Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations

Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5‐flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN‐β) for selected high‐risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long‐term treatment‐related complications that affect most of the survivors.

[1]  A. Ferrari,et al.  The European Paediatric Rare Tumours Network ‐ European Registry (PARTNER) project for very rare tumors in children , 2021, Pediatric blood & cancer.

[2]  H. Amthauer,et al.  Prognostic value of baseline [18F]-fluorodeoxyglucose positron emission tomography parameters MTV, TLG and asphericity in an international multicenter cohort of nasopharyngeal carcinoma patients , 2020, PloS one.

[3]  M. Chua,et al.  Efficacy and Safety of Locoregional Radiotherapy With Chemotherapy vs Chemotherapy Alone in De Novo Metastatic Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial. , 2020, JAMA oncology.

[4]  S. Revel-Vilk,et al.  Nasopharyngeal carcinoma in children and young adults—Beyond 5‐year survival , 2020, Pediatric blood & cancer.

[5]  M. Chua,et al.  Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation? , 2020, International journal of cancer.

[6]  D. Kannarunimit,et al.  Comparison between the seventh and eighth edition of the AJCC/UICC staging system for nasopharyngeal cancer integrated with pretreatment plasma Epstein-Barr virus DNA level in a non-Chinese population: secondary analysis from a prospective randomized trial. , 2019, Japanese journal of clinical oncology.

[7]  Y. Lu,et al.  Validation of the 8th edition of AJCC/UICC staging system for nasopharyngeal carcinoma: Results from a non-endemic cohort with 10-year follow-up. , 2019, Oral oncology.

[8]  A. Pappo,et al.  Treatment of Childhood Nasopharyngeal Carcinoma With Induction Chemotherapy and Concurrent Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  D. Orbach,et al.  Update in pediatric nasopharynx undifferentiated carcinoma. , 2019, The British journal of radiology.

[10]  J. Noh,et al.  Early clinical outcomes of helical tomotherapy/intensity‐modulated proton therapy combination in nasopharynx cancer , 2019, Cancer science.

[11]  H. Mai,et al.  Effect of local treatment for metastasis and its sequence with chemotherapy on prognosis of post-treatment metastatic nasopharyngeal carcinoma patients. , 2019, Oral oncology.

[12]  D. Orbach,et al.  Adapted strategy to tumor response in childhood nasopharyngeal carcinoma: the French experience , 2019, Strahlentherapie und Onkologie.

[13]  Brian O'Sullivan,et al.  The addition of pretreatment plasma Epstein–Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification , 2019, International journal of cancer.

[14]  Ying Sun,et al.  Relationship between pretreatment concentration of plasma Epstein‐Barr virus DNA and tumor burden in nasopharyngeal carcinoma: An updated interpretation , 2018, Cancer medicine.

[15]  Ying Sun,et al.  Proposed modifications and incorporation of plasma Epstein‐Barr virus DNA improve the TNM staging system for Epstein‐Barr virus‐related nasopharyngeal carcinoma , 2018, Cancer.

[16]  K. Oktay,et al.  Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  N. Picard,et al.  Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx , 2018 .

[18]  V. Bišof,et al.  Comparison of intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) and a 3-dimensional conformal parotid gland-sparing radiotherapy (ConPas 3D-CRT) in treatment of nasopharyngeal carcinoma: a mono-institutional experience , 2018, La radiologia medica.

[19]  San-Gang Wu,et al.  Demographic and clinicopathological characteristics of nasopharyngeal carcinoma and survival outcomes according to age at diagnosis: A population-based analysis. , 2017, Oral oncology.

[20]  L. Liang,et al.  Quantification of familial risk of nasopharyngeal carcinoma in a high‐incidence area , 2017, Cancer.

[21]  L. Kong,et al.  Use of Radiation Therapy in Metastatic Nasopharyngeal Cancer Improves Survival: A SEER Analysis , 2017, Scientific Reports.

[22]  Xiang Guo,et al.  A retrospective study comparing the outcomes and toxicities of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescent nasopharyngeal carcinoma , 2017, Journal of Cancer Research and Clinical Oncology.

[23]  Yun-bin Chen,et al.  Unidimensional measurement may be superior to assess primary tumor response after neoadjuvant chemotherapy for nasopharyngeal carcinoma , 2017, Oncotarget.

[24]  C. Borg,et al.  Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach. , 2017, Seminars in oncology.

[25]  Shi Qi,et al.  18F-FLT and 18F-FDG PET/CT in Predicting Response to Chemoradiotherapy in Nasopharyngeal Carcinoma: Preliminary Results , 2017, Scientific Reports.

[26]  F. Liu,et al.  PET/CT-guided dose-painting versus CT-based intensity modulated radiation therapy in locoregional advanced nasopharyngeal carcinoma , 2017, Radiation oncology.

[27]  Jianji Pan,et al.  Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial , 2016, The Lancet.

[28]  V. Lee,et al.  Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma , 2016, Proceedings of the National Academy of Sciences.

[29]  Y. Mao,et al.  The Tumour Response to Induction Chemotherapy has Prognostic Value for Long-Term Survival Outcomes after Intensity-Modulated Radiation Therapy in Nasopharyngeal Carcinoma , 2016, Scientific Reports.

[30]  T. Jovanović,et al.  Characterization of the Variability of Epstein-Barr Virus Genes in Nasopharyngeal Biopsies: Potential Predictors for Carcinoma Progression , 2016, PloS one.

[31]  J. W. Lam,et al.  Clinical utility of circulating Epstein-Barr virus DNA analysis for the management of nasopharyngeal carcinoma. , 2016, Chinese clinical oncology.

[32]  A. Garden,et al.  Intensity‐modulated proton therapy for nasopharyngeal carcinoma: Decreased radiation dose to normal structures and encouraging clinical outcomes , 2016, Head & neck.

[33]  P. Sham,et al.  Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma , 2016, Proceedings of the National Academy of Sciences.

[34]  Jianji Pan,et al.  International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents , 2016, Cancer Chemotherapy and Pharmacology.

[35]  Wei Zheng,et al.  Multimodality Treatment May Improve the Survival Rate of Patients with Metastatic Nasopharyngeal Carcinoma with Good Performance Status , 2016, PloS one.

[36]  Ying Sun,et al.  Plasma Epstein-Barr viral DNA complements TNM classification of nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy , 2015, Oncotarget.

[37]  H. Mai,et al.  Plasma Epstein–Barr Viral Deoxyribonucleic Acid Predicts Worse Outcomes in Pediatric Nonmetastatic Nasopharyngeal Carcinoma Patients , 2015, Medicine.

[38]  Ying Sun,et al.  The Prognostic Value of Plasma Epstein-Barr Viral DNA and Tumor Response to Neoadjuvant Chemotherapy in Advanced-Stage Nasopharyngeal Carcinoma. , 2015, International journal of radiation oncology, biology, physics.

[39]  Jun Ma,et al.  Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up. , 2015, European Journal of Cancer.

[40]  Longzhen Zhang,et al.  A Randomized Pilot Trial Comparing Position Emission Tomography (PET)-Guided Dose Escalation Radiotherapy to Conventional Radiotherapy in Chemoradiotherapy Treatment of Locally Advanced Nasopharyngeal Carcinoma , 2015, PloS one.

[41]  W. Liang,et al.  Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma , 2015, Medical Oncology.

[42]  T. Gupta,et al.  PO-120: Clinical impact of metabolic and anatomic imaging in nasopharyngeal carcinoma treated with chemo-radiotherapy , 2015 .

[43]  Christopher W. Dawson,et al.  Epstein-Barr virus and nasopharyngeal carcinoma , 2014, Chinese journal of cancer.

[44]  G. Shen,et al.  Meta-analysis of diagnostic value of 18F-FDG PET or PET/CT for detecting lymph node and distant metastases in patients with nasopharyngeal carcinoma. , 2014, The British journal of radiology.

[45]  M. Truong,et al.  FDG PET/CT in the management of nasopharyngeal carcinoma. , 2014, AJR. American journal of roentgenology.

[46]  Shuxing Li,et al.  Pretreatment Epstein-Barr Virus DNA Load and Cumulative Cisplatin Dose Intensity Affect Long-Term Outcome of Nasopharyngeal Carcinoma Treated with Concurrent Chemotherapy: Experience of an Institute in an Endemic Area , 2014, Oncology Research and Treatment.

[47]  R. Sun,et al.  Locoregional radiotherapy in patients with distant metastases of nasopharyngeal carcinoma at diagnosis , 2013, Chinese journal of cancer.

[48]  M. Kohli,et al.  Response criteria in oncologic imaging: review of traditional and new criteria. , 2013, Radiographics : a review publication of the Radiological Society of North America, Inc.

[49]  Y. Shih,et al.  Long‐term survival analysis of nasopharyngeal carcinoma by plasma Epstein‐Barr virus DNA levels , 2013, Cancer.

[50]  Ji-An Liang,et al.  Accuracy of whole-body FDG-PET and FDG-PET/CT in M staging of nasopharyngeal carcinoma: a systematic review and meta-analysis. , 2013, European journal of radiology.

[51]  X. An,et al.  Triplet combination with paclitaxel, cisplatin and 5-FU is effective in metastatic and/or recurrent nasopharyngeal carcinoma , 2013, Cancer Chemotherapy and Pharmacology.

[52]  X. An,et al.  Salvage gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. , 2012, Oral oncology.

[53]  H. Christiansen,et al.  Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults , 2012, Cancer.

[54]  S. Zhang,et al.  A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[55]  Wen-Qi Jiang,et al.  Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma , 2012, Journal of Cancer Research and Clinical Oncology.

[56]  A. Ferrari,et al.  A prospective protocol for nasopharyngeal carcinoma in children and adolescents , 2012, Cancer.

[57]  Matthew J. Krasin,et al.  PET/CT for staging and follow-up of pediatric nasopharyngeal carcinoma , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[58]  X. An,et al.  Plasma Epstein‐Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy , 2011, Cancer.

[59]  T. Yau,et al.  A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma. , 2011, Oral oncology.

[60]  E. Tan,et al.  Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  A. King,et al.  Primary nasopharyngeal carcinoma: diagnostic accuracy of MR imaging versus that of endoscopy and endoscopic biopsy. , 2011, Radiology.

[62]  Hao Liu,et al.  Adoptive Transfer of EBV-specific T Cells Results in Sustained Clinical Responses in Patients With Locoregional Nasopharyngeal Carcinoma , 2010, Journal of immunotherapy.

[63]  M. Chua,et al.  Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngeal carcinoma , 2009, Head & neck.

[64]  Riccardo Calandrino,et al.  Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. , 2008, International journal of radiation oncology, biology, physics.

[65]  F. Bray,et al.  Age-Incidence Curves of Nasopharyngeal Carcinoma Worldwide: Bimodality in Low-Risk Populations and Aetiologic Implications , 2008, Cancer Epidemiology Biomarkers & Prevention.

[66]  T. Mok,et al.  A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein–Barr virus DNA as a biomarker of efficacy , 2008, Cancer Chemotherapy and Pharmacology.

[67]  J. Klijanienko,et al.  Radiation and chemotherapy combination for nasopharyngeal carcinoma in children: Radiotherapy dose adaptation after chemotherapy response to minimize late effects , 2008, Pediatric blood & cancer.

[68]  Uwe Oelfke,et al.  Radiation Oncology Intensity-modulated Radiotherapy of Nasopharyngeal Carcinoma: a Comparative Treatment Planning Study of Photons and Protons , 2022 .

[69]  T. Yen,et al.  18F-FDG PET Can Replace Conventional Work-up in Primary M Staging of Nonkeratinizing Nasopharyngeal Carcinoma , 2007, Journal of Nuclear Medicine.

[70]  D. Yeung,et al.  Nasopharyngeal cancers: which method should be used to measure these irregularly shaped tumors on cross-sectional imaging? , 2007, International journal of radiation oncology, biology, physics.

[71]  Jin-Ching Lin,et al.  Long-term prognostic effects of plasma epstein-barr virus DNA by minor groove binder-probe real-time quantitative PCR on nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. , 2007, International journal of radiation oncology, biology, physics.

[72]  H. Heslop,et al.  A Single Institution Experience With Pediatric Nasopharyngeal Carcinoma: High Incidence of Toxicity Associated With Platinum-based Chemotherapy Plus IMRT , 2007, Journal of pediatric hematology/oncology.

[73]  T. Yen,et al.  [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  Jang-Yang Chang,et al.  Phase II study of gemcitabine plus vinorelbine in the treatment of cisplatin‐resistant nasopharyngeal carcinoma , 2006, Head & neck.

[75]  C. Hess,et al.  Treatment of nasopharyngeal carcinoma in children and adolescents , 2005, Cancer.

[76]  A. Kuten,et al.  Pediatric nasopharyngeal carcinoma: Better prognosis and increased c‐Kit expression as compared to adults , 2005, Pediatric blood & cancer.

[77]  B. Vicandi,et al.  Fine‐needle aspiration cytology of metastatic nasopharyngeal carcinoma , 2005, Diagnostic cytopathology.

[78]  G. Swanson,et al.  Preradiation chemotherapy with methotrexate, cisplatin, 5‐fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma , 2005, Cancer.

[79]  Y. Shugart,et al.  Complex segregation analysis of nasopharyngeal carcinoma in Guangdong, China: evidence for a multifactorial mode of inheritance (complex segregation analysis of NPC in China) , 2005, European Journal of Human Genetics.

[80]  Y. Cheung,et al.  Phase II study of irinotecan (CPT‐11) as salvage therapy for advanced nasopharyngeal carcinoma , 2005, Cancer.

[81]  A. Kuten,et al.  Prevalence and relevance of EBV latency in nasopharyngeal carcinoma in Israel , 2004, Journal of Clinical Pathology.

[82]  S. M. Kollur,et al.  Fine‐needle aspiration cytology of metastatic nasopharyngeal carcinoma in cervical lymph nodes: Comparison with metastatic squamous‐cell carcinoma, and Hodgkin's and non‐Hodgkin's lymphoma , 2003, Diagnostic cytopathology.

[83]  L. Peters,et al.  Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  D Machin,et al.  Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[85]  A. Chan,et al.  The use of brush cytology and directed biopsies for the detection of nasopharyngeal carcinoma and precursor lesions , 2001, Head & neck.

[86]  C. Dykewicz Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[87]  O. Uzel,et al.  Nasopharyngeal carcinoma in childhood: long-term results of 32 patients. , 2001, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[88]  A. King,et al.  Paranasopharyngeal space involvement in nasopharyngeal cancer: detection by CT and MRI. , 2000, Clinical oncology (Royal College of Radiologists (Great Britain)).

[89]  D. Chua,et al.  A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. , 2000, European journal of cancer.

[90]  M. Serin,et al.  Nasopharyngeal carcinoma in childhood and adolescence. , 1998, Medical and pediatric oncology.

[91]  Kathryn Flynn,et al.  Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. , 1995, The New England journal of medicine.

[92]  M. Chan,et al.  Fine needle aspiration cytodiagnosis of nasopharyngeal carcinoma in cervical lymph nodes. A study of 40 cases. , 1989, Acta cytologica.

[93]  M. Loriot,et al.  [Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks]. , 2018, Bulletin du cancer.

[94]  D. Orbach,et al.  Childhood Nasopharyngeal Carcinoma: State-of-the-Art, and Questions for the Future , 2018, Journal of pediatric hematology/oncology.

[95]  Shu-xu Zhang,et al.  Comparison of SPECT/CT, MRI and CT in diagnosis of skull base bone invasion in nasopharyngeal carcinoma. , 2014, Bio-medical materials and engineering.

[96]  R. Ribeiro,et al.  Prognostic factors and long‐term outcomes of childhood nasopharyngeal carcinoma , 2011, Cancer.

[97]  T. Ciuleanu,et al.  Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study. , 2008, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[98]  Jin-Ching Lin,et al.  Comparison of the prognostic impact of serum anti-EBV antibody and plasma EBV DNA assays in nasopharyngeal carcinoma. , 2007, International journal of radiation oncology, biology, physics.

[99]  Sarbani Ghosh,et al.  Nasopharyngeal carcinoma in children: ten years' experience at the Tata Memorial Hospital, Mumbai. , 2004, International journal of radiation oncology, biology, physics.

[100]  N. Al-Rajhi,et al.  Nasopharyngeal Carcinoma in Children and Adolescents , 2000 .

[101]  K. Shanmugaratnam Histological typing of nasopharyngeal carcinoma. , 1978, IARC scientific publications.