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

General Information About Nasopharyngeal Carcinoma

Tumors of many histologies can occur in the nasopharynx, but only nasopharyngeal carcinomas (also called NPC) are covered in this summary. The American Joint Committee on Cancer nasopharynx staging refers exclusively to the World Health Organization's (WHO) classification of grades I, II, and III nasopharyngeal carcinoma.

Incidence and Mortality

Less than one person out of 100,000 is diagnosed with nasopharyngeal carcinoma in the world each year, with most cases found in southern China, Southeast Asia, the Arctic, and the Middle East/North Africa. The incidence is higher in males than in females.[1,2,3] WHO grade I nasopharyngeal carcinoma (keratinizing subtype) accounts for less than 20% of cases in the United States and WHO grades II and III represent the endemic form of nasopharyngeal carcinoma and are found mostly in Asia. Nonkeratinizing subtypes are associated with Epstein-Barr virus (EBV) infection and account for most cases.[4]

Anatomy

The nasopharynx has a cuboidal shape. The lateral walls are formed by the eustachian tube and the fossa of Rosenmuller. The roof, sloping downward from anterior to posterior, is bordered by the pharyngeal hypophysis, pharyngeal tonsil, and pharyngeal bursa with the base of the skull above. Anteriorly, the nasopharynx abuts the posterior choanae and nasal cavity, and the posterior boundary is formed by the muscles of the posterior pharyngeal wall. Inferiorly, the nasopharynx ends at an imaginary horizontal line formed by the upper surface of the soft palate and the posterior pharyngeal wall. Nasopharyngeal carcinoma originates from the epithelial cells that line the nasopharynx.

Anatomy of the pharynx.

Risk Factors

Risk factors for nasopharyngeal carcinoma include the following:[4,5,6,7,8]

Risk factors for keratinizing squamous cell carcinoma (WHO grade I):

• Heavy alcohol intake.
• History of smoking.

Risk factors for nonkeratinizing carcinoma (WHO grades II and III):

• Asian race.
• EBV exposure.
• Family history.

Clinical Features

Signs and symptoms at presentation include the following:

• Headache caused by cranial nerve dysfunction (usually II–VI or IX–XII).
• Diplopia.
• Facial numbness.
• Cervical adenopathy (present in approximately 75% of patients and often bilateral and posterior).
• Nasal obstruction.
• Epistaxis.
• Diminished hearing.
• Tinnitus.
• Otitis media.
• Sore throat.

In patients who present with cervical adenopathy alone, the finding of EBV genomic material in the tissue using polymerase chain reaction (PCR) is strong evidence of a nasopharyngeal primary tumor, and that area should be examined closely.[9]

Diagnostic Evaluation

Diagnostic tests and procedures

Diagnosis is made by biopsy of the nasopharyngeal mass. The following tests and procedures are used in the diagnosis of nasopharyngeal carcinoma:[10]

• Careful visual examination by fiberoptic nasal endoscopic examination and/or examination under anesthesia.
• Endoscopic biopsy.
• Physical examination and health history. Documentation of the size and location of the tumor and cervical lymph nodes is noted.
• Evaluation of cranial nerve function including neuro-ophthalmological evaluation and audiological evaluation.
• Computed tomography (CT) scan and/or positron emission tomography (PET)-CT scan.
• Magnetic resonance imaging (MRI) to evaluate skull base invasion.
• Circulating cancer-derived EBV DNA in plasma.[11]
• Human papillomavirus (HPV) type 16 blood test if EBV negative.

Any clinical or laboratory finding that suggests distant metastasis may prompt further evaluation of other sites. MRI is often more helpful than CT scans in assessing skull base involvement and in defining the extent of abnormalities detected.[10,12,13]

Circulating cancer-derived EBV DNA

EBV DNA in plasma samples in endemic populations may be useful in screening for early asymptomatic nasopharyngeal carcinoma. Circulating cancer-derived EBV DNA in plasma is an established tumor marker for nasopharyngeal carcinoma, with a sensitivity of 96% and a specificity of 93%.[14,15,16] The presence of short EBV DNA fragments of fewer than 181 base pairs in the plasma of nasopharyngeal carcinoma patients suggests that EBV DNA molecules are released into the circulation by apoptosis of cancer cells rather than by active viral replication.[17]

Evidence (EBV DNA in plasma for screening and diagnosis of nasopharyngeal carcinoma):

1. In a study of 20,174 participants in China, EBV DNA in plasma was used to screen for early nasopharyngeal carcinoma.[14]
   • Initially, 1,112 participants tested positive for EBV DNA in plasma.
   • Three hundred and nine participants (1.5% of all participants, and 27.8% of those who initially tested positive) had persistently detectable EBV DNA in plasma at baseline and follow-up.
   • Among the 309 participants, nasopharyngeal carcinoma was confirmed after nasal endoscopic examination, MRI, and biopsy in 34 participants (11.0%).

HPV

Differentiating HPV-related nasopharyngeal carcinoma requires identification of p16 immunohistochemical staining, in situ hybridization, and/or PCR similar to the method for differentiating HPV-related oropharyngeal cancer. Less than 10% of nonkeratinizing nasopharyngeal carcinomas are associated with HPV infection.[18,19]

Prognostic Factors

Major prognostic factors that adversely influence treatment outcome include the following:[20]

• WHO grade I.
• A higher tumor (T) stage.
• The presence of involved cervical lymph nodes (N).
• High plasma/serum EBV DNA levels before and after treatment.[21,22]
• Large tumor volume.[23][Level of evidence C1]

Follow-Up Testing and Late Effects

Follow-up testing for tumor recurrence includes the following:[24]

• Routine periodic examination of the original tumor site and neck.
• CT or PET-CT scan.
• MRI scan.
• Plasma/serum EBV DNA levels.

Patients should be monitored for the following potential late effects of treatment:[25,26]

• Xerostomia.
• Dental and oral complications.
• Hearing loss.
• Vision loss.
• Dysphagia.
• Trismus.
• Thyroid and pituitary function.
• Cranial neuropathies.
• Cognitive impairment.

Although most recurrences occur within 5 years of diagnosis, relapse can be seen at longer intervals. The incidence of second primary malignancies after treatment is lower for nasopharyngeal carcinoma than for other head and neck cancer sites.[27]

Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who have received radiation therapy that delivered external-beam radiation therapy (EBRT) to the entire thyroid gland or to the pituitary gland. Thyroid-function testing of patients should be considered before therapy and as part of posttreatment follow-up.[28,29]

Careful dental and oral hygiene evaluation and therapy is particularly important before initiation of radiation treatment. Intensity-modulated radiation therapy (IMRT) results in a lower incidence of xerostomia and may provide a better quality of life than conventional three-dimensional or two-dimensional radiation therapy (2DRT).[30,31][Level of evidence A3]

Evidence (IMRT vs. 2DRT and incidence of xerostomia):

1. A randomized prospective study assessed the incidence of xerostomia in patients with early-stage nasopharyngeal carcinoma treated with IMRT (n = 28) or 2DRT (n = 28).[32] Long-term toxicities were graded with the Radiation Therapy Oncology Group (RTOG) criteria.
   • The incidence of grade 2 xerostomia was 20% for patients who received IMRT and 90% for patients who received 2DRT (P = .001). There was no significant difference found between the groups with the xerostomia questionnaire.
   • Patients who received IMRT had lower scores for dry mouth than patients who received 2DRT.
   • The overall survival rate was 82% in the IMRT group versus 54% in the 2DRT group.
   • The relapse-free survival rate was 70% in the IMRT group versus 54% in the 2DRT group.
   • More late complications were reported among patients in the 2DRT group.
2. The phase II RTOG-0225 study tested the feasibility of IMRT in a multi-institutional setting.[33]
   • The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%.
   • The rate of grades 3 and 4 xerostomia was minimal.
     • Only 2 of 68 patients were reported with grade 3 xerostomia.
     • None of the patients had grade 4 xerostomia.

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