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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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).

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 very uncommon in children younger than 10 years but increases in incidence to 0.8 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.[3-5]

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 younger than 20 years.[4,5]

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]

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 distinguished by the presence of lymphoid infiltration as type IIa or IIb.
• Type III—undifferentiated carcinoma. Type III is distinguished by the presence of lymphoid infiltration as type IIIa or IIIb.

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

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.

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]

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.[1,2]

More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[3,4] Population-based studies have reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did adult patients.[5,6] However, less than 10% of children and adolescents with nasopharyngeal carcinoma presented with distant metastases at diagnosis.[3,4,7]

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%.[1-8] 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.[1-3,6]

Treatment of Newly Diagnosed Childhood Nasopharyngeal Carcinoma

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.[1-3] The addition of neoadjuvant chemotherapy to concomitant chemoradiation has further improved outcomes, whereas the impact of adjuvant chemotherapy is less defined.[2,3]
   2. In children, most studies have used neoadjuvant chemotherapy with cisplatin and fluorouracil (5-FU) followed by concomitant chemoradiation with single-agent cisplatin.[4-6][Level of evidence: 2A] Using this approach, 5-year overall survival (OS) estimates are consistently above 80%.[5,6]
      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 estimate of 97.1%.[5]
      • A randomized prospective trial compared cisplatin and 5-FU with cisplatin, 5-FU, and docetaxel.[6][Level of evidence: 1iiA] 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.[1-3] 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.[4,5]
   4. The Children's Oncology Group performed a prospective trial to evaluate the impact of induction chemotherapy and concurrent chemoradiation therapy.[7] 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 versus two chemoradiation therapy cycles of cisplatin had improved 5-year postinduction EFS rates (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.[4,8,9]; [10][Level of evidence: 3iiiA] The use of proton radiation therapy may reduce the toxicity to the brain and skull base region without compromising disease control.[11] (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
2. Surgery. Surgery has a limited role in the management of nasopharyngeal carcinoma; the disease is usually considered unresectable because of extensive local spread.

Treatment of 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 was 34%, and the overall survival 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, with response rates of 20.5% to 25.9% (33% in patients with PD-L1–positive tumors) and evidence of long-term remissions.[4,5]

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, refer to 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer 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 for children and adolescents with cancer. 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.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[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 in these trials 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 therapy that is currently accepted as standard. 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 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and they are estimated to account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP]) defines a pediatric rare tumor as one with an incidence of less than two cases per 1 million population per year and is not included in other clinical trials.[7]
• The Children's Oncology Group has opted to define rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
  Most cancers within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low incidence 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 the PDQ summary on Nasopharyngeal Cancer Treatment (Adult).

Changes to This Summary (01/31/2020)

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.

Treatment of Newly Diagnosed Childhood Nasopharyngeal Carcinoma

Added text about the results of a Children's Oncology Group prospective trial that evaluated the impact of induction chemotherapy and concurrent chemoradiation therapy (cited Rodriguez-Galindo et al. as reference 7).

Added text to state that the use of proton radiation therapy may reduce the toxicity to the brain and skull base region without compromising disease control (cited Uezono et al. as reference 11).

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary