Nasopharyngeal cancer: Treatment - Health Professional Information [NCI PDQ]

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Nasopharyngeal Cancer

General Information

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, Epstein-Barr virus (EBV) exposure,[1] and as yet 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, and 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]

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

Diagnosis is made by biopsy of the nasopharyngeal mass. Workup includes 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; and 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.[4,5,6]

Major prognostic factors adversely influencing outcome of treatment include large size of the tumor, higher T stage, and the presence of involved neck nodes.[7] 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, and certain EBV antibody titer patterns.

Small cancers of the nasopharynx are highly curable by radiation therapy and 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 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, are poorly controlled locally by radiation therapy with or without surgery and often develop distant metastases despite local control.[9,10]

Although most recurrences occur within 5 years of diagnosis, relapse can be seen at longer intervals. The incidence of second primary malignancies appears less than other head and neck sites.[11]

Follow-up for patients includes routine periodic examination of the original tumor site and neck, chest x-ray, MRI or CT scan, and blood work. Positron emission tomography scans may be useful in planning treatment for patients with suspected recurrence.[12] 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 those related to vision and hearing; and evaluation of systemic complaints to identify distant metastasis.

Poorly differentiated squamous 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.

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.
2. Decker J, Goldstein JC: Risk factors in head and neck cancer. N Engl J Med 306 (19): 1151-5, 1982.
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.
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.
5. Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989.
6. Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology - Head and Neck Surgery. Saint Louis, Mo: Mosby-Year Book, Inc., 1998.
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.
8. Bailet JW, Mark RJ, Abemayor E, et al.: Nasopharyngeal carcinoma: treatment results with primary radiation therapy. Laryngoscope 102 (9): 965-72, 1992.
9. Fandi A, Altun M, Azli N, et al.: Nasopharyngeal cancer: epidemiology, staging, and treatment. Semin Oncol 21 (3): 382-97, 1994.
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.
11. 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.
12. 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.
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.
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.

Cellular Classification

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 others varies substantially with histology. Subdivisions of squamous cell carcinoma in this site include lymphoepithelioma (Schminke tumor); transitional cell tumors, well to poorly differentiated grade; and keratinizing or nonkeratinizing variety. The presence of keratin has been associated with reduced local control and survival.

Stage Information

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]

TNM Definitions

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

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**

*Midline nodes are considered ipsilateral nodes.

**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

AJCC Stage Groupings

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.
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.
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.
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.
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

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.[2,3,4,5] 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.[6,7,8,9,10] 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.[11]

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.[12,13]

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

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.
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.
3. Lee AW, Law SC, Foo W, et al.: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol 66 (786): 528-36, 1993.
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.
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.
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.
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.
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.
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.
11. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992.
12. 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.
13. 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.

Stage I Nasopharyngeal Cancer

STANDARD TREATMENT OPTIONS:

• High-dose radiation therapy to the primary tumor site and prophylactic radiation therapy to the nodal drainage.[1,2,3]

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.
2. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.
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 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.[2,3,4]

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.
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.
3. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.
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 for more information.)

STANDARD TREATMENT OPTIONS:

1. Chemoradiation therapy.[1,2] [3,4,5,6,7,8]
2. High-dose or superfractionated radiation therapy to the primary tumor site and bilateral neck nodes that are clinically positive.[9,10,11,12]
3. Neck dissection may be indicated for persistent or recurrent nodes if the primary tumor site is controlled.[11]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

• 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];[13][Level of evidence: 1iiDi] Although disease-free survival was improved in the chemotherapy group for both groups, improvement in overall survival was reported only from the intergroup 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.[14,15,16,17] Information about ongoing clinical trials is available from the NCI Web site.

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.
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.
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.
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.
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.
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.
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.
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.
9. 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.
10. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.

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 for more information.)

STANDARD TREATMENT OPTIONS:

1. Chemoradiation therapy.[1,2,3,4,5,6,7,8,9]
2. High-dose or superfractionated radiation therapy to the primary tumor site and bilateral lymph nodes that are clinically positive.[10,11,12,13]
3. Neck dissection should be reserved for persistent or recurrent nodes.[12]
4. Chemotherapy for patients with stage IVC disease.[14]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

1. 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. 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];[15,16][Level of evidence: 1iiDi] Although disease-free survival was improved in the chemotherapy group for both groups, improvement in overall survival was reported only from the intergroup 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.[17,18,19,20] Information about ongoing clinical trials is available from the NCI Web site.

2. New radiation therapy techniques such as intensity-modulated radiation therapy.[21]

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
11. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 37 (6): 2605-12, 1976.
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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.

Recurrent Nasopharyngeal Cancer

STANDARD TREATMENT OPTIONS:

1. Selected patients may be re-treated with moderate-dose external-beam radiation therapy using limited ports and an intracavitary or interstitial radiation boost to the site of recurrence.[1,2,3,4]
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.[5,6,7]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

• Clinical trials such as those evaluating chemotherapy and interferon should be considered.[8] Information about ongoing clinical trials is available from the NCI Web site.

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.
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.
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.
5. Al-Sarraf M: Head and neck cancer: chemotherapy concepts. Semin Oncol 15 (1): 70-85, 1988.
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.
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.
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.

Changes to This Summary (03/12/2007)

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.

GENERAL INFORMATION

Added text about positron emission tomography scans being useful in planning treatment for patients with recurrence (cited Zheng et al. as reference 12).

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ABOUT PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

ADDITIONAL PDQ SUMMARIES

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

IMPORTANT:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Date Last Modified: 2007-03-12

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