Chan, A.T.C.

Felip, E.

Grégoire, V.

Hui, E.P.

Lefebvre, J.-L

Leung, S.F.

Licitra, L.

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Nasopharyngeal cancer: EHNS–ESMO–ESTRO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up†A.T.C. Chan1, V. Grégoire2, J.-L. Lefebvre3, L. Licitra4, E.P. Hui1, S.F. Leung1 & E. Felip5, on behalfof the EHNS–ESMO–ESTRO Guidelines Working Group*1Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong;2Department of Radiation Oncology, St-Luc University Hospital, Brussels, Belgium; 3Department of Head and Neck Surgery, Centre Oscar Lambret, Lille, France;4Medical Oncology Head and Neck Unit, Istituto Nazionale dei Tumori, Milan, Italy; 5Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, SpainincidenceCancer of the nasopharynx (NPC) is rare in Europe, with anannual crude incidence rate of 1.1 per 100 000. On theEuropean scale, NPC accounts for 4760 new cases per year.Incidence is higher in men than women. [1, 2].In Europe, the relative survival for NPC was 76% at 1 yearand 50% at 5 years in adults. There were no survivaldifferences between the sexes. The effect of age on survival ismarked. Survival at 5 years was 72% for the youngest agegroup (15–45 years) and 36% in the oldest group of patients(65–74 years) [1, 2].diagnosisDeﬁnitive diagnosis is made by endoscopic-guided biopsy ofthe primary nasopharyngeal tumor. The histological typeshould be classiﬁed according to World Health Organization(WHO) classiﬁcation [3]. Since the ﬁrst disease sign inpatients is often the appearance of neck nodes it is notinfrequent that patients undergo neck biopsy and/or necknodal dissection. This procedure is not recommended sinceit may reduce cure probability and have an impact on latetreatment sequelae.staging and risk assessmentNPC is clinically staged according to the InternationalUnion Against Cancer (UICC) and American JointCommittee on Cancer (AJCC) staging system (Table 1).Routine staging procedures include history, physicalexamination including cranial nerve examination, completeblood cell count, serum biochemistry (including liverfunction test), chest X-ray, nasopharyngoscopy, computedtomography (CT) scan or magnetic resonance imaging(MRI) of nasopharynx and base of skull and neck. AlthoughMRI is generally preferred if available, each center willchoose the best imaging technique according to their usualclinical practice and experience [III, B]. Imaging for distantmetastases including isotope bone scan and CT scan ofchest and upper abdomen could be considered for at-risksubsets (node positive, especially N3 stage) and for thosepatients with clinical or biochemical abnormalities detected[III, B]. The use of positron emission tomography CT scancan replace the traditional work-up for detection of distantmetastatic disease since it has proved to be the mostsensitive, speciﬁc and accurate diagnostic method. Both thepre-treatment and post-treatment plasma/serum load ofEpstein-Barr viral DNA has been shown to be of prognosticvalue [III, B] [4–8].treatmentThe optimal treatment strategy of patients with advanced NPCshould be discussed in a multidisciplinary team. Radiationtherapy (RT) is the mainstay of treatment and is an essentialcomponent of curative-intent treatment of non-disseminatedNPC. Stage I disease is treated by RT alone, while stage III,IVA, IVB disease are treated by RT with concurrentchemotherapy [I, A]. Concurrent chemotherapy isrecommended for stage II disease [I, B] [9]. Patients should betreated by intensity-modulated radiation therapy (IMRT) [II,A] [10]. RT is targeted to the primary tumor and the adjacentregions considered at risk of microscopic spread from thetumor, and to both the sides of the neck (levels Ib–V, andretropharyngeal nodes). For patients with lower neck nodes,the supraclavicular fossa should be included as well. Electivenodal irradiation is recommended for N0 stage disease. Theconsensus is that a total dose of 70 Gy is needed for†Approved by the ESMO Guidelines Working Group: December 2006, last update June2012. This publication supersedes the previously published version—Ann Oncol 2010;21 (Suppl 5): v187–v189.*Correspondence to: ESMO Guidelines Working Group, ESMO Head Ofﬁce, ViaL. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalguidelines@esmo.orgclinicalpracticeguidelinesclinical practice guidelines Annals of Oncology 23 (Supplement 7): vii83–vii85, 2012doi:10.1093/annonc/mds266© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.eradication of gross tumor and either 50–60 Gy or 46–60 Gyfor elective treatment of potential risk sites. To minimize therisk of late toxicity (particularly, to adjacent neurologicalstructures), fractional dose >2 Gy per daily fraction andexcessive acceleration with multiple fractions >1.9 Gy/fractionshould be avoided [III, E]. IMRT may offer improvement inlocal tumor control [II, A], and reduction in radiationxerostomia in early-stage disease [II, A]. The standard agentused in concurrent chemotherapy–RT is cisplatin [I, A]. Thisprovides a beneﬁt in terms of overall survival and on bothlocoregional and distant control [9, 11–15]. While three cyclesof adjuvant cisplatin-5FU has been a standard part of manyconcurrent chemoradiotherapy regimens, its beneﬁt isuncertain and toxic effect is substantial [16]. Cisplatinum-based induction chemotherapy has been shown to improvedisease-free survival and may be considered in locallyadvanced disease although it is not seen as a standardtreatment [II, B] [17]. In no case should inductionchemotherapy negatively affect the optimal administration ofconcomitant chemoradiation.follow-upDocumentation of complete remission in the nasopharynx andneck through clinical and endoscopic examination and/orimaging studies is important. MRI is often used to evaluate theresponse to RT or chemoradiotherapy, especially for T3 and T4tumors, though distinction between post-irradiation changesand recurrent tumors may be difﬁcult. Follow-up for patientsincludes periodic examination of the nasopharynx and neck,cranial nerve function and evaluation of systemic complaints toidentify distant metastasis. For T3 and T4 tumors, MRI mightbe used on a 6- to 12-month basis to evaluate the nasopharynxand the base of the skull at least for the ﬁrst few years aftertreatment. Evaluation of thyroid function in patients withirradiation to the neck is recommended at 1, 2 and 5 years.Table 1. The International Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC) staging system for NPC, seventh edition(2010)Primary tumor (T)T1 Tumor conﬁned to the nasopharynx, or extends to oropharynx and/or nasal cavitywithout parapharyngeal extensionT2 Tumor with parapharyngeal extensionT3 Tumor involves bony structures of skull base and/or paranasal sinusesT4 Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit,or with extension to the infratemporal fossa/masticator spaceRegional lymph nodes (N)N1 Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension,above the supraclavicular fossa, and/or unilateral or bilateral, retropharyngeallymph nodes, ≤6 cm, in greatest dimensionN2 Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension,above the supraclavicular fossaN3 Metastasis in a lymph node(s) >6 cm and/or to supraclavicular fossaN3a >6 cm in dimensionN3b Extension to the supraclavicular fossaDistant metastasis (M)M0 No distant metastasisM1 Distant metastasisAnatomic stage/prognostic groupsStage 0 Tis N0 M0Stage I T1 N0 M0Stage II T1 N1 M0T2 N0 M0T2 N1 M0Stage III T1 N2 M0T2 N2 M0T3 N0 M0T3 N1 M0T3 N2 M0Stage IVA T4 N0 M0T4 N1 M0T4 N2 M0Stage IVB Any T N3 M0Stage IVC Any T Any N M1clinical practice guidelines Annals of Oncologyvii | Chan et al. Volume 23 | Supplement 7 | October 2012treatment of recurrent or metastaticdiseaseSmall local recurrences are potentially curable and the mainissue is the choice of the most appropriate therapeutic options,which include nasopharyngectomy, brachytherapy,radiosurgery, stereotactic RT, IMRT or a combination ofsurgery and RT, with or without concurrent chemotherapy.Treatment decisions are tailored to the speciﬁc situation ofindividual cases, taking into consideration the volume, locationand extent of the recurrent tumor [III, A]. Regional recurrenceis managed by radical neck dissection if resectable [III, A].In metastatic NPC, palliative chemotherapy should beconsidered for patients with adequate performance status.Platinum combination regimens are commonly used as ﬁrst-line therapy since cisplatin represents the most effective drug.Other active agents include paclitaxel, docetaxel, gemcitabine,capecitabine, irinotecan, vinorelbine, ifosfamide, doxorubicinand oxaliplatin, which can be used as single agents or incombination [III, B]. Polychemotherapy is more active thanmonotherapy. In this context treatment choice should be basedon previous treatments and the expected toxicity [18].notesLevels of evidence [I–V] and grades of recommendation [A–E]adapted from the Infectious Diseases Society of American-United States Public Health Service Grading System are givenin square brackets. Statements without grading were consideredjustiﬁed standard clinical practice by the experts.conﬂict of interestProf. Lefebvre has reported: lecturer and advisory board forMerck Serono and Sanoﬁ-Aventis. Dr. Licitra has reported:advisory board of Bristol-Myers Squibb, GlaxoSmithKine, Lilly,Merck Serono and Amgen; institution has received clinical andresearch support from EISAI, Exelixis, Lilly, Merck-Serono,Amgen; and travel support from Merck Serono. Prof. Chan hasreported receiving honoraria and research support fromMerck-Serono, Amgen, Novartis, Roche, Pﬁzer andSanoﬁAventis. Dr. Felip has reported: consultancy/honorariafrom Lilly, GlaxoSmithKline, Merck Serono, Roche, BoehringerIngelheim. Dr. Hui has reported: consultancy and advisoryboard for Sanoﬁ-Aventis and Pﬁzer. Prof. Grégoire hasreported no conﬂicts of interest.references1. Curado MP, Edwards B, Shin HR et al. (eds). Cancer Incidence in FiveContinents, Vol. IX. IARC Scientiﬁc Publications No. 160. Lyon: IARC 2007.2. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 Cancer Incidence,Mortality and Prevalence Worldwide. IARC CancerBase No. 5, version 2.0. Lyon:IARC Press 2004.3. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health OrganizationClassiﬁcation of Tumours. Pathology and Genetics of Head and Neck Tumours.Lyon: IARC Press 2005.4. Chua DT, Ji M, Zong Y et al. Screening of nasopharyngeal carcinoma by serologyand nasopharyngoscopy and treatment outcome in endemic region. J Clin Oncol2009; 27: 15s.5. Chua ML, Ong SC, Wee JT et al. Comparison of 4 modalities for distantmetastasis staging in endemic nasopharyngeal carcinoma. Head Neck 2009; 31:346–354.6. Chan AT, Lo YM, Zee B et al. Plasma Epstein–Barr virus DNA and residualdisease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J NatlCancer Inst 2002; 94: 1614–1619.7. Lin JC, Wang WY, Chen KY et al. Quantiﬁcation of plasma Epstein-Barr virusDNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004;350 (24): 2461.8. Leung SF, Zee B, Ma BB et al. Plasma Epstein-Barr viral deoxyribonucleic acidquantitation complements TNM staging in nasopharyngeal carcinomaprognostication. J Clin Oncol 2006; 34: 5414–5418.9. Chen QY, Wen YF, Guo L et al. Concurrent chemoradiotherapy vs radiotherapyalone in Stage II nasopharyngeal carcinoma: phase III randomized Trial. J NatlCancer Inst 2011; 103 (23): 1761.10. Kam MK, Leung SF, Zee B et al. Prospective randomized study of intensitymodulated radiotherapy on salivary gland function in early-stage nasopharyngealcarcinoma patients. J Clin Oncol 2007; 25: 4873–4879.11. Kwong DL, Sham JS, Au GK et al. Concurrent and adjuvant chemotherapy fornasopharyngeal carcinoma: a factorial study. J Clin Oncol 2004; 22:2643–2653.12. Chan AT, Leung SF, Ngan RK et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advancednasopharyngeal carcinoma. J Natl Cancer Inst 2005; 97: 536–539.13. Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemoradiotherapyversus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effecton overall and progression-free survival. J Clin Oncol 2003; 21: 631–637.14. Wee J, Tan EH, Tai BC et al. Randomized trial of radiotherapy versus concurrentchemoradiotherapy followed by adjuvant chemotherapy in patients with AmericanJoint Committee on Cancer/International Union against cancer stage III and IVnasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23:6730–6738.15. Lee AW, Tung SY, Chua DT et al. Randomized trial of radiotherapy plusconcurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advancednasopharyngeal carcinoma. J Natl Cancer Inst 2010; 102 (15): 1188.16. Chen L, Hu CS, Chen XZ et al. Concurrent chemoradiotherapy plus adjuvantchemotherapy versus concurrent chemoradiotherapy alone in patients withlocoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentrerandomised controlled trial. Lancet Oncol 2012; 13(2): 163–171.17. Chua DT, Ma J, Sham JS et al. Long-term survival after cisplatin-based inductionchemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled dataanalysis of two phase III trials. J Clin Oncol 2005; 23: 1118–1124.18. Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome innasopharyngeal carcinoma: current and future directions. Cancer Sci 2008; 99(7): 1311–1318.Table 2 Summary of treatment recommendations for Cancer of thenasopharynx (NPC)Early stage Stage I Radiation aloneIntermediate stage Stage II Concurrent chemoradiotherapy(I, B)Advanced stage Stage III, IVA,IVBConcurrent chemoradiotherapy+/− adjuvant chemotherapy(I, A)Problematic radiationtherapy (RT)planning (e.g.tumor abuttingchiasm)Stage IVA,IVBInduction chemotherapyfollowed by concurrentchemoradiotherapy (II, B)Annals of Oncology clinical practice guidelinesVolume 23 | Supplement 7 | October 2012 doi:10.1093/annonc/mds266 | vii

Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment andfollow-up

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