ReviewNasopharyngeal carcinoma: Current management, future directions and dental implications
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.
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