initial PET scan was negative.In sum-mary,all patients with detectable NPC had a positive PET scan at diagnosis.Treatment ResponseThe patient with low-risk NPC achieved a good PR with a small,distinct residual tumor5weeks after end of radio-therapy and had a CR3months after the end of radiother-apy and2months after starting IFN-b treatment.In the 44high-risk patients,response after3cycles of neoadju-vant chemotherapy was evaluated on MRI studies in41 patients and on PET/PET-CT scans in30patients.MRI studies indicated that5of41patients(12.2%)achieved a CR,12patients(29.3%)had a VGPR,23patients (56.1%)had a PR,and1patient(2.4%)had SD.Tumor progression was not observed in any patient.In the3 remaining patients,a PR was documented on PET/PET-CT scans.The overall response rate to neoadjuvant chem-otherapy was43of44patients(98%).MRI studies and PET scans at the same time point after neoadjuvant chemotherapy were available for28 patients.The results from PET scans in relation to MRI studies are provided in Table2.All4patients who had achieved a CR on MRI studies also had negative PET scans, and all patients who had a VGPR or a PR had negative(n¼12)or weakly positive(n¼12)PET scans.MRI results dur-ing the course of further treatment are provided in Table3. Table1.TNM Classification in the Study Patients aTNM Status:No.of Patients Tumor Classification N0N1N2N3T11050 T20160 T312101 T403150 a T1N0and T2N0disease was defined as low risk,and all other disease was defined as high risk.Original ArticleOne patient who had SD after neoadjuvant therapy achieved a VGPR after radiotherapy and had a CR at end of IFN treatment.One of the 2patients who had PD at end of IFN treatment developed metastatic disease.One patient had the appearance of tumor progression on an MRI study at end of therapy,but the biopsy taken had no evidence of tumor during further follow-up,and the patient maintained a CR without further treatment.In summary,a CR or a VGPR was achieved by 41.5%of the documented patients after neoadjuvant chemotherapy and in 79%after radiotherapy.At the end of IFN treatment,all but 2patients had a CR or a VGPR,and 10patients still had slight changes on MRI studies.During further follow-up,these changes subsided in some of the patients and persisted without progression in others.The EFS and OS rates after a median follow-up of 30months (range,6-95months)were 92%(95%CI,77.9%-97.5%)and 97%(95%CI,80.9%-99.6%),respectively (Fig.2).Comparison Between Positron EmissionTomography and Magnetic Resonance ImagingPET scans were obtained from 30patients after neoadju-vant chemotherapy,from 20patients 6weeks after radio-therapy,and from 14patients after IFN treatment.Acomplete metabolic response was observed in 15patients (75%)after radiotherapy and in 11patients (78%)after IFN treatment.A partial metabolic response was observed in 4patients (20%)after the end of radiotherapy and in 2patients (14%)after the end of IFN treatment.None of these patients experienced a subsequent relapse.One patient had suspicious FDG uptake in a PET scan obtained at the end of the therapy,but the biopsy taken had no evidence of tumor.In 2of the 3patients who developed a relapse,there was abnormal FDG uptake at the site/sites of relapse;and,in the third patient,a PET scan was not obtained at relapse.Relapsed/Refractory PatientsIn 2patients who had extensive primary tumors (T4N2),there was only a PR at the primary site,and distant metas-tases occurred 6months and 10months after diagnosis.One of these patients received palliative treatment and died 10months after relapse,and the other patient is stillTable 2.Positron Emission T omography Results in Relation to Magnetic Resonance Imaging Results After Neoadjuvant ChemotherapyPET Results:No.of PatientsMRI ResultsNegativeWeakly Positive/Partial Metabolic ResponsePositiveCR 400VGPR 450PR 870SDAbbreviations:CR,complete response;MRI,magnetic resonance imaging;PD,progressive disease;PET,positron emission tomography;PD,progres-sive disease;PR,partial response;SD,stable disease;VGPR,very good partial response.Table 3.Magnetic Resonance Imaging Results During the Course of TreatmentMRI Results:No.of PatientsAssessment PointNot Done/No InformationCRVGPRPRSDPDTotalAfter neoadjuvant chemotherapy a 3b 5122310446Wk after the end of radiotherapy 7171380045After the end of interferon therapy82510245Abbreviations:CR,complete response;MRI,magnetic resonance imaging;PD,progressive disease;PR,partial response;SD,stable disease;VGPR,very good partial response.aThis assessment included only high-risk patients.bPR was determined by positron emission tomography or positron emission/computed tomographyscan.Figure 2.This Kaplan-Meier curve illustrates event-free and overall survival.Asterisks indicate censored observations.NPC-2003-GPOH/DCOG—Preliminary Results/Buehrlen et alreceiving treatment.Another patient(also with a T4N2 tumor)achieved complete remission but developed a sin-gle pelvic bone metastasis21months after diagnosis.This patient received relapse treatment with chemotherapy (5-FU,carboplatin,and docetaxel)and irradiation of the metastasis with59.4Gy and was still in secondary com-plete remission2years after relapse.ToxicityAcute,severe toxicity(WHO grade3/4)from neoadjuvant chemotherapy was observed mainly as mucositis(after53% of ChA cycles(see above)),nausea(after36%of ChA cycles),and neutropenia(after63%of ChA cycles).Severe infections occurred after8%of ChA cycles,and none of them were lethal.During chemoradiotherapy,severe mucositis was observed in42%of patients.Grade3or4 ototoxicity was noted after16%of ChA cycles and after 19%of ChB cycles.Grade1nephrotoxicity occurred after 8.6%of ChA cycles and was reversible in all but1patient, who had persistent,mild creatinine elevation.Central neu-rotoxicity was observed in3patients and was completely re-versible in all patients.Concerning cardiotoxicity,a mild reduction of the shortening fraction was observed in2 patients and was reversible in both.During IFN treatment,grade3leucopenia was observed in11patients(10received Fiblaferon,and 1received Rebif),and grade4leucopenia was observed in 1patient(Fiblaferon).Eight patients experienced low-grade fever that was easily prevented with paracetamol in subsequent administrations.IFN treatment was termi-nated because of leucopenia in1patient,and the dose was reduced to twice weekly in another patient.Severe infec-tions caused by leucopenia were not observed.Late effects concern mainly ototoxicity(14%)and hypothyroidism(25%).In addition,there were single epi-sodes reported of mild,persistent creatinine elevation; osteonecrosis of the femur and tibia;hyperprolactinemia; and growth retardation.DISCUSSIONIn this preliminary evaluation of the NPC-2003-GPOH study,promising results from the NPC-91-GPOH study can be confirmed.In accordance with other pediatric col-lectives,10-12,14these patients presented with advanced tumors.We used a relatively old version of the AJCC stag-ing system(the fourth edition from1993).It is important to note that the AJCC staging system underwent signifi-cant changes in subsequent versions.Four patients of our current series would have been classified with stage II disease(T2N0or T1-T2N1)according to the current seventh edition31but were classified with stage III diseaseand,thus,were considered high-risk patients according tothe fourth edition.Because pediatric patients with earlystage NPC are very rare,treatment guidelines are derivedfrom adult protocols.For adults with stage I NPC withoutlymph node involvement,radiotherapy alone remains thestandard treatment.For patients who have primarytumors classified as T2b and higher or who have positivelymph nodes,additional chemotherapy improves the out-come.32Corresponding to these findings,the AJCCfourth edition is still adequate to distinguish between low-risk and high-risk patients when studying children.According to the AJCC seventh edition,for pediatricpatients,only those with stage I NPC should be treated aslow-risk patients.CT and MRI scans are the established diagnostictools for staging,response evaluation,and detection of localrelapse in patients with NPC.In recent years,PET scansand PET-CT scans also have been described as prognostictools in NPC.33-35Chan et al reported a positive correla-tion between metabolic parameters in PET-CT and T-clas-sification at diagnosis.33Gordin et al demonstrated a betterdiagnostic performance with PET-CT scans comparedwith stand-alone PET scans or conventional diagnosticimaging studies.34The possible prognostic value of high 18F-FDG uptake before therapy and the metabolic response after radiotherapy was reported by Xie et al.36Our data demonstrate a gradual tumor response totreatment measured by MRI studies in the majority ofpatients.This does not predict a negative outcome.Theremaining mass observed on MRI may or may not be via-ble tumor.Because no further surgery is performed afterdiagnostic biopsy,information about the vitality of theremaining tissue can be obtained only indirectly by diag-nostic imaging studies.PET/PET-CT scans produced no false-negativeresults in any patient and produced only1false-positiveresult at the end of therapy(no evidence of tumor in thebiopsy taken;the patient remained in remission withoutfurther treatment).Among the patients who had only aPR observed on an MRI study after neoadjuvant chemo-therapy,there was a complete metabolic response in8patients and a partial metabolic response in7patients.These data suggest that,in the subset of patients who hadonly a PR on MRI studies but had a complete metabolicresponse on PET-CT scans,the remaining tumor on MRImay not have represented viable malignant tissue.We conclude that PET/PET-CT scanning is a usefuldiagnostic tool in addition to the well established MRIevaluation in children and young adults with NPC.ScansOriginal Articlerevealed abnormal FDG uptake in all patients who had tumor present at first diagnosis or at relapse and appeared to be better at distinguishing between good and partial chemotherapy responses during treatment.However,a PR after chemotherapy and chemoradiotherapy was not associated with an increased risk of relapse.A secondary increase in FDG-uptake certainly needs to be clarified by biopsy but is not necessarily associated with relapse.Another option for follow-up of NPC patients is an endoscopic examination of the nasopharynx with biopsies taken of any suspicious lesion.This is commonly per-formed in adults.In children,noninvasive procedures like MRI,CT,and PET usually are preferred.In our cohort, endoscopy and biopsy were only performed in patients who had suspicious MRI and/or PET findings.Treatment results from pediatric patients with NPC that have been published in the literature during the past 10years were mostly from retrospective analyses at single centers,and the patients received different therapy regi-mens,all of which included radiotherapy and most of which also included chemotherapy.10,13-22The results vary between55%and87%for OS and60.6%and77% for EFS or DFS,and the median length of observation for these cohorts was between3.5years and15years.Varan et al reported10retrospectively analyzed patients who received the same regimen(4cycles of docetaxel/cisplatin plus irradiation59.4Gy)23:After a median observation of 2years,the OS rate was90%,and the EFS rate was70%. There are2reported prospective studies about NPC treat-ment in children and adolescents.Rodriguez-Galindo et al reported17patients(1low risk and16high risk).12 The high-risk patients received4cycles of neoadjuvant chemotherapy and irradiation with a total dose of50.4 Gy to the target volume and61.2Gy to the primary tu-mor and involved lymph nodes.The cumulative doses of chemotherapeutic agents were480mg/m2methotrexate, 400mg/m2cisplatin,600mg leucovorin,and12,000 mg/m25-FU.In this group,the4-year EFS and OS rates were77%and75%,respectively.Another prospective, multicenter study(NPC-91-GPOH)was conducted within the GPOH11in which59patients(1low risk and 58high risk)received3cycles of methotrexate,cisplatin, leucovorin,and5-FU along with irradiation(45Gy to the target volume,59.4Gy tumor boost)and also received IFN-b for6months.The cumulative chemotherapy doses were360mg/m2methotrexate,300mg/m2cisplatin,450 mg/m2leucovorin,and15,000mg/m25-FU.The sur-vival rates exceeded all other reported results with an OS rate of95%and an EFS rate of91%after a median fol-low-up of48months.Since then,8patients were lost tofurther follow-up27to57months after diagnosis.All other patients were observed for at least5years and up to 16years.In our cohorts(104patients from1992to2010) and in other publications about pediatric NPC,relapses usually occurred within the first2years after diagno-sis.3,10,12,13Therefore,it is unlikely that further relapses developed in those patients who were lost to follow-up.This subsequent NPC-2003-GPOH/DCOG study confirms the positive results from the NPC-91-GPOH study after slight changes were made to the therapy regi-men.The outcomes after a median follow-up of30 months have resulted in an OS rate of97%and an EFS rate of92%,which are similar to the rates reported for NPC-91-GPOH.The omission of methotrexate in the neoadjuvant chemotherapy regimen did not have an impact on prognosis and did not lead to the intended reduction in the rate of severe mucositis.All patients received45-Gy radiation to the nasophar-ynx and regional lymph nodes,as described above,and the tumor boost generally was14.4Gy but was reduced to9Gy in5patients who were in complete remission after neoadju-vant chemotherapy.None of these patients experienced a relapse.These results indicate that,in a well defined group,a reduction in the irradiation dose is feasible to reduce long-term toxicity.Although this difference in dose is relatively small,it may especially diminish long-term complications, such as xerostomia,hearing loss,and endocrine deficits.Fol-low-up will be continued to consolidate these data concern-ing survival rates as well as late toxicities.To our knowledge,the outcome achieved with the NPC-GPOH studies is superior to all other reported results.The main difference in the treatment between the GPOH studies and others is the addition of IFN-b for6 months after the completion of chemotherapy and radio-therapy.The best comparable study is that by Rodriguez-Galindo et al.12A similar chemotherapy regimen has been used in both cohorts with only slight differences in cumu-lative doses of chemotherapy and radiotherapy(for details,see above).The relapse rates for different groups indicate that minimal residual tumor still was present in some patients after chemotherapy and radiotherapy.We conclude that IFN-b can provide a substantial benefit for the outcome of pediatric patients with NPC.It has been demonstrated that EBV-positive patients have a profound impairment in long-term T-cell immunity to EBV.The antiviral and antitumoral properties of IFN-b have been discussed in detail by Mertens et al.37Wolff et al also reported on6adults with undiffer-entiated NPC who were treated according to the NPC-GPOH protocols,including IFN-b.38The treatment was NPC-2003-GPOH/DCOG—Preliminary Results/Buehrlen et al。