Elsevier

Oral Oncology

Volume 44, Issue 7, July 2008, Pages 617-627
Oral Oncology

Review
Nasopharyngeal carcinoma: Current management, future directions and dental implications

https://doi.org/10.1016/j.oraloncology.2007.08.003Get rights and content

Summary

Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck. Approximately 70% of patients with NPC present with locally advanced disease. Phase III clinical trials support combined chemotherapy and radiotherapy for the initial treatment of these patients. Current treatment approaches for metastatic disease are variable. Oral complications of therapy for NPC are very common. In order to support cancer therapy the dental provider must be aware of the diagnosis, prognosis and approach to treatment. Dental care requires that radiation fields be understood as well as the permanent changes that occur with high dose radiation therapy. Radiation causes changes in bone and soft tissue that may result in acute and chronic oral complications. The most common acute complications are mucositis, infection, xerostomia and taste changes. Mucositis is of increased severity and duration when chemotherapy is combined with radiation therapy. Chronic complications are due to late effects of radiation therapy including hyposalivation, infection, taste change, dysphagia and trismus. Treatment innovations with molecularly targeted therapies and immunotherapy are being assessed to improve treatment outcomes in NPC and will impact oral complications and oral care.

Introduction

Nasopharyngeal carcinoma (NPC) is a distinct form of head and neck cancer that differs from other malignancies of the upper aerodigestive tract in etiology, epidemiology, pathology, clinical presentation and response to treatment. Outside of endemic areas in Southeast Asia, this tumor is rare, occurring in less than 1/100,000 people.1 In North America, NPC accounts for approximately 0.2% of all malignancies with approximately 1–2 cases per 100,000 males and about one-third of that in females.2, 3, 4 In high-risk populations such as the Cantonese Chinese, a 30-fold increased incidence is reported with 30 cases per 100,000 males and 13 cases per 100,000 females.3, 5 A review of all patients diagnosed with NPC between November 1988 and July 1992 in Vancouver, Canada identified 57 patients, 13 of these were Caucasian and nearly half of those were of Canadian descent,6 showing that this malignancy is not solely of Asian origin. Therefore, dismissal of the suspicion of NPC in other populations is not prudent.

While NPC may occur at any age, it has a bimodal distribution with the first peak of occurrence in the 15–25 years age range and the second peak in the fourth to fifth decade. NPC is associated with the consumption of salted fish,3, 7 and in more remote cases, cigarette smoke,8 occupational exposure to dusts,9 herbal medicine use,9 formaldehyde exposure9 and the use of wood fire in cooking.10 EBV infection is clearly associated with NPC.3, 7 EBV is present in the cells of almost all primary and metastatic NPC, regardless of tumor histology, stage of disease, or patient geographic location. Plasma EBV DNA quantification has been recommended to follow patients and predict outcome of treatment11 and may serve as an independent biomarker to predict survival.12

Staging patients according to the American Joint Committee on Cancer staging manual13 (Table 1), patients with stage I and II disease have a high rate of cure with radiotherapy (RT) alone. Unfortunately, the majority of cases are identified with advanced disease, and the prognosis for those with distant metastatic spread remains poor. There are few symptoms associated with early stage disease. NPC can mimic temporomandibular disorders (TMD) with facial pain and limited jaw movement due to involvement of the pterygoid muscles.14 Signs and symptoms that overlap TMD include aching pain, limited jaw movement, and coincidental clicking of the temporomandibular joint (TMJ). Symptoms related to ear, nose and throat including decreased hearing, plugged sensation or auditory drainage, epistaxis or nasal obstruction and cranial nerve involvement or presenting with enlarged cervical lymph nodes14 are critical symptoms that are not seen with TMD.

The prognosis for patients with NPC depends on the stage of the disease at diagnosis. Unfortunately, most cases are diagnosed with advanced disease, often detected due to metastatic lymph nodes in the neck, cranial nerve involvement or involvement of the base of the skull.5, 14, 15, 16, 17 Approximately 70% of patients present with locally advanced, non-metastatic stage III or IV disease. Chen et al. report a cumulative 5-year survival rate of 38% in treated patients who were not diagnosed until later-stage symptoms,15, 16 commonly with delay in diagnosis from first symptoms of 6–9-months.14, 16, 17 Due to poor survival rates and complications of treatment, new therapeutic approaches are sought.

RT delivered in combination with chemotherapy has become the standard of care, although the optimal regimens of chemotherapy and radiotherapy remain controversial. This review focuses on the evidence to support treatment of locally advanced NPC and provides an update of current therapies and those that are on the horizon.

Section snippets

Chemotherapy and radiotherapy for locally advanced NPC

Fifteen phase III clinical trials have been reported in the English literature that seek to establish the best care for patients with locally advanced NPC. While all trials have utilized a RT alone arm as the control, the timing, dosing and cytotoxic chemotherapy regimen has differed greatly. Bleomycin, cisplatin, epirubicin, vincristine, cyclophosphamide, adriamycin, methotrexate, oxaliplatin, leucovorin, uracil-tegafur have all been tried either in combination or as single agents. The timing

RT for locally advanced NPC

Control of NPC is correlated with the RT dose delivered to the tumor. Radiation doses delivered in the trials described above are summarized in Table 4. The dosing is similar in these trials, with most using two lateral opposed facial fields and an anterior field if necessary. A few studies use hyperfractionated RT (twice per day), but the majority report conventional fractionation to a tumor dose of greater than 67 gray (Gy). In 1998, use of intensity-modulated RT (IMRT) for NPC was

Molecular targeted therapy and immunotherapy

Recurrent or metastatic NPC remains largely incurable, although there have been reports of long-term survivors among those who achieved complete responses to conventional chemotherapy54 and to re-irradiation for local recurrent disease (see above). Combinations of cytotoxic chemotherapeutic agents such as the platinums, 5-FU, methotrexate, anthracyclines, gemcitabine, and taxanes typically yield high response rates of limited duration, and are associated with normal tissue toxicity frequently

Oral and dental care

The evolution of care for NPC will not change the need for oral/dental preventive care and ongoing considerations for care due to the need to continue utilizing radiation therapy for early stage and locally recurrent disease and in combination with chemotherapy for advanced disease and potential future advances as outlined above. The evolution of IMRT with increasing ability to reduce exposure to major salivary glands may reduce hyposalivation, the principle chronic complication of therapy. The

Conclusions

Current evidence strongly supports a role for concomitant chemoradiotherapy followed by adjuvant chemotherapy in treating NPC. Concomitant chemoradiotherapy has shown statistically significant improvement in OS and DFS for all histological types of locally advanced NPC, and achieving 5-year OS rates of about 70% in patients with non-metastatic stage III and IV disease. IMRT and increasing total RT dose to the tumor has shown improved outcomes. IMRT has been associated with reduced xerostomia.

Conflicts of Interest Statement

Drs. Silverman and Epstein are members of the Zila Medical Advisory Board. Dr. Bride is VP, Medical Affairs for Zila Pharmaceuticals.

References (65)

  • M.A. Hunt et al.

    Treatment planning and delivery of intensity-modulated radiation therapy for primary nasopharynx cancer

    Int J Radiat Oncol Biol Phys

    (2001)
  • S.L. Wolden et al.

    Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan–Kettering experience

    Int J Radiat Oncol Biol Phys

    (2006)
  • N. Lee et al.

    Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience

    Int J Radiat Oncol Biol Phys

    (2002)
  • K. Sultanem et al.

    Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California-San Francisco experience

    Int J Radiat Oncol Biol Phys

    (2000)
  • P. Xia et al.

    Comparison of treatment plans involving intensity-modulated radiotherapy for nasopharyngeal carcinoma

    Int J Radiat Oncol Biol Phys

    (2000)
  • M.K. Kam et al.

    Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience

    Int J Radiat Oncol Biol Phys

    (2004)
  • Q.T. Le et al.

    Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma

    Int J Radiat Oncol Biol Phys

    (2003)
  • D.T. Chua et al.

    Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy

    Radiother Oncol

    (2005)
  • J.C. Li et al.

    Dose escalation of three-dimensional conformal radiotherapy for locally recurrent nasopharyngeal carcinoma: a prospective randomised study

    Clin Oncol (R Coll Radiol)

    (2006)
  • G. Bar-Sela et al.

    Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach

    Mod Pathol

    (2003)
  • J. Yan et al.

    Absence of evidence for HER2 amplification in nasopharyngeal carcinoma

    Cancer Genet Cytogen

    (2002)
  • K.C. Straathof et al.

    Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes

    Blood

    (2005)
  • A. Fandi et al.

    Nasopharyngeal cancer: epidemiology, staging, and treatment

    Semin Oncol

    (1994)
  • V.F. Chong et al.

    Maxillary nerve involvement in nasopharyngeal carcinoma

    AJR Am J Roentgenol

    (1996)
  • D.P. Huang

    Epidemiology of nasopharyngeal carcinoma

    Ear Nose Throat J

    (1990)
  • D. Jeannel et al.

    Increased risk of nasopharyngeal carcinoma among males of French origin born in Maghreb (North Africa)

    Int J Cancer

    (1993)
  • D.W. Skinner et al.

    Nasopharyngeal carcinoma: methods of presentation

    Ear Nose Throat J

    (1990)
  • X. Zheng et al.

    Epstein-Barr virus infection, salted fish and nasopharyngeal carcinoma. A case-control study in southern China

    Acta Oncol

    (1994)
  • K.E. Chapman et al.

    Nasopharyngeal carcinoma: a 15-year retrospective study

    Spec Care Dentist

    (1993)
  • S. West et al.

    Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study

    Int J Cancer

    (1993)
  • C. Perez et al.

    Nasopharynx principles and practice of radiation oncology

    (1997)
  • J.C. Lin et al.

    Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma

    New Engl J Med

    (2004)
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