Purpose of This PDQ Summary
General Information About Nasopharyngeal Cancer

Anatomy Risk Factors Signs and Symptoms Diagnostic Tests Prognosis Follow-up

Cellular Classification of Nasopharyngeal Cancer
Stage Information for Nasopharyngeal Cancer

TNM Definitions AJCC Stage Groupings

Treatment Option Overview
Stage I Nasopharyngeal Cancer

Current Clinical Trials

Stage II Nasopharyngeal Cancer

Current Clinical Trials

Stage III Nasopharyngeal Cancer

Current Clinical Trials

Stage IV Nasopharyngeal Cancer

Current Clinical Trials

Recurrent Nasopharyngeal Cancer

Current Clinical Trials

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Changes to This Summary (07/09/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of nasopharyngeal cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Risk factors and signs and symptoms.
• Prognostic factors, diagnostic tests, and follow-up.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the 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 Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information About Nasopharyngeal Cancer

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.

Unlike other squamous cell cancers of the head and neck, nasopharyngeal cancer does not appear to be linked to excess use of tobacco and alcohol. Factors thought to predispose to this tumor include:

• Chinese (or Asian) ancestry.[1]
• Epstein-Barr virus (EBV) exposure.
• Unknown factors that result in very rare familial clusters.[2]

Symptoms and signs at presentation include:

• Painless, enlarged lymph nodes in the neck (present in approximately 75% of patients and often bilateral and posterior).
• Nasal obstruction.
• Epistaxis.
• Diminished hearing.
• Tinnitus.
• Recurrent otitis media.
• Cranial nerve dysfunction (usually II–VI or IX–XII).
• Sore throat.
• Headache.

In the patient who presents with only cervical adenopathy, the finding of EBV genomic material in the tissue after amplification of DNA with the polymerase chain reaction lends strong evidence for a nasopharyngeal primary tumor, and a concerted search should be conducted in that area.[3]

Diagnosis is made by biopsy of the nasopharyngeal mass. Workup includes: [4]

• Careful visual examination (by mirror or endoscopic examination).
• Documentation of the size and location of the tumor and neck nodes.
• Evaluation of cranial nerve function and hearing.
• Skull films (especially base-of-skull views) evaluating neural foramina.
• Complete computed tomographic (CT) scan or magnetic resonance imaging (MRI) with views delineating the upper and lower extent of the lesion.
• Chest x-ray.
• Hemogram.
• Chemistry panel.

Any clinical or laboratory suggestion of distant metastasis may prompt further evaluation of other sites. Careful dental and oral hygiene evaluation and therapy is particularly important prior to initiation of radiation treatment. MRI is often more helpful than CT scans in detecting abnormalities and in defining their extent.[4-6]

Major prognostic factors adversely influencing outcome of treatment include:[7]

• Large tumor size.
• A higher tumor (T) stage.
• The presence of involved neck nodes.

Other factors linked to diminished survival that were present in some, but not all, studies include:

• Age.
• Nonlymphoepithelial histology.
• Long interval between biopsy and initiation of radiation therapy.
• Diminished immune function at diagnosis.
• Incomplete excision of involved neck nodes.
• Pregnancy during treatment.
• Locoregional relapse.
• Certain EBV antibody titer patterns.

Small cancers of the nasopharynx are highly curable by radiation therapy, and patients with these small cancers have shown survival rates of 80% to 90%.[8]

Moderately advanced lesions without clinical evidence of spread to cervical lymph nodes are often curable, and patients with these lesions have shown survival rates of 50% to 70%.

Patients with advanced lesions, especially those associated with clinically positive cervical lymph nodes, cranial nerve involvement, and bone destruction have disease that is poorly controlled locally by radiation therapy with or without surgery, and the lesions often develop distant metastases despite local control.[9,10]

Follow-up for patients includes:

• Routine periodic examination of the original tumor site and neck.
• Chest x-ray.
• MRI or CT scan.
• Blood work.

Positron emission tomography scans may be useful in planning treatment for patients with suspected recurrence.[11] Monitoring of patients should include:

• Surveillance of thyroid and pituitary function.
• Dental and oral hygiene.
• Jaw exercises to avoid trismus.
• Evaluation of cranial nerve function, especially as it relates to vision and hearing.
• Evaluation of systemic complaints to identify distant metastasis.

Although most recurrences occur within 5 years of diagnosis, relapse can be seen at longer intervals. The incidence of second primary malignancies is less than after treatment of tumors at other head and neck sites.[12]

Poorly differentiated squamous cell cancer has been associated with EBV antibodies.[3,13] High-titer antibodies to virus capsid antigen and early antigen, especially of high IgA class, or high titers that persist after therapy, have been associated with a poorer prognosis.[14] This finding remains under evaluation.

Tumors of many histologies can occur in the nasopharynx, but this discussion, like the American Joint Committee on Cancer nasopharynx staging, refers exclusively to squamous cell types of tumors.

References

1. Chien YC, Chen JY, Liu MY, et al.: Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345 (26): 1877-82, 2001.  [PUBMED Abstract]
   
   
2. Decker J, Goldstein JC: Risk factors in head and neck cancer. N Engl J Med 306 (19): 1151-5, 1982.  [PUBMED Abstract]
   
   
3. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992.  [PUBMED Abstract]
   
   
4. Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology - Head and Neck Surgery. Saint Louis, Mo: Mosby-Year Book, Inc., 1998. 
   
   
5. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
6. Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989. 
   
   
7. Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997.  [PUBMED Abstract]
   
   
8. Bailet JW, Mark RJ, Abemayor E, et al.: Nasopharyngeal carcinoma: treatment results with primary radiation therapy. Laryngoscope 102 (9): 965-72, 1992.  [PUBMED Abstract]
   
   
9. Fandi A, Altun M, Azli N, et al.: Nasopharyngeal cancer: epidemiology, staging, and treatment. Semin Oncol 21 (3): 382-97, 1994.  [PUBMED Abstract]
   
   
10. Teo PM, Chan AT, Lee WY, et al.: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43 (2): 261-71, 1999.  [PUBMED Abstract]
    
    
11. Zheng XK, Chen LH, Wang QS, et al.: Influence of [18F] fluorodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 65 (4): 1020-5, 2006.  [PUBMED Abstract]
    
    
12. Cooper JS, Scott C, Marcial V, et al.: The relationship of nasopharyngeal carcinomas and second independent malignancies based on the Radiation Therapy Oncology Group experience. Cancer 67 (6): 1673-7, 1991.  [PUBMED Abstract]
    
    
13. Neel HB 3rd, Pearson GR, Taylor WF: Antibodies to Epstein-Barr virus in patients with nasopharyngeal carcinoma and in comparison groups. Ann Otol Rhinol Laryngol 93 (5 Pt 1): 477-82, 1984 Sep-Oct.  [PUBMED Abstract]
    
    
14. Lin JC, Chen KY, Wang WY, et al.: Detection of Epstein-Barr virus DNA the peripheral-blood cells of patients with nasopharyngeal carcinoma: relationship to distant metastasis and survival. J Clin Oncol 19 (10): 2607-15, 2001.  [PUBMED Abstract]
    
    

Cellular Classification of Nasopharyngeal Cancer

Although a wide variety of malignant tumors may arise in the nasopharynx, only squamous cell carcinoma is considered in this discussion because management of the other types varies substantially with histology. Subdivisions of squamous cell carcinoma in this site include:

• Lymphoepithelioma (Schminke tumor).
• Transitional cell tumors.
• Well to poorly differentiated grade.
• Keratinizing or nonkeratinizing variety.

The presence of keratin has been associated with reduced local control and survival.

Stage Information for Nasopharyngeal Cancer

Staging systems are all clinical staging and are based on the best possible estimate of the extent of disease before treatment.[1,2] Assessment of the primary tumor is based on inspection and palpation when possible and by both indirect mirror examination and direct endoscopy when necessary. The tumor must be confirmed histologically, and any other pathologic data obtained on biopsy may be included. Evaluation of the function of the cranial nerves is especially appropriate for tumors of the nasopharynx. The appropriate nodal drainage areas are examined by careful palpation.[3,4] Information from diagnostic imaging studies may be used in staging. Magnetic resonance imaging offers an advantage over computed tomographic scanning in the detection and localization of head and neck tumors and the distinction of lymph nodes from blood vessels.[5] Positron emission tomography scans may be useful in detecting skeletal metastases in patients with advanced nasopharyngeal cancer.[6]

If a patient has a relapse, a complete reassessment must be done to select the appropriate additional therapy.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define nasopharyngeal cancer.[7]

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor confined to the nasopharynx
• T2: Tumor extends to soft tissues
  • T2a: Tumor extends to the oropharynx and/or nasal cavity without parapharyngeal extension*
  • T2b: Any tumor with parapharyngeal extension*
• T3: Tumor invades bony structures and/or paranasal sinuses
• T4: Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space

 [Note: Parapharyngeal extension denotes posterolateral infiltration of tumor beyond the pharyngobasilar fascia.]

The distribution and the prognostic impact of regional lymph node spread from nasopharynx cancer, particularly of the undifferentiated type, are different from those of other head and neck mucosal cancers and justify the use of a different regional lymph node classification scheme.

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Unilateral metastasis in lymph node(s), not more than 6 cm in greatest dimension, above the supraclavicular fossa*
• N2: Bilateral metastasis in lymph node(s), not more than 6 cm in greatest dimension, above the supraclavicular fossa*
• N3: Metastasis in a lymph node(s)* larger than 6 cm and/or to supraclavicular fossa
  • N3a: Larger than 6 cm
  • N3b: Extension to the supraclavicular fossa**

* [Note: Midline nodes are considered ipsilateral nodes.]

** [Note: Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described in the Ho-stage classification for nasopharyngeal cancer. It is defined by three points: (1) the superior margin of the sternal end of the clavicle; (2) the superior margin of the lateral end of the clavicle; and, (3) the point where the neck meets the shoulder. Note that this would include caudal portions of Levels IV and V. All cases with lymph nodes (whole or part) in the fossa are considered N3b.]

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Stage 0

• Tis, N0, M0

Stage I

• T1, N0, M0

Stage IIA

• T2a, N0, M0

Stage IIB

• T1, N1, M0
• T2, N1, M0
• T2a, N1, M0
• T2b, N0, M0
• T2b, N1, M0

Stage III

• T1, N2, M0
• T2a, N2, M0
• T2b, N2, M0
• T3, N0, M0
• T3, N1, M0
• T3, N2, M0

Stage IVA

• T4, N0, M0
• T4, N1, M0
• T4, N2, M0

Stage IVB

• Any T, N3, M0

Stage IVC

• Any T, any N, M1

Results of radiation therapy for nasopharyngeal carcinoma (locoregional control and survival) are usually reported by T stage and N stage separately or by specific T and N subgroupings rather than by numerical stages I to IV. Outcome also depends on a variety of biologic and technical factors related to treatment.

References

1. Teo PM, Leung SF, Yu P, et al.: A comparison of Ho's, International Union Against Cancer, and American Joint Committee stage classifications for nasopharyngeal carcinoma. Cancer 67 (2): 434-9, 1991.  [PUBMED Abstract]
   
   
2. Lee AW, Foo W, Law SC, et al.: Staging of nasopharyngeal carcinoma: from Ho's to the new UICC system. Int J Cancer 84 (2): 179-87, 1999.  [PUBMED Abstract]
   
   
3. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
4. Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989. 
   
   
5. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988.  [PUBMED Abstract]
   
   
6. Liu FY, Chang JT, Wang HM, et al.: [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 24 (4): 599-604, 2006.  [PUBMED Abstract]
   
   
7. Pharynx (including base of tongue, soft palate and uvula). In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 31-46. 
   
   

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatments for patients with nasopharyngeal cancer include:

• Radiation therapy.
• Chemotherapy.
• Surgery.

High-dose radiation therapy with chemotherapy is the primary treatment of nasopharyngeal cancer, both for the primary tumor site and the neck.[1] When feasible, surgery is usually reserved for nodes that fail to regress after radiation therapy or for nodes that reappear following clinical complete response. Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.[2-5] Although most tumors are treated with external-beam radiation therapy (EBRT) exclusively, in some tumors radiation therapy may be boosted with intracavitary or interstitial implants or by the use of stereotactic radiosurgery when clinical expertise is available, and the anatomy is suitable.[6-10] Intensity-modulated radiation therapy may result in a lower incidence of xerostomia and provide a better quality of life than conventional radiation therapy.[11,12][Level of evidence: 1iiC] A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[13]

Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who have received radiation therapy that delivered EBRT to the entire thyroid gland or to the pituitary gland. Thyroid-function testing of patients should be considered prior to therapy and as part of posttreatment follow-up.[14,15]

Treatments under clinical evaluation for patients with nasopharyngeal cancer include:

• New radiation therapy techniques such as intensity-modulated radiation therapy.
• Biologic therapy.

Information about ongoing clinical trials is available from the NCI Web site ⁵.

References

1. Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006.  [PUBMED Abstract]
   
   
2. Perez CA, Devineni VR, Marcial-Vega V, et al.: Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 23 (2): 271-80, 1992.  [PUBMED Abstract]
   
   
3. Lee AW, Law SC, Foo W, et al.: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol 66 (786): 528-36, 1993.  [PUBMED Abstract]
   
   
4. Geara FB, Sanguineti G, Tucker SL, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol 43 (1): 53-61, 1997.  [PUBMED Abstract]
   
   
5. Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997.  [PUBMED Abstract]
   
   
6. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
7. Itami J, Anzai Y, Nemoto K, et al.: Prognostic factors for local control in nasopharyngeal cancer (NPC): analysis by multivariate proportional hazard models. Radiother Oncol 21 (4): 233-9, 1991.  [PUBMED Abstract]
   
   
8. Levendag PC, Schmitz PI, Jansen PP, et al.: Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx. J Clin Oncol 16 (6): 2213-20, 1998.  [PUBMED Abstract]
   
   
9. Teo PM, Leung SF, Lee WY, et al.: Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship above conventional tumoricidal dose. Int J Radiat Oncol Biol Phys 46 (2): 445-58, 2000.  [PUBMED Abstract]
   
   
10. Le QT, Tate D, Koong A, et al.: Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 56 (4): 1046-54, 2003.  [PUBMED Abstract]
    
    
11. Pow EH, Kwong DL, McMillan AS, 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 66 (4): 981-91, 2006.  [PUBMED Abstract]
    
    
12. 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 25 (31): 4873-9, 2007.  [PUBMED Abstract]
    
    
13. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992.  [PUBMED Abstract]
    
    
14. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995.  [PUBMED Abstract]
    
    
15. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995.  [PUBMED Abstract]
    
    

Stage I Nasopharyngeal Cancer

Standard treatment options:

• High-dose radiation therapy to the primary tumor site and prophylactic radiation therapy to the nodal drainage.[1-3]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I nasopharyngeal cancer ⁶. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁷.

References

1. Mesic JB, Fletcher GH, Goepfert H: Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 7 (4): 447-53, 1981.  [PUBMED Abstract]
   
   
2. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.  [PUBMED Abstract]
   
   
3. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   

Stage II Nasopharyngeal Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

1. Chemoradiation therapy.[1][Level of evidence: 3iiiA]



2. High-dose radiation therapy to the primary tumor site and prophylactic radiation therapy to the nodal drainage.[2-4]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II nasopharyngeal cancer ⁸. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁷.

References

1. Cheng SH, Tsai SY, Yen KL, et al.: Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma. J Clin Oncol 18 (10): 2040-5, 2000.  [PUBMED Abstract]
   
   
2. Mesic JB, Fletcher GH, Goepfert H: Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 7 (4): 447-53, 1981.  [PUBMED Abstract]
   
   
3. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.  [PUBMED Abstract]
   
   
4. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   

Stage III Nasopharyngeal Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

1. Chemoradiation therapy, as evidenced in INT-0099 ⁹, for example.[1-9]



2. High-dose or superfractionated radiation therapy to the primary tumor site and bilateral neck nodes that are clinically positive.[10-13]



3. Neck dissection may be indicated for persistent or recurrent nodes if the primary tumor site is controlled.[12]

Treatment options under clinical evaluation:

• Neoadjuvant chemotherapy.

  Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors, which renders them more definitively treatable with radiation therapy. Chemotherapy is given prior to the other modalities, hence the designation neoadjuvant to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy. Two randomized prospective trials compared combination chemotherapy (cisplatin, epirubicin, and bleomycin or cisplatin plus fluorouracil [5-FU] infusion) plus radiation therapy to radiation therapy alone.[1][Level of evidence: 1iiA];[14][Level of evidence: 1iiDii] Although disease-free survival was improved in the chemotherapy group for both groups, improvement in overall survival was reported only from the Intergroup trial in which chemotherapy with cisplatin was ever concurrently given.[1]

  Clinical trials for advanced tumors evaluating the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant therapy after radiation therapy should be considered.[15-18]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III nasopharyngeal cancer ¹⁰. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁷.

References

1. Al-Sarraf M, LeBlanc M, Giri PG, et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16 (4): 1310-7, 1998.  [PUBMED Abstract]
   
   
2. Teo PM, Chan AT, Lee WY, et al.: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43 (2): 261-71, 1999.  [PUBMED Abstract]
   
   
3. Chan AT, Teo PM, Ngan RK, et al.: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20 (8): 2038-44, 2002.  [PUBMED Abstract]
   
   
4. Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25 (3): 219-23, 2002.  [PUBMED Abstract]
   
   
5. Chua DT, Ma J, Sham JS, et al.: Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol 23 (6): 1118-24, 2005.  [PUBMED Abstract]
   
   
6. Wee J, Tan EH, Tai BC, et al.: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23 (27): 6730-8, 2005.  [PUBMED Abstract]
   
   
7. Zhang L, Zhao C, Peng PJ, et al.: Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 23 (33): 8461-8, 2005.  [PUBMED Abstract]
   
   
8. Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006.  [PUBMED Abstract]
   
   
9. Baujat B, Audry H, Bourhis J, et al.: Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma. Cochrane Database Syst Rev (4): CD004329, 2006.  [PUBMED Abstract]
   
   
10. Mesic JB, Fletcher GH, Goepfert H: Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 7 (4): 447-53, 1981.  [PUBMED Abstract]
    
    
11. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.  [PUBMED Abstract]
    
    
12. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
    
    
13. Johnson CR, Schmidt-Ullrich RK, Wazer DE: Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. Cancer 69 (11): 2749-54, 1992.  [PUBMED Abstract]
    
    
14. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 35 (3): 463-9, 1996.  [PUBMED Abstract]
    
    
15. Azli N, Armand JP, Rahal M, et al.: Alternating chemo-radiotherapy with cisplatin and 5-fluorouracil plus bleomycin by continuous infusion for locally advanced undifferentiated carcinoma nasopharyngeal type. Eur J Cancer 28A (11): 1792-7, 1992.  [PUBMED Abstract]
    
    
16. Chan AT, Teo PM, Leung TW, et al.: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33 (3): 569-77, 1995.  [PUBMED Abstract]
    
    
17. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996.  [PUBMED Abstract]
    
    
18. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000.  [PUBMED Abstract]
    
    

Stage IV Nasopharyngeal Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

1. Chemoradiation therapy, as evidenced in INT-0099 ⁹, for example.[1-10]



2. High-dose or superfractionated radiation therapy to the primary tumor site and bilateral lymph nodes that are clinically positive.[11-14]



3. Neck dissection should be reserved for persistent or recurrent nodes.[13]



4. Chemotherapy for patients with stage IVC disease.[15]

Treatment options under clinical evaluation:

1. Neoadjuvant chemotherapy.

   Neoadjuvant chemotherapy as given in clinical trials, as evidenced in NPC-9901 ¹¹, for example, has been used to shrink tumors, which renders them more definitively treatable with radiation therapy. Chemotherapy is given prior to the other modalities, hence the designation neoadjuvant to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy. Three randomized prospective trials compared combination chemotherapy (cisplatin, epirubicin, and bleomycin or cisplatin plus fluorouracil [5-FU] infusion) plus radiation therapy to radiation therapy alone.[1][Level of evidence: 1iiA];[16,17][Level of evidence: 1iiDii] Although disease-free survival was improved in the chemotherapy group for both groups, improvement in overall survival was reported only from the Intergroup trial in which chemotherapy with cisplatin was ever concurrently given.[1]

   Clinical trials for advanced tumors to evaluate the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant therapy after radiation therapy should be considered.[18-21]




2. Concurrent radiation therapy with chemotherapy.

   A study of 1,355 patients compared concurrent radiation therapy with carboplatin or cisplatin administered with 96-hour infusion of 5-FU monthly for three cycles.[22] The 3-year disease-free survival rate was 63.4% for patients in the cisplatin arm and 60.9% for patients in the carboplatin arm (P = .961; HR = 0.70; 95% CI, 0.50–0.98). Overall survival rates were 77% for patients in the cisplatin arm and 79% for patients in the carboplatin arm (P = .988; HR = 0.83; 95% CI, 0.63–1.010).[22][Level of evidence: 1iiA] Toxicity to kidneys and red blood cell count was greater in patients in the cisplatin group.




3. New radiation therapy techniques such as intensity-modulated radiation therapy.[23]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV nasopharyngeal cancer ¹². The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁷.

References

1. Al-Sarraf M, LeBlanc M, Giri PG, et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16 (4): 1310-7, 1998.  [PUBMED Abstract]
   
   
2. Teo PM, Chan AT, Lee WY, et al.: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43 (2): 261-71, 1999.  [PUBMED Abstract]
   
   
3. Chan AT, Teo PM, Ngan RK, et al.: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20 (8): 2038-44, 2002.  [PUBMED Abstract]
   
   
4. Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25 (3): 219-23, 2002.  [PUBMED Abstract]
   
   
5. Lin JC, Jan JS, Hsu CY, et al.: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 21 (4): 631-7, 2003.  [PUBMED Abstract]
   
   
6. Chua DT, Ma J, Sham JS, et al.: Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol 23 (6): 1118-24, 2005.  [PUBMED Abstract]
   
   
7. Wee J, Tan EH, Tai BC, et al.: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23 (27): 6730-8, 2005.  [PUBMED Abstract]
   
   
8. Zhang L, Zhao C, Peng PJ, et al.: Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 23 (33): 8461-8, 2005.  [PUBMED Abstract]
   
   
9. Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006.  [PUBMED Abstract]
   
   
10. Baujat B, Audry H, Bourhis J, et al.: Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma. Cochrane Database Syst Rev (4): CD004329, 2006.  [PUBMED Abstract]
    
    
11. Mesic JB, Fletcher GH, Goepfert H: Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 7 (4): 447-53, 1981.  [PUBMED Abstract]
    
    
12. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.  [PUBMED Abstract]
    
    
13. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
    
    
14. Johnson CR, Schmidt-Ullrich RK, Wazer DE: Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. Cancer 69 (11): 2749-54, 1992.  [PUBMED Abstract]
    
    
15. Ma BB, Tannock IF, Pond GR, et al.: Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer 95 (12): 2516-23, 2002.  [PUBMED Abstract]
    
    
16. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 35 (3): 463-9, 1996.  [PUBMED Abstract]
    
    
17. Lee AW, Lau WH, Tung SY, et al.: Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 23 (28): 6966-75, 2005.  [PUBMED Abstract]
    
    
18. Dimery IW, Peters LJ, Goepfert H, et al.: Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 11 (10): 1919-28, 1993.  [PUBMED Abstract]
    
    
19. Chan AT, Teo PM, Leung TW, et al.: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33 (3): 569-77, 1995.  [PUBMED Abstract]
    
    
20. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996.  [PUBMED Abstract]
    
    
21. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000.  [PUBMED Abstract]
    
    
22. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al.: Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer 43 (9): 1399-406, 2007.  [PUBMED Abstract]
    
    
23. Hunt MA, Zelefsky MJ, Wolden S, et al.: Treatment planning and delivery of intensity-modulated radiation therapy for primary nasopharynx cancer. Int J Radiat Oncol Biol Phys 49 (3): 623-32, 2001.  [PUBMED Abstract]
    
    

Recurrent Nasopharyngeal Cancer

Standard treatment options:

1. Selected patients may be retreated with moderate-dose external-beam radiation therapy using limited ports and an intracavitary or interstitial radiation boost to the site of recurrence.[1-4]



2. In highly selected patients, surgical resection of recurrent lesions may be considered.



3. If a patient has metastatic disease or local recurrence that is no longer amenable to surgery or radiation therapy, chemotherapy should be considered.[5-7]

Treatment options under clinical evaluation:

• Clinical trials such as those evaluating chemotherapy and interferon should be considered.[8]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent nasopharyngeal cancer ¹³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁷.

References

1. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
2. Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985.  [PUBMED Abstract]
   
   
3. Pryzant RM, Wendt CD, Delclos L, et al.: Re-treatment of nasopharyngeal carcinoma in 53 patients. Int J Radiat Oncol Biol Phys 22 (5): 941-7, 1992.  [PUBMED Abstract]
   
   
4. Hwang JM, Fu KK, Phillips TL: Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 41 (5): 1099-111, 1998.  [PUBMED Abstract]
   
   
5. Al-Sarraf M: Head and neck cancer: chemotherapy concepts. Semin Oncol 15 (1): 70-85, 1988.  [PUBMED Abstract]
   
   
6. Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992.  [PUBMED Abstract]
   
   
7. Foo KF, Tan EH, Leong SS, et al.: Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 13 (1): 150-6, 2002.  [PUBMED Abstract]
   
   
8. Boussen H, Cvitkovic E, Wendling JL, et al.: Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol 9 (9): 1675-81, 1991.  [PUBMED Abstract]
   
   

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Changes to This Summary (07/09/2008)

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 Option Overview ¹⁷

Added text ¹⁸ about the possible benefits of intensity-modulated radiation therapy (cited Pow et al. as reference 11 and Kam et al. as reference 12 and level of evidence 1iiC).

Stage IV Nasopharyngeal Cancer ¹⁹

Added text ²⁰ and a related study about concurrent radiation therapy with chemotherapy as a treatment option under clinical evaluation (cited Chitapanarux et al. as reference 22 and level of evidence 1iiA).

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with carefully assessed quality of life as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.