Childhood Nasopharyngeal Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Incidence

Nasopharyngeal carcinoma arises in the lining of the nasal cavity and pharynx, and it accounts for about one-third of all cancers of the upper airways in children.[1,2]

Nasopharyngeal carcinoma is rare in children younger than 10 years but increases in incidence to 0.5 cases per 1 million per year in children aged 10 to 14 years and 1.3 cases per million per year in children aged 15 to 19 years.[3,4,5,6]

The incidence of nasopharyngeal carcinoma is characterized by racial and geographic variations, with an endemic distribution among well-defined ethnic groups, such as inhabitants of some areas in North Africa and the Mediterranean basin, and, particularly, Southeast Asia. In the United States, the incidence of nasopharyngeal carcinoma is higher in Black children and adolescents compared with White children and adolescents.[4,5]

References:

1. Ayan I, Kaytan E, Ayan N: Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol 4 (1): 13-21, 2003.
2. 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 77 (9): 1454-60, 2013.
3. Horner MJ, Ries LA, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2006. National Cancer Institute, 2009. Also available online. Last accessed December 22, 2022.
4. Sultan I, Casanova M, Ferrari A, et al.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 55 (2): 279-84, 2010.
5. Richards MK, Dahl JP, Gow K, et al.: Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. JAMA Otolaryngol Head Neck Surg 142 (3): 217-22, 2016.
6. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 6, 2022.

Risk Factors

Nasopharyngeal carcinoma is strongly associated with Epstein-Barr virus (EBV) infection. In addition to the serological evidence of infection in more than 98% of patients, EBV DNA is present as a monoclonal episome in the nasopharyngeal carcinoma cells, and tumor cells can have EBV antigens on their cell surface.[1] The circulating levels of EBV DNA and serologic documentation of EBV infection may aid in the diagnosis.[2] Specific HLA subtypes, such as the HLA A2Bsin2 haplotype, are associated with a higher risk of nasopharyngeal carcinoma.[3]

References:

1. Dawson CW, Port RJ, Young LS: The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol 22 (2): 144-53, 2012.
2. Lo YM, Chan LY, Lo KW, et al.: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59 (6): 1188-91, 1999.
3. Ayan I, Kaytan E, Ayan N: Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol 4 (1): 13-21, 2003.

Histology

Three histologic subtypes of nasopharyngeal carcinoma are recognized by the World Health Organization (WHO):

• Type I: Keratinizing squamous cell carcinoma.
• Type II: Nonkeratinizing squamous cell carcinoma. Type II is further defined by the presence or absence of lymphoid infiltration as type IIa or IIb, respectively.
• Type III: Undifferentiated carcinoma. Type III is further defined by the presence or absence of lymphoid infiltration as type IIIa or IIIb, respectively.

Children with nasopharyngeal carcinoma are more likely to have WHO type II or type III disease.[1,2]

References:

1. Sultan I, Casanova M, Ferrari A, et al.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 55 (2): 279-84, 2010.
2. Richards MK, Dahl JP, Gow K, et al.: Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. JAMA Otolaryngol Head Neck Surg 142 (3): 217-22, 2016.

Clinical Presentation

Signs and symptoms of nasopharyngeal carcinoma include the following:[1,2]

• Cervical lymphadenopathy.
• Nosebleeds.
• Nasal congestion and obstruction.
• Headache.
• Otalgia.
• Otitis media.

Given the rich lymphatic drainage of the nasopharynx, bilateral cervical lymphadenopathy is often the first sign of disease. The tumor spreads locally to adjacent areas of the oropharynx and may invade the skull base, resulting in cranial nerve palsy or difficulty with movements of the jaw (trismus).

Distant metastatic sites may include the bones, lungs, and liver.

References:

1. 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 77 (9): 1454-60, 2013.
2. Hu S, Xu X, Xu J, et al.: Prognostic factors and long-term outcomes of nasopharyngeal carcinoma in children and adolescents. Pediatr Blood Cancer 60 (7): 1122-7, 2013.

Diagnostic and Staging Evaluation

Diagnostic tests will determine the extent of the primary tumor and the presence of metastases. Visualization of the nasopharynx by an otolaryngologist using nasal endoscopy and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor.

A diagnosis can be made from a biopsy of the primary tumor or enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin lymphoma including Burkitt lymphoma, and Hodgkin lymphoma must be considered, as well as benign conditions such as nasal angiofibroma, which usually presents with epistaxis in adolescent males, infectious lymphadenitis, and Rosai-Dorfman disease.

Evaluation of the chest and abdomen by computed tomography (CT) and bone scan is performed to determine whether there is metastatic disease. Fluorine F 18-fludeoxyglucose positron emission tomography (PET)–CT may also be helpful in the evaluation of potential metastatic lesions.[1]

References:

1. Cheuk DK, Sabin ND, Hossain M, et al.: PET/CT for staging and follow-up of pediatric nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging 39 (7): 1097-106, 2012.

Genomics of Childhood Nasopharyngeal Carcinoma

Four tertiary academic medical centers in China studied 30 patients (25 male and 5 female) with pathologically confirmed nasopharyngeal carcinoma who were younger than 20 years.[1] Nasopharyngeal primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Several genes such as SHOC1 (formerly known as C9orf84) (20%), ZFHX4 (16.7%), ZC3H6 (16.7%), and RBM38 (16.7%) were frequently mutated in nasopharyngeal carcinoma. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3%) and losses of TOLLIP at 11p15.5 (20%). Recurrent NUTM1 (16.7%) fusion variants were found for the first time in nasopharyngeal carcinoma. The study also showed that 8 of 30 patients (26.7%) with nasopharyngeal carcinoma carried germline pathogenic and/or likely pathogenic variants in known cancer predisposition genes.

References:

1. Wu B, Shen L, Peng G, et al.: Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing. Oral Oncol 135: 106218, 2022.

Stage Information for Childhood Nasopharyngeal Carcinoma

Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC).[1,2]

The AJCC has designated staging by TNM classification to define nasopharyngeal carcinoma.[3]

Table 1. Definition of TNM Stage 0^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
0	Tis, N0, M0	Tis = Carcinomain situ.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 2. Definition of TNM Stage I^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
I	T1, N0, M0	T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 3. Definition of TNM Stage II^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
a Reprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
II	T0, Tis, T1, N1, M0	T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
		Tis = Carcinomain situ.
		T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
		N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	T2, N0, M0	T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.
	T2, N1, M0	T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
		N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.

Table 4. Definition of TNM Stage III^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
a Reprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
III	T0, Tis, T1, N2, M0	T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
		Tis = Carcinomain situ.
		T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
		N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	T2, N2, M0	T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
		N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	T3, N0, M0	T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.
	T3, N1, M0	T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
		N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	T3, N2, M0	T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
		N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.

Table 5. Definition of TNM Stages IVA and IVB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
a Reprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
IVA	T4, N0, M0	T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.
	T4, N1, M0	T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
		N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	T4, N2, M0	T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
		N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
	Any T, N3, M0	TX = Primary tumor cannot be assessed.
		T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
		Tis = Carcinomain situ.
		T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
		T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
		T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
		T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
		N3 = Unilateral or bilateral metastasis in cervical lymph node(s), >6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage.
		M0 = No distant metastasis.
IVB	Any T, Any N, M1	Any T = See Stage IVA above.
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastasis.
		N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
		N3 = Unilateral or bilateral metastasis in cervical lymph node(s), >6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage.
		M1 = Distant metastasis.

More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[4,5] Population-based studies have reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did adult patients.[6,7] However, less than 10% of children and adolescents with nasopharyngeal carcinoma presented with distant metastases at diagnosis.[4,5,8]

References:

1. Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
2. Lee AWM, Lydiatt WM, Colevas AD, et al.: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 103-11.
3. Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 103–11.
4. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011.
5. Casanova M, Bisogno G, Gandola L, et al.: A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer 118 (10): 2718-25, 2012.
6. Sultan I, Casanova M, Ferrari A, et al.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 55 (2): 279-84, 2010.
7. Richards MK, Dahl JP, Gow K, et al.: Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. JAMA Otolaryngol Head Neck Surg 142 (3): 217-22, 2016.
8. Buehrlen M, Zwaan CM, Granzen B, et al.: Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer 118 (19): 4892-900, 2012.

Prognosis

The overall survival of children and adolescents with nasopharyngeal carcinoma has improved over the last four decades; with state-of-the-art multimodal treatment, 5-year survival rates exceed 80%.[1,2,3,4,5,6,7,8] After controlling for stage, children with nasopharyngeal carcinoma have significantly better outcomes than do adults.[1,7] However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities, including subsequent neoplasms.[1,2,3,6]

References:

1. Sultan I, Casanova M, Ferrari A, et al.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 55 (2): 279-84, 2010.
2. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011.
3. Casanova M, Bisogno G, Gandola L, et al.: A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer 118 (10): 2718-25, 2012.
4. Buehrlen M, Zwaan CM, Granzen B, et al.: Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer 118 (19): 4892-900, 2012.
5. Hu S, Xu X, Xu J, et al.: Prognostic factors and long-term outcomes of nasopharyngeal carcinoma in children and adolescents. Pediatr Blood Cancer 60 (7): 1122-7, 2013.
6. Sahai P, Mohanti BK, Sharma A, et al.: Clinical outcome and morbidity in pediatric patients with nasopharyngeal cancer treated with chemoradiotherapy. Pediatr Blood Cancer 64 (2): 259-266, 2017.
7. Richards MK, Dahl JP, Gow K, et al.: Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. JAMA Otolaryngol Head Neck Surg 142 (3): 217-22, 2016.
8. Gioacchini FM, Tulli M, Kaleci S, et al.: Prognostic aspects in the treatment of juvenile nasopharyngeal carcinoma: a systematic review. Eur Arch Otorhinolaryngol 274 (3): 1205-1214, 2017.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

For information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group (COG) defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers, colorectal cancers, etc.).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]

  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of the cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Nasopharyngeal Cancer Treatment.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed December 8, 2022.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 6, 2022.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 13, 2023.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Treatment of Newly Diagnosed Childhood Nasopharyngeal Carcinoma

The European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project (Paediatric Rare Tumours Network–European Registry) have published comprehensive recommendations for the diagnosis and treatment of nasopharyngeal carcinoma in children and adolescents.[1]

Treatment of nasopharyngeal carcinoma is multimodal and includes the following:

1. Combined-modality therapy with chemotherapy and radiation. High-dose radiation therapy alone has a role in the management of nasopharyngeal carcinoma; however, studies in both children and adults show that combined-modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.
   1. Several studies have investigated the role of chemotherapy in the treatment of adult nasopharyngeal carcinoma. The use of concomitant chemoradiation therapy has been consistently associated with a significant survival benefit, including improved locoregional disease control and reduction in distant metastases.[2,3,4] The addition of neoadjuvant chemotherapy to concomitant chemoradiation has further improved outcomes, whereas the impact of adjuvant chemotherapy is less defined.[3,4]
   2. In children, most studies have used neoadjuvant chemotherapy with cisplatin and fluorouracil (5-FU) followed by concomitant chemoradiation with single-agent cisplatin.[5,6,7][Level of evidence B4] Using this approach, 5-year overall survival (OS) rate estimates are consistently above 80%.[6,7]

      The following two modifications of this approach have been investigated:

      • The NPC-2003-GPOH study included a 6-month maintenance therapy phase with interferon-beta, and reported a 30-month OS rate estimate of 97.1%.[6]
      • A randomized prospective trial compared cisplatin and 5-FU with cisplatin, 5-FU, and docetaxel.[7][Level of evidence A1] The addition of docetaxel was not associated with improved outcome.
   3. While nasopharyngeal carcinoma is a very chemosensitive neoplasm, high radiation doses to the nasopharynx and neck (approximately 65–70 Gy) are required for optimal locoregional control.[2,3,4] However, in children, studies using neoadjuvant chemotherapy have shown that it is possible to reduce the radiation dose to 55 Gy or 60 Gy for good responders.[5,6]
   4. The Children's Oncology Group performed a prospective trial to evaluate the impact of induction chemotherapy and concurrent chemoradiation therapy.[8] Patients were scheduled to receive three cycles of induction chemotherapy with cisplatin and 5-FU, followed by chemoradiation therapy with three cycles of cisplatin. Patients with complete or partial responses to induction chemotherapy received 61.2 Gy of radiation to the nasopharynx and neck, and patients with stable disease received 71.2 Gy of radiation. After a feasibility analysis, the study was amended to reduce cisplatin to two cycles during chemoradiation therapy.
      • The 5-year event-free survival (EFS) rate estimate was 84.3%, and the OS rate estimate was 89.2%.
      • The 5-year EFS rates were 100% for patients with stage IIb disease, 82.8% for patients with stage III disease, and 82.7% for patients with stage IV disease.
      • The 5-year cumulative incidence estimates of local, distant, and combined relapses were 3.7%, 8.7%, and 1.8%, respectively.
      • Patients who were treated with three chemoradiation therapy cycles of cisplatin were observed to have higher 5-year postinduction EFS rates than patients who were treated with two cycles, although the difference was not statistically significant (90.7% vs. 81.2%; P = .14).
   5. The combination of cisplatin-based chemotherapy and high doses of radiation therapy to the nasopharynx and neck are associated with a high probability of hearing loss, hypothyroidism and panhypopituitarism, trismus, xerostomia, dental problems, and chronic sinusitis or otitis.[5,9,10]; [11][Level of evidence C1] The use of proton radiation therapy may reduce the toxicity to the brain and skull base region without compromising disease control.[12] For more information, see Late Effects of Treatment for Childhood Cancer.
   6. In a group of 549 pediatric patients with nasopharyngeal carcinoma diagnosed between 2005 and 2021, recursive partitioning was performed based on stage and Epstein-Barr virus (EBV) viral load. This resulted in three groups of patients: low-risk patients, intermediate-risk patients, and high-risk patients.[13]
      • Intermediate-risk patients (stage IVa nasopharyngeal carcinoma and <4,000 copies/mL of EBV) had significant responses with induction chemotherapy followed by concurrent chemotherapy and radiation therapy. These patients had significantly improved progression-free survival and distant metastases‒free survival rates when compared with intermediate-risk patients who only received concurrent chemotherapy and radiation therapy.
      • In contrast, there were no significant differences between these two treatment regimens in low-risk and high-risk patients.
2. Surgery. Surgery has a limited role in the management of nasopharyngeal carcinoma; the disease is usually considered unresectable because of extensive local spread.

References:

1. Ben-Ami T, Kontny U, Surun A, et al.: Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations. Pediatr Blood Cancer 68 (Suppl 4): e29018, 2021.
2. Langendijk JA, Leemans ChR, Buter J, et al.: The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol 22 (22): 4604-12, 2004.
3. Yan M, Kumachev A, Siu LL, et al.: Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: A Bayesian network meta-analysis. Eur J Cancer 51 (12): 1570-9, 2015.
4. Ribassin-Majed L, Marguet S, Lee AWM, et al.: What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis. J Clin Oncol 35 (5): 498-505, 2017.
5. Casanova M, Bisogno G, Gandola L, et al.: A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer 118 (10): 2718-25, 2012.
6. Buehrlen M, Zwaan CM, Granzen B, et al.: Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer 118 (19): 4892-900, 2012.
7. Casanova M, Özyar E, Patte C, 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. Cancer Chemother Pharmacol 77 (2): 289-98, 2016.
8. Rodriguez-Galindo C, Krailo MD, Krasin MJ, et al.: Treatment of Childhood Nasopharyngeal Carcinoma With Induction Chemotherapy and Concurrent Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study. J Clin Oncol 37 (35): 3369-3376, 2019.
9. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011.
10. Sahai P, Mohanti BK, Sharma A, et al.: Clinical outcome and morbidity in pediatric patients with nasopharyngeal cancer treated with chemoradiotherapy. Pediatr Blood Cancer 64 (2): 259-266, 2017.
11. Hu S, Xu X, Xu J, et al.: Prognostic factors and long-term outcomes of nasopharyngeal carcinoma in children and adolescents. Pediatr Blood Cancer 60 (7): 1122-7, 2013.
12. Uezono H, Indelicato DJ, Rotondo RL, et al.: Proton therapy following induction chemotherapy for pediatric and adolescent nasopharyngeal carcinoma. Pediatr Blood Cancer 66 (12): e27990, 2019.
13. Liang YJ, Wen DX, Luo MJ, et al.: Induction or adjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in paediatric nasopharyngeal carcinoma in the IMRT era: A recursive partitioning risk stratification analysis based on EBV DNA. Eur J Cancer 159: 133-143, 2021.

Treatment of Relapsed or Refractory Childhood Nasopharyngeal Carcinoma

The outcome of patients with relapsed nasopharyngeal carcinoma is poor, and most patients present with distant metastases. However, long-term remissions can be achieved with conventional chemotherapy. In a retrospective review of 14 pediatric patients with relapsed nasopharyngeal carcinoma who were treated with varying chemotherapy regimens, the 3-year event-free survival rate was 34%, and the overall survival rate was 44%.[1]

Given the unique pathogenesis of nasopharyngeal carcinoma, immunotherapy has been explored for patients with refractory disease, as follows:

• The use of Epstein-Barr virus (EBV)–specific cytotoxic T-lymphocyte therapy has shown to be a very promising approach with minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.[2] In a phase I/II study of EBV-specific cytotoxic T-lymphocyte therapy in patients with refractory disease, response rates were observed in 33.3% of patients, and long-term remissions were obtained in 62% of patients treated in their second or subsequent remission.[3]
• Anti–programmed death-ligand 1 (PD-L1) monoclonal antibodies have been studied in two phase II trials in adults with refractory nasopharyngeal carcinoma. Response rates of 20.5% to 25.9% (33% in patients with PD-L1–positive tumors) and evidence of long-term remissions were observed.[4,5]

References:

1. DeRenzo C, Lam C, Rodriguez-Galindo C, et al.: Salvage regimens for pediatric patients with relapsed nasopharyngeal carcinoma. Pediatr Blood Cancer 66 (1): e27469, 2019.
2. Straathof KC, Bollard CM, Popat U, et al.: Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. Blood 105 (5): 1898-904, 2005.
3. 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 33 (9): 983-90, 2010 Nov-Dec.
4. Hsu C, Lee SH, Ejadi S, et al.: Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol 35 (36): 4050-4056, 2017.
5. Ma BBY, Lim WT, Goh BC, et al.: Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol 36 (14): 1412-1418, 2018.

Treatment Options Under Clinical Evaluation for Childhood Nasopharyngeal Carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.

  Patients with tumors that have molecular variants addressed by open treatment arms in the trial may be enrolled in treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Changes to This Summary (03 / 30 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence

Revised text to state that nasopharyngeal carcinoma is rare in children younger than 10 years but increases in incidence to 0.5 cases per 1 million per year in children aged 10 to 14 years and 1.3 cases per million per year in children aged 15 to 19 years (cited National Cancer Institute as reference 6).

Genomics of Childhood Nasopharyngeal Carcinoma

Added this new section.

Stage Information for Childhood Nasopharyngeal Carcinoma

This section was extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood nasopharyngeal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Nasopharyngeal Cancer Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• William H. Meyer, MD (University of Oklahoma Health Sciences Center)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Nasopharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/child/nasopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 29320137]

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Last Revised: 2023-03-30