Subscribe to RSS
DOI: 10.1055/s-0041-111180
Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents – Recommendations of the GPOH-NPC Study Group
Diagnose und Behandlung des Nasopharynxkarzinoms bei Kindern und Jugendlichen – Empfehlungen der GPOH-NPC StudiengruppePublication History
Publication Date:
02 May 2016 (online)
![](https://www.thieme-connect.de/media/klinpaed/201603/lookinside/thumbnails/0855_10-1055-s-0041-111180-1.jpg)
Abstract
Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55–59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5–10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.
Zusammenfassung
Das Nasopharynxkarzinom (NPC) ist ein seltener maligner Tumor, der aus Epithelzellen des Nasopharynx hervorgeht. Der Tumor tritt am häufigsten in Südostasien auf und zeigt einen Altersgipfel in der Adoleszenz und einen zweiten im Alter zwischen 55–59 Jahren. Dem Epstein-Barr-Virus (EBV) kommt eine Schlüsselfunktion bei der Entstehung des NPC zu, dazu kommen Umweltfaktoren, wie die Aufnahme Nitrosamin-haltiger Speisen und bestimmte genetische Polymorphismen. Bei Erstdiagnose sind bis zu 90% der Tumoren bereits lymphogen metastasiert, bei 5–10% lassen sich Fernmetastasen feststellen. Die Diagnose des NPC erfolgt histologisch und wird durch eine abnorme IgA-Immunantwort gegen EBV-VCA und den Nachweis einer hohen Plasma EBV-DNA-Last gestützt. Die besten Behandlungsergebnisse bei Kindern und Jugendlichen mit fortgeschrittenem lokoregionären Befall, mit Gesamt- und Ereignis-freien Überlebensraten>90% wurden durch eine neoadjuvante Chemotherapie, gefolgt von einer Radiochemotherapie und anschließender Erhaltungstherapie mit Interferon-ß erreicht, wie in den GPOH-Studien NPC-91 und 2003 dargestellt. Da der Großteil von Spätkomplikationen wie Xerostomie und Haut- und Gewebsfibrose auf hohe Strahlendosen zurückzuführen ist, sollten bei der Strahlentherapie Verfahren wie die Intensitäts-modulierte Strahlentherapie eingesetzt werden, um die Streustrahlung auf gesundes Gewebe in der Tumorumgebung zu minimieren. Die Heilungsaussichten für Patienten mit Fernmetastasen und einem Rezidiv sind gering. Hier sollten neue Behandlungsverfahren wie die Gabe EBV-spezifischer T-Zellen zur Anwendung kommen.
-
References
- 1 Afquir S, Alaoui K, Ismaili N et al. Nasopharyngeal carcinoma in adolescents: a retrospective review of 42 patients. Eur Arch Otorhinolaryngol 2009; 266: 1767-1773
- 2 Altun M, Fandi A, Dupuis O et al. Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects. Int J Radiat Oncol Biol Phys 1995; 32: 859-877
- 3 Ayan I, Kaytan E, Ayan N. Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol 2003; 4: 13-21
- 4 Baujat B, Audry H, Bourhis J et al. Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma. Cochrane Database Syst Rev 2006; 4: 13-21
- 5 Brennan B. Nasopharyngeal carcinoma. Orphanet J Rare Dis 2006; 1: 23
- 6 Buehrlen M, Zwaan C, Granzen B et al. Multimodal Treatment, Including Interferon Beta, of Nasopharyngeal Carcinoma in Children and Young Adults. Cancer 2012; 118: 4892-4900
- 7 Casanova M, Bisogno G, Gandola L et al. A Prospective Protocol for Nasopharyngeal Carcinoma in Children and Adolescents. Cancer 2012; 118: 2718-2725
- 8 Caudle KE, Thorn CF, Klein TE et al. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013; 94: 640-645
- 9 Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006; 15: 1765-1777
- 10 Cheuk DKL, Billups CA, Martin MG et al. Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 2011; 117: 197-206
- 11 Chia WK, Teo M, Wang WW et al. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 2014; 22: 132-139
- 12 Ghim TT, Briones M, Mason P et al. Effective adjuvant chemotherapy for advanced nasopharyngeal carcinoma in children: a final update of a long-term prospective study in a single institution. J Pediatr Hematol Oncol 1998; 20: 131-135
- 13 Guo Q, Cui X, Lin S et al. Locoregionally advanced nasopharyngeal carcinoma in childhood and adolescence: Analysis of 95 patients treated with combined chemotherapy and intensity-modulated radiotherapy. Head Neck 2015; Apr 13. Epub ahead of print
- 14 Guo X, Johnson RC, Deng H et al. Evaluation of nonviral risk factors for nasopharyngeal carcinoma in a high-risk population of Southern China. Int J Cancer 2009; 124: 2942-2947
- 15 Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014; 89: 292-302
- 16 Ihrler S, Guntinas-Lichius O, Mollenhauer M. The visionary concept of “lymphoepithelioma” by A. Schmincke in 1921. Subsequent confusion over terminology and current approach to a solution. Pathologe 2014; 35: 143-151
- 17 Kaatsch P, Spix C. German Childhood Cancer Registry – Report 2013/14 (1980-2013). Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz 2014
- 18 Kam MK, Leung SF, Zee B et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007; 25: 4873-4879
- 19 Krueger GRF, Wustrow J. Current classification of nasopharyngeal carcinoma at Cologne University. In: Grundmann E, Krueger GRF, Ablashi DV. (eds.) Nasopharyngeal carcinoma. vol 5. Stuttgart, New York: Gustav Fischer Verlag; 1981: 11-15
- 20 Chua DT, Sham JS, Kwong DL et al. Treatment outcome after radiotherapy alone for patients with Stage I-II nasopharyngeal carcinoma. Cancer 2003; 98: 74-80
- 21 Lee AW, Tung SY, Chua DT et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2010; 102: 1188-1198
- 22 Liao XB, Mao YP, Liu LZ et al. How does magnetic resonance imaging influence staging according to AJCC staging system for nasopharyngeal carcinoma compared with computed tomography?. Int J Radiat Oncol Biol Phys 2008; 72: 1368-1377
- 23 Lin DC, Meng X, Hazawa M et al. The genomic landscape of nasopharyngeal carcinoma. Nat Genet 2014; 46: 866-871
- 24 Lo AK, Dawson CW, Jin DY et al. The pathological roles of BART miRNAs in nasopharyngeal carcinoma. J Pathol 2012; 227: 392-403
- 25 Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell 2004; 5: 423-428
- 26 Lo YM, Chan LY, Chan AT et al. Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res 1999; 59: 5452-5455
- 27 Louis CU, Straathof K, Bollard CM et al. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother 2010; 33: 983-990
- 28 McKibbin T, Cheng LL, Kim S et al. Mannitol to prevent cisplatin-induced nephrotoxicity in patients with squamous cell cancer of the head and neck (SCCHN) receiving concurrent therapy. Support Care Cancer 2015; Oct 7. [Epub ahead of print]
- 29 Mertens R, Granzen B, Lassay L et al. Treatment of nasopharyngeal carcinoma in children and adolescents. Definitive results of a multicenter study (NPC-91-GPOH). Cancer 2005; 104: 1083-1089
- 30 Morgan KP, Snavely AC, Wind LS et al. Rates of renal toxicity in cancer patients receiving cisplatin with and without mannitol. Ann Pharmacother 2014; 48: 863-869
- 31 Moumad K, Lascorz J, Bevier M et al. Genetic polymorphisms in host innate immune sensor genes and the risk of nasopharyngeal carcinoma in North Africa. G3 (Bethesda) 2013; 3: 971-977
- 32 National Cancer Institute. Stage Information for nasopharyngeal cancer. Available from http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/HealthProfessional/page3 Accessed January 30, 2011
- 33 National Cancer Intelligence Network. Rare and less common cancers: incidence and mortality in England 2010–2013 (June 2015). Available from http://www.ncin.org.uk/publications/reports
- 34 Orbach D, Brisse H, Helfre S et al. Radiation and chemotherapy combination for nasopharyngeal carcinoma in children: Radiotherapy dose adaptation after chemotherapy response to minimize late effects. Pediatr Blood Cancer 2008; 50: 849-853
- 35 Ozyar E, Selek U, Laskar S et al. Treatment results of 165 pediatric patients with non-metastatic nasopharyngeal carcinoma: a Rare Cancer Network study. Radiother Oncol 2006; 81: 39-46
- 36 Pow EH, Kwong DL, McMillan X et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006; 66: 981-991
- 37 Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 1986; 47: 883-889
- 38 Regaud C, Reverchon L. Sur un cas d`epithelioma épidermoide développé dans le massif maxillaire superior, étendu aux teguments de la face, aux cavités buccale, nasale et orbitaire. Rev de laryng 1921; 42: 369-378
- 39 Robbins KT, Clayman G, Levine PA et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery. Arch Otolaryngol Head Neck Surg 2002; 128: 751-758
- 40 Rodriguez-Galindo C, Wofford M, Castleberry RP et al. Preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma. Cancer 2005; 103: 850-857
- 41 Saleh-Ebrahimi L, Zwicker F, Muenter MW et al. Intensity modulated radiotherapy (IMRT) combined with concurrent but not adjuvant chemotherapy in primary nasopharyngeal cancer – a retrospective single center analysis. Radiat Oncol 2013; 8: 20
- 42 Santoso JT, Lucci JA, Coleman RL et al. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol 2003; 52: 13-18
- 43 Serin M, Erkal HS, Elhan AH et al. Nasopharyngeal carcinoma in childhood and adolescence. Med Pediatr Oncol 1998; 31: 498-505
- 44 Sham JS, Poon YF, Wei WI et al. Nasopharyngeal carcinoma in young patients. Cancer 1990; 65: 2606-2610
- 45 Smith C, Tsang J, Beagley L et al. Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res 2012; 72: 1116-1125
- 46 Song T, Fang M, Zhang XB et al. Sustained improvement of quality of life for nasopharyngeal carcinoma treated by intensity modulated radiation therapy in long-term survivors. Int J. Clin Exp Med 2015; 8: 5658-5666
- 47 Su WH, Hildesheim A, Chang YS. Human leukocyte antigens and Epstein-Barr virus-associated nasopharyngeal carcinoma: old associations offer new clues into the role of immunity in infection-associated cancers. Front Oncol 2013; 3: 299
- 48 Tao CJ, Liu X, Tang LL et al. Long-term outcome and late toxicities of simultaneous integrated boost-intensity modulated radiotherapy in pediatric and adolescent nasopharyngeal carcinoma. Chin J Cancer 2013; 32: 525-532
- 49 Toh HC, Chia WK, Sun L et al. Graft-vs.-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation. Bone Marrow Transplantation 2011; 46: 573-579
- 50 Treuner J, Niethammer D, Dannecker G et al. Successful Treatment of Nasopharyngeal Carcinoma with Interferon. Lancet 1980; 12: 817-818
- 51 Tsai MH, Raykova A, Klinke O et al. Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas. Cell Reports 2013; 5: 458-470
- 52 Tsao SW, Tsang CM, To KF et al. The role of Epstein-Barr virus in epithelial malignancies. J Pathol 2015; 235: 323-333
- 53 Wolff HA, Rödel RM, Gunawan B et al. Nasopharyngeal carcinoma in adults: treatment results after long-term follow-up with special reference to adjuvant interferon-beta in undifferentiated carcinomas. J Cancer Res Clin Oncol 2010; 136: 89-97
- 54 Xie P, Yue JB, Fu Z et al. Prognostic value of 18F-FDG PET/CT before and after radiotherapy for locally advanced nasopharyngeal carcinoma. Ann Oncol 2010; 21: 1078-1082
- 55 Yan Z, Xia L, Huang Y et al. Nasopharyngeal carcinoma in children and adolescents in an endemic area: A report of 185 cases. Int J Pediatr Otorhinolaryngol 2013; 77: 1454-1460
- 56 Yeh SA, Tang Y, Lui CC et al. Treatment outcomes and late complications of 849 patients with nasopharyngeal carcinoma treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 2005; 62: 672-679
- 57 Zeng Y, Zhang LG, Wu YC et al. Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int J Cancer 1985; 36: 545-547
- 58 Zong YS, Sham JS, Ng MH et al. Immunoglobulin A against viral capsid antigen of Epstein-Barr virus and indirect mirror examination of the nasopharynx in the detection of asymptomatic nasopharyngeal carcinoma. Cancer 1992; 69: 3-7
- 59 Zubarreta P, D`Antonio G, Gallo G et al. Nasopharyngeal carcinoma in childhood and adolescence: A single-institution experience with combined therapy. Cancer 2000; 89: 690-695