Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†

•This ESMO-EURACAN Clinical Practice Guideline provides key recommendations for managing nasopharyngeal cancer (NPC).•It covers screening, clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Treatment algorithms for locoregional and recurrent/metastatic NPC are provided.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinion. Nasopharyngeal carcinoma (NPC) is a disease with unique epidemiological features. The distribution of the disease demonstrates a clear regional, racial and gender prevalence. In 2018, the global age-standardised incidence rates (ASIRs) varied from 2.1 to 0.4 per 100 000 in Asia and Europe, respectively.1Ferlay J. Ervik M. Lam F. et al.Global Cancer Observatory: Cancer Today. International Agency for Research on Cancer, Lyon, France2018https://gco.iarc.fr/todayDate accessed: August 11, 2020Google Scholar The highest ASIRs per 100 000 were in East and South East Asia (e.g. seven in Singapore, the Maldives and Indonesia; six in Malaysia and Vietnam; three in China). There were more than 129 000 new cases of NPC reported in 2018, including more than 5000 in Europe.1Ferlay J. Ervik M. Lam F. et al.Global Cancer Observatory: Cancer Today. International Agency for Research on Cancer, Lyon, France2018https://gco.iarc.fr/todayDate accessed: August 11, 2020Google Scholar In recent decades (1970-2007), the incidence of NPC has declined worldwide, with substantial reductions in South and East Asia, North America and the Nordic countries.2Tang L.L. Chen W.Q. Xue W.Q. et al.Global trends in incidence and mortality of nasopharyngeal carcinoma.Cancer Lett. 2016; 374: 22-30Crossref PubMed Scopus (156) Google Scholar NPC has several features that differ according to geographic area. For example, age distribution differs in low-incidence areas compared with endemic areas. In low-incidence areas, the incidence of NPC increases with age and has a bimodal peak: the first in adolescents and young adults and the second after 65 years of age, whereas in endemic areas, the incidence increases after 30 years of age, peaks at 40-59 years and decreases thereafter. The male–female incidence ratio is 2.75.3Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (29125) Google Scholar In Europe, during the period of 2000-2007, the 5-year survival rate for adults with NPC was 49% (www.rarecarenet.eu). Survival rates increased during 1999-2007 in Europe, except in Eastern Europe where it declined over time.4Gatta G. Botta L. Sánchez M.J. et al.Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study.Eur J Cancer. 2015; 51: 2130-2143Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar In the USA, during the period of 2009-2015, the 5-year relative survival rate was 60%, with differences seen across ethnic groups.5Howlader N. Noone A.M. Krapcho M. SEER Cancer Statistics Review, 1975-2017. National Cancer Institute, Bethesda, MD2019https://seer.cancer.gov/csr/1975_2017Date accessed: December 2, 2020Google Scholar Asians seem to have a disease-specific survival advantage independent of gender, age at diagnosis, grade, TNM (tumour–node–metastasis) staging and treatment.6Zhou L. Shen N. Li G. et al.The racial disparity of nasopharyngeal carcinoma based on the database analysis.Am J Otolaryngol. 2019; 40: 102288Crossref PubMed Scopus (1) Google Scholar In addition, the hazard rate patterns for NPC-related mortality appear significantly different between histological subtypes.7Wu S.G. Lian C.L. Wang J. et al.The effect of histological subtypes on survival outcome in nasopharyngeal carcinoma after extensive follow up.Ann Transl Med. 2019; 7: 768Crossref PubMed Google Scholar The effect of age on survival is marked. Five-year survival rates were 72% in the youngest age group (15-45 years) and 36% in the oldest group of patients (65-74 years).8Chua M.L.K. Wee J.T.S. Hui E.P. et al.Nasopharyngeal carcinoma.Lancet. 2016; 387: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar In general, the prognosis is better for women than men.9OuYang P.Y. Zhang L.N. Lan X.W. et al.The significant survival advantage of female sex in nasopharyngeal carcinoma: a propensity-matched analysis.Br J Cancer. 2015; 112: 1554-1561Crossref PubMed Scopus (26) Google Scholar,10Tang L.Q. Li C.F. Li J. et al.Establishment and validation of prognostic nomograms for endemic nasopharyngeal carcinoma.J Natl Cancer Inst. 2016; 108: djv291Crossref PubMed Scopus (140) Google Scholar Definitive diagnosis is made by endoscopic-guided biopsy of the primary nasopharyngeal tumour [II, A]. In case of no clinical primary tumour visible at endoscopy, biopsy of nasopharyngeal tissue positive at magnetic resonance imaging (MRI) or positron emission tomography (PET) is suggested.11King A.D. Woo J.K.S. Ai Q.Y. et al.Complementary roles of MRI and endoscopic examination in the early detection of nasopharyngeal carcinoma.Ann Oncol. 2019; 30: 977-982Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Since the first sign of disease is often the appearance of neck nodes, it is frequent that patients undergo neck biopsy and/or neck nodal dissection. This procedure is not recommended since it may reduce the probability of cure and have an impact on late treatment sequelae. Nevertheless, if carried out (for example, if the primary tumour is not visible), node dissection without capsular effraction or ultrasonography-guided, transcutaneous tru-cut biopsy are the best options; node surgical biopsy should be avoided. Determination of Epstein-Barr virus (EBV) on the histological sample by in situ hybridisation (ISH) is indicated. The histological type should be classified according to the 4th edition of the World Health Organization (WHO) classification (Table 1).12El-Naggar A.K. Chan J.K.C. Grandis J.R. WHO Classification of Head and Neck Tumours. WHO Classification of Tumours. 4th Edition, Volume 9. IARC Publications, Lyon2017Google Scholar The term ‘nasopharyngeal carcinoma’ refers to all squamous cell cancers which are categorised into keratinising, non-keratinising (subdivided into differentiated and undifferentiated) and basaloid carcinoma subtypes. Keratinising cancer is more frequent in non-endemic than endemic areas, whereas non-keratinising cancer comprises the vast majority of cases and is linked to EBV infection.Table 1WHO classification of nasopharyngeal carcinomasICD-O codeNon-keratinising squamous cell carcinoma8072/3Keratinising squamous cell carcinoma8071/3Basaloid squamous cell carcinoma8083/3ICD-O, International Classification of Diseases for Oncology; WHO, World Health Organization. Open table in a new tab ICD-O, International Classification of Diseases for Oncology; WHO, World Health Organization. EBV is considered in ‘Group 1’ by the International Agency for Research on Cancer (IARC) in respect to NPC, i.e. a virus for which there is sufficient evidence of carcinogenicity in humans.13Bouvard V. Baan R. Straif K. et al.A review of human carcinogens--Part B: biological agents.Lancet Oncol. 2009; 10: 321-322Abstract Full Text Full Text PDF PubMed Google Scholar,14de Martel C. Georges D. Bray F. et al.Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis.Lancet Glob Health. 2020; 8: e180-e190Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar EBV is identified by ISH by the presence of EBV-encoded RNAs in NPC tissue. Latent EBV has been found in high-grade dysplasia and NPC cells but not in normal epithelium or low-grade dysplasia.15Pathmanathan R. Prasad U. Sadler R. et al.Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma.N Engl J Med. 1995; 333: 693-698Crossref PubMed Scopus (0) Google Scholar EBV has also been identified in a clonal pattern in pre-invasive lesions of the nasopharynx that contain EBV RNAs characteristic of latent infection. EBV-infected cells express several latent proteins, both as EB nuclear antigens [EBNAs 1, 2, 3A, 3B and 3C and EBNA-leader proteins (LPs)] and as latent membrane proteins (LMPs 1, 2A and 2B).16Bruce J.P. Yip K. Bratman S.V. et al.Nasopharyngeal cancer: molecular landscape.J Clin Oncol. 2015; 33: 3346-3355Crossref PubMed Scopus (90) Google Scholar However, the EBV latent-gene expression in NPC is predominantly restricted to EBNA1, LMP2A and LMP2B. These viral proteins are considered as poorly immunogenic, partially explaining the way in which NPC may elude immune recognition. The role of EBV genomic variants on NPC development has not been completely clarified; however, whole genome sequencing of EBV has revealed a high variability in many genomic regions of NPC biopsy specimens.17Lin D.C. Meng X. Hazawa M. et al.The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014; 46: 866-871Crossref PubMed Scopus (189) Google Scholar EBV is almost always a necessary, even if not sufficiently causative, factor for non-keratinising NPC; its role in keratinising cancer is less pronounced. In regions where NPC is endemic, p16 positivity and human papillomavirus (HPV) expression (screened using RNA probes to detect 13 high-risk and 5 low-risk HPV types) is reported in up to 8% of non-keratinising undifferentiated carcinoma, and carries a better prognosis than its EBV counterpart.18Huang W.B. Chan J.Y.W. Liu D.L. Human papillomavirus and World Health Organization type III nasopharyngeal carcinoma: multicenter study from an endemic area in Southern China.Cancer. 2018; 124: 530-536Crossref PubMed Scopus (19) Google Scholar In non-endemic areas, the presence of HPV data are limited, with a higher frequency seen in keratinising cancer; however, an association with prognosis is not as clear.19Li H. Torabi S.J. Yarbrough W.G. et al.Association of human papillomavirus status at head and neck carcinoma subsites with overall survival.JAMA Otolaryngol Head Neck Surg. 2018; 144: 519-525Crossref PubMed Scopus (28) Google Scholar Whether HPV is involved in carcinogenesis and disease progression has yet to be established. Although no actionable mutations in NPC have been identified, a role for gene signature discovery is increasing. Molecular deciphering is beyond the scope of this guideline. However, gene expression analysis may be useful in identifying patients at higher risk of developing distant metastases.20Tang X.R. Li Y.Q. Liang S.B. et al.Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.Lancet Oncol. 2018; 19: 382-393Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar In addition, mutational signatures relevant to DNA repair pathways show prognostic value with potential clinical implications.21Dai W. Chung D.L. Chow L.K. et al.Clinical outcome-related mutational signatures identified by integrative genomic analysis in nasopharyngeal carcinoma.Clin Cancer Res. 2020; 26(24): 6494-6504Crossref Google Scholar Genetic susceptibility plays a clear role in the development of NPC, as witnessed by the discovery of susceptibility loci and candidate genes in NPC patients or high-risk individuals.22Hildesheim A. Wang C.P. Genetic predisposition factors and nasopharyngeal carcinoma risk: a review of epidemiological association studies, 2000-2011: Rosetta Stone for NPC: genetics, viral infection, and other environmental factors.Semin Cancer Biol. 2012; 22: 107-116Crossref PubMed Scopus (133) Google Scholar Environmental factors are also causal agents, mainly related to the consumption of salted fish, while there is less evidence to support other agents or dietary products.23Tsao S.W. Yip Y.L. Tsang C.M. et al.Etiological factors of nasopharyngeal carcinoma.Oral Oncol. 2014; 50: 330-338Crossref PubMed Google Scholar In regions where NPC is endemic, the use of plasma EBV DNA with a primer/probe assay targeting the BamHI-W region of the EBV genome, carried out in duplicate (at least 4 weeks apart) and coupled with endoscopic examination and MRI, showed a sensitivity and specificity in screening NPC of 97.1% and 98.6%, respectively.24Chan K.C.A. Woo J.K.S. King A. et al.Analysis of plasma Epstein-Barr Virus DNA to screen for nasopharyngeal cancer.N Engl J Med. 2017; 377: 513-522Crossref PubMed Scopus (246) Google Scholar The number of subjects needed to be screened to detect one case was 593. Its use can therefore only be recommended for detecting early asymptomatic NPC in endemic areas and is limited to those considered at higher risk (i.e. males aged 40-62 years) [III, A]. Although overall survival (OS) data for the screened population are not available, the 3-year progression-free survival (PFS) was significantly improved compared with a matched historical cohort [97% versus 70%; hazard ratio (HR) 0.10; 95% confidence interval (CI) 0.05-0.18]. One of the issues related to plasma EBV DNA is the poor standardisation between the different assays used. •Definitive diagnosis is made by endoscopic-guided biopsy of the primary nasopharyngeal tumour [II, A]; diagnostic neck biopsy and/or neck nodal dissection should be avoided.• Determination of EBV on the histological specimen by ISH is indicated [III, B].• In regions where NPC is endemic, the use of plasma EBV DNA, coupled with endoscopic examination and MRI, can be recommended for detecting early, asymptomatic NPC [III, A]. NPC is clinically staged according to the American Joint Committee on Cancer (AJCC) staging classification 8th edition (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.12.007).25Amin M.B. Edge S. Greene F. et al.AJCC Cancer Staging Manual.8th ed. Springer International Publishing, New York2017Crossref Google Scholar Compared with the previous edition, the new classification better delineates the T2 stage to also include prevertebral muscle and medial or lateral pterygoid involvement, and the T4 stage now includes parotid gland and/or infiltration beyond the lateral surface of the lateral pterygoid muscle, thus eliminating other ambiguous terminology. Nodal extension to the supraclavicular fossa has been substituted by the limit of the caudal border of the cricoid cartilage and so better delineates the ‘lower neck’ extension; N3 definition includes both the previous N3a and N3b groups. Moreover, EBV-positive cervical nodes in cancer of unknown primary are staged according to the NPC classification. Routine staging procedures (Table 2) include a medical history, physical examination (including cranial nerve examination), complete blood count (CBC), serum biochemistry [including liver and renal function tests and lactate dehydrogenase (LDH)], nasopharyngoscopy, computed tomography (CT) scan or MRI of the nasopharynx and base of the skull and neck (up to the clavicle) and 18F-fluorodeoxy- glucose (FDG)-PET/CT imaging. MRI is the most accurate way of defining local tumour staging as it is sensitive in depicting small mucosal thickening, parapharyngeal and masticatory space involvement and skull base and cranial nerve infiltration, and it should therefore be preferred whenever available and according to the centre's expertise [III, B]. Accuracy of nodal involvement detection is higher with MRI compared with CT; FDG-PET adds further accuracy in nodal staging [III, B]. The best imaging for detecting distant metastases is FDG-PET in terms of sensitivity and specificity, and it is recommended at least in locally advanced disease [III, B].26Chang M.C. Chen J.H. Liang J.A. et al.Accuracy of whole-body FDG-PET and FDG-PET/CT in M staging of nasopharyngeal carcinoma: a systematic review and meta-analysis.Eur J Radiol. 2013; 82: 366-373Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Moreover, a systematic review and meta-analysis showed that baseline metabolic values of FDG-PET were able to predict survival outcomes for NPC patients.27Lin J. Xie G. Liao G. et al.Prognostic value of 18F-FDG-PET/CT in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis.Oncotarget. 2017; 8: 33884-33896Crossref PubMed Scopus (23) Google ScholarTable 2Diagnostic work-up1.Medical history and physical examination2.CBC, serum biochemistry3.Nasopharyngoscopy4.Tumour biopsy (EBER by ISH [III, B])5.CT scan or MRI of the nasopharynx and base of the skull and neck (to the clavicle) (MRI preferred [III, B])6.18F-FDG-PET/CT imaging [III, B]7.Baseline audiometric testing, dental examination, nutritional status evaluation, ophthalmological and endocrine evaluation8.Plasma EBV DNA [III, B]9.QoL assessment (e.g. EORTC QLQ-C30) [III, B]18F-FDG, 18F-fluorodeoxyglucose; CBC, complete blood count; CT, computed tomography; EBER, Epstein-Barr virus-encoded RNA; EBV, Epstein-Barr virus; EORTC, European Organisation for Research and Treatment of Cancer; ISH, in situ hybridisation; MRI, magnetic resonance imaging; PET, positron emission tomography; QLQ, quality of life questionnaire; QoL, quality of life. Open table in a new tab 18F-FDG, 18F-fluorodeoxyglucose; CBC, complete blood count; CT, computed tomography; EBER, Epstein-Barr virus-encoded RNA; EBV, Epstein-Barr virus; EORTC, European Organisation for Research and Treatment of Cancer; ISH, in situ hybridisation; MRI, magnetic resonance imaging; PET, positron emission tomography; QLQ, quality of life questionnaire; QoL, quality of life. Baseline audiometric testing, dental examination, nutritional status evaluation and ophthalmological and endocrine evaluation should be carried out as appropriate. Pre-treatment quality of life (QoL) scales [e.g. the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30], mainly physical functioning, have been found to be a more accurate predictor of OS than performance status (PS).28Fang F.M. Tsai W.L. Chien C.Y. et al.Pretreatment quality of life as a predictor of distant metastasis and survival for patients with nasopharyngeal carcinoma.J Clin Oncol. 2010; 28: 4384-4389Crossref PubMed Scopus (30) Google Scholar Their application in clinical practice may better delineate the individual risk and prompt medical or physical support before the start of treatment [III, B]. Due to the variability in assessments between laboratories, EBV DNA measurement needs further harmonisation.29Le Q.T. Zhang Q. Cao H. et al.An international collaboration to harmonize the quantitative plasma Epstein-Barr virus DNA assay for future biomarker-guided trials in nasopharyngeal carcinoma.Clin Cancer Res. 2013; 19: 2208-2215Crossref PubMed Scopus (85) Google Scholar Both the pre- and post-treatment plasma/serum load of EBV DNA with a primer/probe set targeting the BamHI-W region of the EBV genome has shown prognostic value [III, B]. A pre-treatment cut-off value of between 1500 and 4000 copies/ml has been proposed in endemic areas.30Chan A.T.C. Lo Y.M.D. Zee B. et al.Plasma Epstein-Barr Virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma.J Natl Cancer Inst. 2002; 94: 1614-1619Crossref PubMed Google Scholar,31Lin J.C. Wang W.Y. Chen K.Y. et al.Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma.N Engl J Med. 2004; 350: 2461-2470Crossref PubMed Scopus (572) Google Scholar The prognostic role of pre-treatment EBV DNA has also been reported in non-endemic areas using PCR, which amplifies the gene coding for the EBNA-1 protein [IV, B].32Alfieri S. Iacovelli N.A. Marceglia S. et al.Circulating pre-treatment Epstein-Barr virus DNA as prognostic factor in locally-advanced nasopharyngeal cancer in a non-endemic area.Oncotarget. 2017; 8: 47780-47789Crossref PubMed Scopus (18) Google Scholar Incorporation of plasma EBV DNA both in the pre- and post-treatment setting may improve the prognostic capacity of the TNM staging system.33Guo R. Tang L.L. Mao Y.P. et al.Proposed modifications and incorporation of plasma Epstein-Barr virus DNA improve the TNM staging system for Epstein-Barr virus-related nasopharyngeal carcinoma.Cancer. 2019; 125: 79-89Crossref PubMed Scopus (51) Google Scholar,34Hui E.P. Li W.F. Ma B.B. et al.Integrating postradiotherapy plasma Epstein-Barr virus DNA and TNM stage for risk stratification of nasopharyngeal carcinoma to adjuvant therapy.Ann Oncol. 2020; 31(6): 769-779Abstract Full Text Full Text PDF Scopus (3) Google Scholar At this time, however, plasma EBV DNA detection has no impact on treatment strategy. Biomolecular signatures with gene expression and microRNA have been shown to add prognostic value to clinical and radiological staging.35Wang H.Y. Sun B.Y. Zhu Z.H. et al.Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival.J Clin Oncol. 2011; 29: 4516-4525Crossref PubMed Scopus (92) Google Scholar,36Liu N. Chen N.Y. Cui R.X. et al.Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis.Lancet Oncol. 2012; 13: 633-641Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar Several nomograms have also been proposed to better stratify patient prognosis in endemic regions using factors such as T and N stage, age, gender, body mass index, haemoglobin, LDH, plasma EBV DNA and C-reactive protein. They may help to determine prognosis, but data are limited to support their use in choosing a treatment strategy [IV, C]. No data in this regard exist for non-endemic areas. •Routine staging procedures include a medical history, physical examination with cranial nerve examination, CBC, serum biochemistry (including liver and renal function tests and LDH), nasopharyngoscopy and radiological imaging.• MRI is the most accurate way of defining local and nodal tumour staging and it should be preferred whenever available and according to the centre's expertise [III, B].• FDG-PET adds further accuracy in nodal staging, is the best imaging method for detecting distant metastases and is recommended at least in locally advanced disease [III, B].• Baseline audiometric testing, dental examination, nutritional status evaluation and ophthalmological and endocrine evaluation should be carried out as appropriate.• Pre-treatment QoL scales may be suggested to better delineate the individual risk and to prompt medical or physical support before the start of treatment [III, B].• Pre- and post-treatment plasma/serum load of EBV DNA has prognostic value [III, B]. Efficacy data and consequent recommendations described here are derived largely from studies in the endemic setting, where non-keratinising, EBV-related carcinomas constitute most cases. Where the evidence is lower, these data will still be considered for non-endemic carcinomas. The optimal treatment strategy for patients with advanced NPC should be discussed within a multidisciplinary team (MDT). Treatment of patients in high-volume facilities is recommended as this was reported as an independent prognostic factor for improved survival, at least in areas where the disease is endemic [IV, B].37Yoshida E.J. Luu M. David J.M. et al.Facility volume and survival in nasopharyngeal carcinoma.Int J Radiat Oncol Biol Phys. 2018; 100: 408-417Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar A proposed treatment algorithm for local and locoregional NPC is shown in Figure 1. Radiotherapy (RT) is the mainstay of treatment and is an essential component of curative-intent treatment of non-disseminated NPC. Intensity-modulated RT (IMRT) is an important milestone in the management of NPC, providing enhanced outcomes and less severe late effects compared with previous RT techniques [conventional two-dimensional (2D) and three-dimensional (3D) by parallel improved dosimetric parameters]. Indeed, a meta-analysis showed a significant improvement in 5-year OS and 5-year local control (LC) favouring IMRT over other techniques [II, A].38Zhang B. Mo Z. Du W. et al.Intensity-modulated radiation therapy versus 2D-RT or 3D-CRT for the treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis.Oral Oncol. 2015; 51: 1041-1046Crossref PubMed Scopus (88) Google Scholar Regarding late effects, a significant reduction in late xerostomia, trismus and temporal lobe injury was reported in favour of IMRT compared with older RT techniques [II, A].38Zhang B. Mo Z. Du W. et al.Intensity-modulated radiation therapy versus 2D-RT or 3D-CRT for the treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis.Oral Oncol. 2015; 51: 1041-1046Crossref PubMed Scopus (88) Google Scholar The largest Asiatic series reported that 5.1% of patients had cranial nerve palsies, 7.1% had severe hearing loss, 3% had dysphagia requiring long-term tube feeding and 0.9% had symptomatic temporal lobe necrosis (TLN) at a median follow-up of 80 months [IV, A].39Au K.H. Ngan R.K.C. Ng A.W.Y. et al.Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: a report of 3328 patients (HKNPCSG 1301 study).Oral Oncol. 2018; 77: 16-21Crossref PubMed Scopus (80) Google Scholar In addition, IMRT improved QoL for long-term survivors over time compared with older techniques both in endemic and non-endemic regions [IV, A].40Huang T.L. Chien C.Y. Tsai W.L. et al.Long-term late toxicities and quality of life for survivors of nasopharyngeal carcinoma treated with intensity-modulated radiotherapy versus non-intensity-modulated radiotherapy.Head Neck. 2016; 38: E1026-E1032Crossref PubMed Scopus (42) Google Scholar,41McDowell L.J. Rock K. Xu W. et al.Long-term late toxicity, quality of life, and emotional distress in patients with nasopharyngeal carcinoma treated with intensity modulated radiation therapy.Int J Radiat Oncol Biol Phys. 2018; 102: 340-352Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Although IMRT represents the current standard RT technique for NPC, particle therapy, including protons and carbon ions, is gaining popularity based on its physical and biological proprieties. In particular, to maintain a high RT dose and avoid neurological structures, proton therapy represents a promising approach for patients with locally advanced NPC. A few small studies with a relatively short follow-up have shown a benefit in terms of clinical outcome when proton therapy was added as a boost for locally advanced disease [III, C].42Alterio D. D'Ippolito E. Vischioni B. et al.Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy.Acta Oncol. 2020; 59: 541-548Crossref PubMed Scopus (0) Google Scholar, 43Lewis G.D. Holliday E.B. Kocak-Uzel E. et al.Intensity-modulated proton therapy for nasopharyngeal carcinoma: decreased radiation dose to normal structures and encouraging clinical outcomes.Head Neck. 2016; 38: E1886-E1895Crossref PubMed Scopus (51) Google Scholar, 44Beddok A. Feuvret L. Noël G. et al.Cancer Radiother. 2019; 23: 304-311Crossref PubMed Scopus (0) Google Scholar In particular, significantly lower rates of severe (grade 3) mucositis and salivary dysfunctions were reported in NPC patients receiving IMRT followed by proton therapy boost (55.6% of whom had T4-stage disease) compared with patients receiving a full course of IMRT only (41.2% of whom had T4-stage disease).42Alterio D. D'Ippolito E. Vischioni B. et al.Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy.Acta Oncol. 2020; 59: 541-548Crossref PubMed Scopus (0) Google Scholar Target volume definition represents a major issue during IMRT planning for NPC, as witnessed by the need for international guidelines for appropriate target contouring.45Lee A.W. Ng W.T. Pan J.J. et al.International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma.Radiother Oncol. 2018; 126: 25-36Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Overall, RT is targeted according to the primary tumour and pathological nodes, but also to the adjacent regions considered at risk of microscopic spread from the tumour and generally to both sides of the neck (levels II-V and retropharyngeal nodes) because of the high incidence of occult neck node involvement.45Lee A.W. Ng W.T. Pan J.J. et al.International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma.Radiother Oncol. 2018; 126: 25-36Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar A total dose of 70 Gy is needed for the eradication of macroscopic disease and 50-60 Gy for the treatment of potential at-risk sites, usually by conventional or moderately accelerated RT.46Ng W.T. Lee M.C. Hung W.M. et al.Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma.Int J Radiat Oncol Biol Phys. 2011; 79: 420-428Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar IMRT may be applied using either a sequential boost or a simultaneous integrated boost (SIB). A recent randomised trial comparing these two techniques found no difference in terms of clinical outcome and toxicities. Due to the convenience of an SIB strategy, this approach can be considered the technique of choice for NPC treatment [II, B].47Lertbutsayanukul C. Prayongrat A. Kannarunimit D. et al.A randomized phase III study between sequential versus simultaneous integrated boost inten