External beam radiation therapy with or without chemotherapy is the primary mode of therapy for previously untreated nasopharyngeal carcinoma (NPC). Recurrent or persistent disease remains a challenge to clinicians. Typically, re-irradiation is advocated. In some institutions, salvage nasopharyngectomy is used for the treatment of recurrent disease.[1]
External beam radiation therapy is the primary mode of management of NPC, both at the primary site and in the neck. This is mainly because of this tumor's high degree of sensitivity to radiation, as well as the anatomical constraints for surgical access to the highly complex nasopharyngeal region.
Management of locally recurrent diseases can be accomplished with either re-irradiation or salvage nasopharyngectomy. Patients whose treatment failed regionally can be treated with either re-irradiation or salvage neck dissection. A high prevalence of distant metastases has been observed for patients with NPC.
In 1988, Fee and Tu published results of salvage nasopharyngectomy in a series of patients with recurrent NPC who failed previous treatment with radiation.[2, 3] The results were encouraging[2] and inspired other investigators to start using surgery in the treatment of patients with recurrent NPC. Since then, various surgical approaches to the nasopharynx have been proposed. These include the transpalatal-maxillary-cervical, maxillary swing, transmandibular, transcervico-mandibulo-palatal, infratemporal fossa, lateral temporal, endoscopic, and robotic approaches.
Despite recent advances in the management of NPC, locoregional failure is still significant, with reported rates of 15.6-58% (median, 34%).[4, 5, 6, 7] Salvage treatment for local failure continues to be challenging because of the proximity of tumors to vital structures.
Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia.[8] In areas such as southern China, Hong Kong, Singapore, Malaysia, and Taiwan, the reported incidence rate ranges from 10-53 cases per 100,000 persons per year. The incidence is also high among Eskimos in Alaska and Greenland and in Tunisians, ranging from 15-20 cases per 100,000 persons per year. Although NPC is a relatively uncommon disease in Western countries (< 1 case per 100,000 persons), it poses a significant health problem in regions of the United States with large Asian populations. The prevalence rate for people of Asian descent in the United States is 3.0-4.2 cases per 100,000 persons.
A study by Tang et al found that between 1970 and 2007, the age-standardized incidence rate of NPC saw significant reductions in southern and eastern Asia, North America, and the Nordic nations, with the average annual percent declines being 0.9-5.4% in males and 1.1-4.1% in females. Age-standardized mortality rates between 1970 and 2013 also fell, showing average annual percent reductions of 0.9-3.7% in males and 0.8-6.5% in females. The investigators suggested that the incidence reductions were associated with tobacco control, dietary changes, and economic development, while the drop in mortality rates stemmed not only from the reduced incidence but also from diagnostic advancements and improved radiotherapy techniques.[9]
Using 1992-2013 information from the Surveillance, Epidemiology, and End Results (SEER) Program database, Challapalli et al looked at the disease-specific survival rates in the United States for adult blacks, Hispanics, Asians/Pacific Islanders, and American Indians/Alaska natives, with NPC, finding the worst disease-specific survival rate to be among non-Hispanic American Indians/Alaska natives. The best disease-specific survival rate was found in non-Hispanic Asians/Pacific Islanders.[10]
A clear etiology for nasopharyngeal carcinoma (NPC) is still lacking. In general, NPC is thought to be the result of both genetic susceptibility and environmental factors such as carcinogens and infection with Epstein-Barr virus (EBV). Evidence in support of genetic factors is the association of NPC with genotypes HLA-A2 and HLA-Bsin2, which are prevalent in individuals from southern China but rare in whites. Furthermore, abnormalities of multiple chromosomes, including 1, 2, 3, 4, 5, 6, 8, 9, 11, 13, 14, 15, 16, 17, 22, and X, have been identified.
Possible environmental or cultural factors that may be associated with NPC include the ingestion of Cantonese-style salted fish and preserved foods that contain carcinogenic nitrosamines, especially during childhood. Evidence of EBV-DNA in almost all NPC cells that were studied supports the association of NPC with EBV. Further, the detection of clonal EBV-DNA in NPC suggests that the malignancy is a clonal expansion of a single EBV-infected progenitor cell. This finding indicates that EBV is present within the cell at the time of malignant transformation and suggests a role for the virus in contributing to the early transformation event. The contribution of both genetic factors and environmental factors for this disease is reflected in the observation that the incidence of NPC for American-born, second-generation Chinese individuals is lower than that for Chinese-born individuals in China but remains higher than that for white individuals in the United States.
Although reported in all age groups, a bimodal peak incidence appears to occur in individuals aged 30-40 years and 50-60 years. Nasopharyngeal carcinoma (NPC) is observed predominantly in males, with a male-to-female ratio of 3:1. Clinically, NPC has few early warning signs, which often means late diagnosis. Early but nonspecific symptoms include nasal obstruction, blood-tinged sputum or nasal discharge, tinnitus, headache, ear fullness, and unilateral conductive hearing loss from serous otitis media or recurrent acute otitis media. In advanced cases, the tumor can invade the skull base and spread intracranially through one of the many nearby foramina. Evidence of cranial nerve involvement (III-VI), including diplopia and numbness of the face, suggests cavernous sinus invasion.
The abundant supply of regional lymphatic vessels in the nasopharynx contributes to the high prevalence of cervical metastasis. Approximately 44-57% of patients initially seek medical attention because of a metastatic lymph node that manifests as a neck mass. At the time of diagnosis, 60-85% of patients already have cervical metastasis.
Systemic dissemination also occurs more readily in NPC than in other head and neck cancers. The most frequently involved sites are bone, lung, and liver. Distant metastases are present in 5-10% of patients at the initial presentation.
Salvage nasopharyngectomy and neck dissection may be indicated in patients with nasopharyngeal carcinoma (NPC) that persisted or recurred locoregionally following prior treatment with radiation with or without chemotherapy. The proper selection of patients and surgical approach are essential for a successful outcome.
The nasopharynx is defined anteriorly by the posterior choanae, posteriorly by the clivus and the first 2 cervical vertebrae, superiorly by the floor of the sphenoid, and inferiorly by the level of the free border of the soft palate. The nasopharynx is divided into 3 subsites: the posterosuperior wall, the lateral walls, and the posterosuperior surface of the soft palate. The torus tubarius is the opening of the eustachian tube into the lateral nasopharyngeal wall. The fossa of Rosenmüller is the groove or recess posterior to the torus at the junction between the lateral and posterior walls. Nasopharyngeal carcinoma (NPC) most commonly occurs in this location.
The posterior and lateral nasopharyngeal walls are composed of 3 layers of tissue. The mucosal epithelium of the nasopharynx is complex, consisting mainly of pseudostratified columnar ciliated epithelium near the choanae and the adjacent part of the roof of the nasopharynx, a transitional epithelium in the roof and the lateral walls, and stratified squamous epithelium along the posterior and inferior portions of the nasopharynx. The superior constrictor muscle and the buccopharyngeal fascia surround the mucosa. Superiorly, the buccopharyngeal fascia unites with the pharyngobasilar fascia, which is attached to the skull base.
The buccopharyngeal fascia extends posterolaterally from the free edge of the medial pterygoid plate to the lateral border of the carotid artery. This fascia separates the nasopharynx from the parapharyngeal (paranasopharyngeal) space. A line joining the free edge of the medial pterygoid plate posterolaterally to the styloid process divides the paranasopharyngeal space into the prestyloid space anteriorly and the retrostyloid space (containing the carotid sheath and the cranial nerves) posteriorly.
The paranasopharyngeal space is bound anteriorly by the pterygomandibular raphe, which joins the lateral pterygoid plate to the mandible. The retropharyngeal space contains the retropharyngeal lymph nodes and the node of Rouviere. This space is located posterior to the buccopharyngeal fascia and anterior to the prevertebral fascia; therefore, lesions that extend beyond the buccopharyngeal fascia posteriorly involve the retropharyngeal space, while lesions extending laterally beyond this fascia reach the parapharyngeal space.
The nasopharynx is an anatomically difficult area to expose surgically. This area is in close proximity to several foramina and associated vital neurovascular structures. These include the foramen ovale, the foramen spinosum, the foramen lacerum, the carotid canal, and the jugular foramen.
Neck
Ho originally described the supraclavicular fossa as a triangular region defined by 3 points: the sternal end of the clavicle, the lateral end of the clavicle, and the point where the neck meets the shoulder.[11] This area is clinically significant in that any nodal involvement within this triangle is, by definition, an N3 lesion and, therefore, stage IV cancer.
Salvage nasopharyngectomy is contraindicated in patients with locally unresectable recurrent nasopharyngeal cancer and patients with distant metastasis.
Many studies have shown that nasopharyngeal carcinoma (NPC) is closely associated with EBV. Elevated EBV titers may also be associated with other disease entities, such as sinonasal undifferentiated carcinoma (SNUC), sinonasal lymphoma, and tongue cancer.
Seroepidemiologic studies have demonstrated that 80-90% of patients with World Health Organization (WHO) type 2 NPC and WHO type 3 NPC have elevated levels of immunoglobulin A (IgA) antibodies to viral capsid antigen (VCA) and early antigen (EA). However, only 10-20% of patients with WHO type 1 NPC have elevated levels of IgA to VCA.
Low et al examined the EBV serology in 111 patients with NPC and in 111 healthy patients.[12] In the patients with NPC, 80.2% tested positive for IgA to EA, and 97.3% tested positive for IgA to VCA. In the control group, 100% tested negative for IgA to EA, but only 46.8% tested negative for IgA to VCA. In other words, the positive predictive value (PPV) of the EA serology is 100%, while the negative predictive value (NPV) is 83.5%. For VCA serology, the PPV is 64.7%, while the NPV is 94.5%. Therefore, a patient who tested positive for EA serology has a 100% chance of having NPC. A patient who has negative VCA serology only has a 5.5% chance of having NPC. A difficult clinical situation arises if a patient has a negative EA serology test but has a positive VCA serology. This serology combination predicts a 37.8% chance of having NPC. See Tables 1-2.
Table 1. Diagnostic profiles of IgA to EA and IgA to VCA[12]
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Table 2. Predictive Value of Epstein-Barr Virus Serology Combinations
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Other serologic tests include IgA antibodies directed against EBV, EBV nuclear antigen (EBNA)–1 (found in about 90% of patients with NPC), and immunoglobulin G (IgG) antibodies to the EBV replication activator (ZEBRA) and BRLF1 transcription activator (Rta). Cai et al[13] investigated the diagnostic significance of 4 EBV antibodies in 211 NPC patients and 413 healthy controls and found similar sensitivity and specificity for IgA to EA and IgA to VCA (Table 3), as described by Low et al. (Table 2). They then determined the diagnostic accuracy based on different combinations of these 4 EBV antibody titers (Table 4).
The utility of using a combination of IgA to VCA and IgA to EBNA-1 as a screening tool in an endemic area of Southern China was reported by Liu et al.[14] In this study, 28,688 patients were screened and 862 patients were found to have positive serology. These patients underwent further diagnostic evaluation including fiberoptic nasopharyngoscopy and nasopharyngeal biopsy. Of these, 38 (4.4%) were eventually diagnosed with NPC, the majority of which was at early stages.
Table 3. Diagnostic Values of the 4 EBV Antibodies[13]
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Table 4. Diagnostic Accuracy based on Different Combination of the 4 EBV Antibodies
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Recently, several authors also reported on the potential use of plasma EBV DNA as a screening tool either alone or in combination with other serological EBV antibodies.[15, 16]
MRI with gadolinium and fat suppression is the radiologic modality of choice.[17] Determine if any intracranial extension of the tumor involves the brain parenchyma or the cavernous sinus. Intracranial spread can occur through several foramina that are in close proximity to the nasopharynx. These foramina include the foramen ovale, the foramen spinosum, the foramen lacerum, the carotid canal, and the jugular foramen.
Detect any tumor extension into the retropharyngeal, parapharyngeal, and pterygomaxillary spaces, as well as the infratemporal fossa and the sinuses.
Workup for metastatic disease
In a study involving 150 patients with untreated nasopharyngeal carcinoma (NPC), whole-body MRI and18 F-FDG positron emission tomography (PET)/CT showed similar diagnostic accuracy of 90.5% and 87.8% respectively in assessing distant site metastasis.[18]
In another study involving 78 patients, PET-CT scan was shown to be more sensitive and specific than CT scan in assessing for distant metastasis to lungs, liver, and bones.[19]
Detection of residual and/or recurrent nasopharyngeal carcinoma following definitive radiation with or without chemotherapy
Detection of residual and/or recurrent NPC following radiation treatment can be challenging because of radiation-induced scarring, fibrosis, and edema of the nasopharyngeal tissue. This treatment-related anatomic distortion may limit the role of anatomic-based imaging modalities such as MRI and CT. Function-based imaging modalities, such as18 F-FDG PET scan, are not affected by this anatomic distortion. In a systemic review of 21 articles, Liu et al found that18 F-FDG PET scan has an average sensitivity 95% in detection of local residual or recurrent disease, which is significantly higher compared with CT scan (76%) and MRI (78%).[20]
Function-based imaging modality, however, also has its limitations in cancer detection. The fact that both the cancer and the inflammatory tissues take up18 F-FDG limits the ability of the18 F-FDG PET-CT scan to distinguish viable tumor tissue from radionecrosis or osteomyelitis, resulting in high false-positive interpretation. Furthermore, because the hypermetabolic brain tissue provided a high background, recurrent/residual tumor located intracranially may be missed by18 F-FDG PET-CT scan, resulting in a high false-negative rate.
Another function-based imaging,201 TI single photon emission computed tomography (SPECT)/CT scan is based on thallium-201, which is a potassium analogue that competes with potassium for intracellular transport across the cell membrane via sodium-potassium-ATPase pump system in tumor cell membrane.[21] Because the necrotic tissue cell membrane lack the sodium-potassium-ATPase pump,201 TI does not accumulate in areas of osteoradionecrosis, and its uptake reflects the presence of viable tumor. This modality, however, is limited by spatial resolution and can miss tumors less than 1.5 cm in size.[22]
In a study comparing the use of201 TI SPECT/CT versus18 F-FDG PET-CT in detecting recurrent skull base nasopharyngeal carcinoma, Yen et al found the accuracy of these 2 modalities to be similar. The sensitivity and specificity for201 TI SPECT/CT were 66.7% and 100%, and those for18 F-FDG PET-CT were 86.7% and 75%.[22]
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Axial T2-weighted image shows a left-sided cervical nodal metastasis resulting from nasopharyngeal cancer.
Obtain multiple biopsy samples of the primary site to accurately determine the WHO histologic type of the tumor; an accurate determination is important because the classification has a significant prognostic implication. Although most NPCs are homogenous, Shanmugaratnam found that 26.4% of NPCs had features of more than 1 histologic type.[23] Fee encountered similar findings in 35% of recurrent NPC cases.[24] These heterologous tumors are classified according to the predominant histologic type.
Because of a mixture of large numbers of lymphocytes, detecting NPC by routine histopathology may be difficult. Diagnosing NPC from biopsy samples obtained from previous irradiated tissue can also be challenging. Because the association between NPC and EBV is well established, EBV-specific molecules can be used as markers for the detection of NPC in biopsy specimens. One of the EBV-specific molecules is the EBV-encoded small RNA (EBER). In a study from Taiwan, in situ hybridization assay for EBV-encoded RNA 1 (EBER1) was reported to have a sensitivity of 96.4% in detecting primary NPC.[25] When divided into subtypes, the sensitivity is 80% for WHO type 1, 97.3% for WHO type 2, and 97.3% for WHO type 3.
Another useful marker is the EBV gene that encodes the latent membrane protein 1 (LMP1). Although the gene that encodes LMP1 (LMP1) is not expressed consistently in all NPC (only about 65%), LMP1 is detected in every NPC cell. With the advent of the polymerase chain reaction (PCR) technique, only a few NPC cells are needed for detection of LMP1. Therefore, swabbing of the nasopharynx and testing for LMP1 could theoretically be used as a screening tool for early detection of NPC in areas of high incidence. However, the inability of this test to detect submucosal tumors limits its usefulness. Hao et al reported using LMP1 as a potential marker to help differentiate recurrent NPC from osteoradionecrosis in sequestrectomy specimens.[26]
The normal nasopharynx is rich in lymphoid tissue, which makes this area a well-known target for EBV infection in conditions such as mononucleosis. A large amount of lymphocyte infiltration is also present in NPC. Therefore, obvious concern is raised because the EBV-specific molecules that are detected from the nasopharynx may come from previously EBV-infected cells and not from NPC cells. Chen et al address this issue and use immunohistochemistry to demonstrate that EBV-DNA is localized only within NPC cells and not in the lymphocytes surrounding the tumor cells or in the normal nasopharyngeal tissue.[25] Other investigators have also shown that latent EBV infection does not occur in normal nasopharyngeal epithelial cells.
Other malignancies, such as human T-cell leukemia virus type 1 (HTLV-1)–associated adult T-cell lymphoma, nasal lymphoma, tongue cancer, and some lethal midline granuloma, are also associated with EBV. Although these lesions are rare, they must be included in the differential diagnoses when a patient tests positive for EBV-specific molecules.
The histological diagnosis of persistent disease following radiotherapy may sometimes be misleading. Biopsies obtained immediately following radiation may reveal viable cancer cells, even those that eventually undergo cell death. Kwong et al studied 803 patients with NPC by obtaining serial postradiotherapy nasopharyngeal biopsies.[27] They found that cancer cells may take up to 10 weeks after the completion of radiation to undergo cell death. Thus, biopsies to exclude persistent disease should usually be obtained at least 10 weeks following completion of radiation treatment to avoid a false-positive diagnosis.
Fine-needle aspiration of a neck mass
Fine-needle aspiration of a neck mass may be useful for the detection of an occult nasopharyngeal primary tumor.
The PCR technique can be used to evaluate the aspirate for the presence of EBV-DNA, or in situ hybridization can be used to determine the presence of EBER (EBER1-ISH). The in situ assay was reported to have a sensitivity of 98.1% and a specificity of 100%, even in an area such as Taiwan, where a large proportion of the population is infected with EBV.[28] The PCR technique has a lower sensitivity of 90.7% and was positive in 7 out of 61 patients without NPC (specificity of 88.5%). Several publications from Western countries demonstrate the use of this test in nonendemic areas. Dictor et al reported a sensitivity of 88.9% and a specificity of 100% using EBER1-ISH on biopsy samples from cervical metastasis.[29] The 2 cases of false-negative results were cervical metastasis from keratinizing NPC.
External beam radiation therapy is the primary mode of management of nasopharyngeal carcinoma (NPC), both at the primary site and in the neck. This is mainly because of this tumor's high degree of sensitivity to radiation as well as the anatomical constraints for surgical access to the highly complex nasopharyngeal region. Recent advances in imaging capabilities (eg, the ability to more accurately define tumor location) and improved radiotherapy techniques (eg, stereotactic radiotherapy boost) have helped to improve the locoregional control rate. At the same time, complications associated with radiation therapy have been reduced. Various sophisticated fractionation schema and boosting techniques have been advocated, with a minimum of 65-75 Gy of radiation delivered to the primary site.
Although radiation therapy alone is a well-accepted management of stages I and II NPC, the administration of chemotherapy adjunctive to radiotherapy in advanced NPC (stages III-IV) has remained a controversial issue because of conflicting reports in the literature. When interpreting these data, the inherent difference in disease type in endemic areas (eg, Southeast Asia) and nonendemic areas (eg, North America and Western Europe) must be noted. WHO type 1 makes up fewer than 5% of all NPC cases in Southeast Asia, while it accounts for 25% of tumor types in the Intergroup Study from North America.[30] WHO type 1 NPC is generally considered to be less radiosensitive than WHO type 2 and 3 NPC; therefore, WHO type 1 NPC is associated with the worst prognosis. Not surprisingly then, the locoregional control and survival rates reported from Southeast Asia are, in general, better than rates reported from the West.
Another important thing to remember is that the radiation regimens reported in Asian studies are typically more aggressive than ones reported in nonendemic areas in the West.[31] This may account for the better outcome in the radiation-alone arm seen in Asian studies, making it harder to show survival benefit with the addition of chemotherapy. Finally, many different types of chemotherapeutic regimens (different drugs, concentrations, and different timing) were used in these trials, which may also account for some of the differences in outcome.
Chemotherapy can be delivered before (neoadjuvant), during (concurrent), or following (adjuvant) radiation therapy. Active chemotherapeutic agents include cisplatin, 5-fluorouracil (5-FU), doxorubicin, epirubicin, bleomycin, mitoxantrone, methotrexate, and vinca alkaloids. Various chemotherapeutic approaches have been devised to improve the response rates while minimizing toxicities.
In 1998, a landmark study (Intergroup Study 0099) was reported by Al-Saraaf et al.[30] This was a large, prospective, randomized trial from North America that demonstrated that concomitant chemoradiation (cisplatin 100 mg/m2 infused on days 1, 22, and 43) followed by adjuvant chemotherapy with cisplatin (80 mg/m2) and 5-FU (1 g/m2) every 4 weeks for 3 cycles improved overall survival (OS) at 3 years for patients with advanced stages of NPC over radiation therapy alone (75% vs 46%).
In an updated report, Al-Saraaf reported that patients treated with chemoradiation continued to have superior OS rates over patients treated with radiation alone at 5 years (67% vs 37%).[32] This study was the first large randomized trial that demonstrated a significant improvement in OS with the addition of chemotherapy to radiation. Following this landmark study, a major change in the treatment paradigm for patients with advanced stage NPC occurred in the United States. Most centers now treat patients who have advanced-stage NPC with a combination of chemotherapy and radiation. However, this treatment regimen is certainly not routinely practiced in other parts of the world, especially in endemic regions in Asia.
In contrast to the Intergroup Study 0099, several large, prospective, randomized trials failed to show any survival benefit with the addition of chemotherapy for treatment of advanced NPC (see Table 5 below). Most of these earlier studies from Asia, however, used chemotherapy either in the neoadjuvant or adjuvant fashion instead of the concurrent and adjuvant regimen used in Intergroup Study. Using chemotherapy in an adjuvant setting, the Taiwan Cooperative Oncology Group Trial failed to demonstrate any survival benefit from the addition of adjuvant chemotherapy in advanced stages of NPC. The 5-year OS for the chemoradiation group was 61% versus 55% survival for radiation alone group.[33]
Studies using chemotherapy in a neoadjuvant setting also failed to show survival advantage.[34] A randomized trial from the Asian-Oceanian Clinical Oncology Association compared induction chemotherapy followed by radiotherapy versus radiotherapy alone.[35] The 3-year OS rate was 78% for the induction chemotherapy group, which was not significantly different from the 3-year OS of 71% for the radiation alone group.
In a similar large, randomized trial, Ma et al reported a 5-year OS of 63% for the group that received induction chemotherapy followed by radiation versus a 5-year OS of 56% for the group that underwent radiation alone.[36] Statistically significant improvement in survival was not achieved (P =0.11). Finally, Chan et al evaluated the addition of both neoadjuvant and adjuvant chemotherapy and reported a 5-year OS rate of 80% for the chemoradiation group and 81% for the radiation alone group with P =0.1.[37]
Unfortunately, the disparate results in these well-conducted large, prospective, randomized trials are difficult to interpret, for several reasons. First, the difference in the proportion of the 3 types of NPC in each of these studies may contribute to some of the disparities in the effect of chemotherapy in these different studies. As stated previously, most of the NPC cases (>95%) in Southeast Asia involve type 2 NPC and type 3 NPC, which are extremely radiosensitive. Treatment with radiation alone usually results in an excellent 5-year OS rate, ranging from 60-80%. Improving on this excellent survival rate is difficult with the addition of chemotherapy. Although fewer than 5% of patients in these studies from Southeast Asia have type 1 NPC, a large proportion of patients (25%) in the Intergroup Study have type 1 NPC, which is less radiosensitive and is associated with a much lower survival rate than radiation alone.[30]
The possibility exists that the significant improvement in survival reported from the Intergroup Study may be more applicable to patients with type 1 NPC than patients with type 2 or 3 NPC.[30] Subgroup analysis of the Intergroup Study seems to support the significant beneficial effect of adding chemotherapy for patients with WHO type I NPC (see Table 6 below). In patients with WHO type I treated by radiation alone, the 5-year OS rate is only 14%. The survival rate increased to 59% in the same group of patients treated with chemoradiation. However, one must be cautious in drawing conclusion from subset analysis, especially given the small number of patients in this subset of WHO type I (n = 36).
The debate over whether chemotherapy is beneficial in the treatment of advanced NPC is further complicated because different trials used different chemotherapeutic agents (eg, vincristine, cisplatin, bleomycin, epirubicin, 5-FU, methotrexate) as well as different delivery schedules (ie, neoadjuvant, concurrent, adjuvant, combination). The improved survival rate from the Intergroup Study may result from the concurrent use of chemotherapy with radiation, whereas many prior studies from Asian countries mainly use chemotherapy in the adjuvant setting, neoadjuvant setting, or both.
To test this hypothesis, several phase III randomized trials were conducted in Asia using chemotherapy in the concurrent fashion with radiotherapy. Unfortunately, the results were again inconclusive. Chi et al reported that the concurrent use of cisplatin, 5-FU, and leucovorin with radiation failed to improve 5-year overall survival in stage IV NPC patients when compared with radiation alone (61% versus 55%). On the other hand, Chan et al reported on a phase III randomized study comparing concurrent use of weekly infusion of cisplatin (40 mg/m2) during radiation versus radiation alone.[37] They demonstrated that for patients with stage II and III NPC, the 5-year OS rate is better in patients treated with concurrent chemoradiotherapy (70.3%) than for patients treated with radiation alone (58.6%).
Another study from Taiwan reported by Lin et al also demonstrated that the use of concurrent chemoradiotherapy is superior to radiotherapy alone.[38] In that study, patients were treated with 2 cycles of cisplatin and 5-FU during radiation. The 5-year OS rate in the chemoradiation group (72.3%) was significantly better than that for the radiation alone group (54.2%).
Two published randomized phase III clinical trials, using the exact same treatment schema that was used in the Intergroup Study 0099, however, gave contradictory results. Using concurrent chemoradiation with cisplatin followed by adjuvant chemotherapy with cisplatin and 5-FU, Wee et al reported a statistically significant (P =0.008) improvement in 5-year OS rate in patients who received chemoradiotherapy (67%) versus patients who received radiation alone (49%).[39, 40] However, using this same regimen, Lee et al reported no statistically significant difference (P =0.22) in 5-year OS rate in patients treated with chemoradiotherapy (68%) versus patients treated with radiation alone (64%) (see Table 5 below).[41, 42] Nonetheless, the locoregional control rate in the chemoradiation group (92%) is statistically significantly (P =0.027) better than that for the radiation alone group (82%).
Further, this was the first randomized trial to include a more contemporary standard of radiation, with approximately 60% of patients receiving some form of intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT). As stated earlier, radiation regimens used in Asian studies are typically more aggressive and treatment with radiation alone usually results in an excellent 5-year OS rate. Thus, it may be more difficult to improve on this excellent survival rate (using radiation alone) with the addition of chemotherapy.
Finally, a recently published randomized phase III trial from Chen et al involved 316 patients from Chinese mainland.[43, 44] Patients in the combined treatment arm were given concurrent cisplatin (40 mg/m2) weekly during 7 weeks of radiation followed by cisplatin (80 mg/m2 on day 1) and fluorouracil (800 mg/ m2 on days 1-5) every 4 weeks for 3 cycles after radiation. The 5-year OS for the chemoradiation arm and radiation-alone arm were 72% and 62%, respectively (hazard ratio, 0.69; 95% CI, 0.48-0.99; P =0.043.[44]
A meta-analysis involving 1,528 patients from 6 randomized studies comparing combined chemotherapy-radiation therapy versus radiation therapy alone in locally advanced NCP showed that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the OS increased by 20% at 2 years, 19% at 3 years, and 21% at 4 years with chemotherapy plus radiation therapy.[45]
A report from the Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) reviewed individual patient data from 8 well-designed randomized trials that compared chemotherapy plus radiotherapy versus radiotherapy alone in locally advanced NPC.[46] A total of 1753 patients were included in this review. All trials used conventional radiotherapy and cisplatin-based chemotherapy. The authors found that the addition of chemotherapy improved 5-year OS from 56% to 62% (absolute survival benefit, 6%) and improved EFS from 42% to 52% (absolute benefit, 10%).
They also observed a significant interaction between chemotherapy timings and OS (P =.005), which explained the heterogeneity of clinical trial results previously noted. The use of concurrent chemotherapy with radiation was found to result in the highest survival benefit. In the sensitivity analysis, chemotherapy was found to be more efficient against WHO type 1 disease than other types. The authors concluded that the addition of chemotherapy to standard radiotherapy provides a small but significant survival benefit in patients with nasopharyngeal carcinoma. This benefit is especially observed when chemotherapy is administered concomitantly with radiotherapy. The role of induction chemotherapy and adjuvant chemotherapy is more questionable.
A recent large, phase 3, multicenter, randomized control trial[47] compared the effect of the addition of adjuvant chemotherapy (cisplatin and 5-FU) to concurrent chemotherapy with cisplatin in locoregionally advanced NPC. This trial involved 7 institutions in China and enrolled patients with stage III or IV NPC, except for T3-4N0. A total of 251 patients were randomized to the concurrent chemoradiation plus adjuvant chemotherapy (C+A) group, while 257 were randomized to the concurrent chemoradiation alone (C) group. After a median follow-up of 37.8 months, the estimated 2 year failure-free survival rate was 86% (95% CI, 81-90) in the C+A group and 84% (95% CI, 78-88) in the C group (hazard ratio 0.74; 95% CI, 0.49-1.10; P =0.13).
Similarly, in a meta-analysis of 5 studies involving 394 patients in the C+A group and 399 patients in the C only group, Liang et al showed that the addition of adjuvant chemotherapy to concurrent chemoradiation did not improve outcome compared with concurrent chemoradiation alone. Risk ratios of 1.02 (95% CI, 0.89-1.15), 0.93 (95% CI, 0.72-1.21), 1.07 (95% CI, 0.87-1.32), and 0.95 (95% CI, 0.80-1.13) were observed for 3 years OS, 5 years failure-free survival, 5 years locoregional failure-free survival, and 5 years distant metastasis failure-free survival, respectively.[48]
In his recent review paper, Al-Sarraf[32] commented on reversing the sequence of chemotherapy from adjuvant to neoadjuvant. Using this protocol of induction chemotherapy with 3 courses of cisplatin and 5-FU followed by concurrent chemoradiation using 3 courses of cisplatin, he reported an unpublished 5 year OS of approximately 90%. Kong et al[49] recently reported on the use of neoadjuvant chemotherapy consisting of a taxane, cisplatin, and 5-FU (TPF regimen) followed by concurrent chemoradiation in 52 stage III and 64 stage IVA/IVB NPC patients. The 3-year OS was 94.8% (95% CI, 87.6-100%) for stage III patients and 90.2% (95% CI, 81.8-98.6%) for stage IVA/IVB patients. This excellent result is very encouraging and warrants randomized controlled trials.
Table 5. Prospective Randomized Clinical Trials of Chemoradiation Versus Radiation Alone in the Treatment of Locally Advanced NPC
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Table 6. Intergroup Study 0099. Subgroup Analysis of 5-Year Overall Survival Based on WHO Types[30]
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Neck
Radiation therapy more readily controls neck disease that arises from NPC than comparable neck disease from other head and neck carcinomas. Regional control remains a possibility even with extensive nodal disease. Delivery of radiation at a minimum of 65-75 Gy to the clinically positive neck node is recommended. Given the high propensity of NPC to metastasize to the neck, most authors recommend elective treatment of the N0 neck. Furthermore, treatment of both sides of the neck is recommended. The retropharyngeal and parapharyngeal lymph nodes are included in the treatment volume of the primary tumor.
Persistent or recurrent nasopharyngeal carcinoma (locoregional failures)
Despite recent advances in the management of NPC, locoregional failure is still significant, with reported rates of 15.6-58% (median, 34%).[4, 5, 6, 7]
Nasopharynx - Local failure
The frequency of local failure is reported to range from 18-58%.[54, 55] Management of locally recurrent diseases can be accomplished with either re-irradiation or salvage nasopharyngectomy. Re-irradiation is associated with a high frequency of complications, including temporal lobe necrosis, brainstem damage, cranial neuropathy, endocrine dysfunction, visual and hearing impairments, osteonecrosis, soft tissue necrosis, and trismus. These complications can be reduced with the use of brachytherapy or stereotactic radiotherapy. Although the potential for these complications is high, only 10-30% of patients achieve local control after the second course of irradiation.[56, 57] A survival rate of 34-48% at 3 years has been reported, although only about 15-23% of patients achieve disease-free survival.[56, 57]
Neck - Regional failure
The frequency of persistent or recurrent neck disease is reported to range from 8-34%.[58] Patients whose treatment failed regionally can be treated with either re-irradiation or salvage neck dissection. The control rate after re-irradiation is reported to be between 28% and 33%.[57] In contrast, Wei et al reported a regional control rate of 66% after radical neck dissection.[59] Despite a relatively good chance of regional control, these patients who presented with recurrent or persistent neck disease usually have a high risk of distant metastases.
Distant metastases
A high prevalence of distant metastases has been observed for patients with NPC, with a substantial number eventually experiencing distant failure despite lasting locoregional control. The distant failure rate was reported to range from 18-35%. At the time of initial presentation, 5-10% of patients may already have distant metastases. The occurrence of distant disease does not appear to be associated with the size of the primary tumor. However, a strong association exists between nodal disease and the development of distant disease, with 38% of patients with N+ neck disease exhibiting distant metastases versus 11% of patients with N0 neck disease. Some series have reported a rate of up to 80% of distant metastasis in patients with N3 neck disease.
The lung is the most common site of metastasis, followed by bone and the liver. Currently, available treatment modalities are ineffective in curing distant metastases. Palliative treatment is directed toward pain relief, symptom control, and prolongation of life. Radiation can be extremely effective in palliating pain from bone metastasis. Although the use of palliative chemotherapy in a patient who experiences symptoms is reasonable, the use of palliative chemotherapy in a patient without any symptoms is not as clear. The desire for prolongation of life must be balanced against the patient's quality of life, which should be the first priority.
Because of the tumor's high degree of sensitivity to radiation and the anatomical constraints for surgical access to the highly complex nasopharyngeal region, nasopharyngectomy is reserved only for treatment of recurrent NPC with limited disease.
Persistent or recurrent nasopharyngeal carcinoma (locoregional failures)
Nasopharynx - Local failure
Although nasopharyngectomy can achieve slightly better local control and a lower rate of complication as compared with re-irradiation, this surgery is only applicable in patients with limited disease such as rT1, rT2, rT3. A recurrent or residual disease that involves the middle cranial fossa may be amenable to resection through the craniofacial approach. Most surgeons consider the involvement of the cavernous sinus, the cranial nerves, and the carotid artery as a contraindication for surgical intervention. Even though tumors in these areas are technically resectable, salvage surgery is not advised because of the high morbidity associated with resection of the internal carotid artery and the cranial nerves in the setting of a very low probability of cure. A recent meta-analysis of 779 patients from 17 published studies showed a 5-year overall survival of 51.2% following salvage surgery with or without reirradiation for recurrent nasopharyngeal carcinoma.[60]
Various surgical approaches to the nasopharyngeal region have been described. Each approach has its own merit, and no single approach has clearly been shown to be superior to the other approaches. Because of the nature of the disease process, which involves an extremely complex anatomical region, the surgeon needs to be familiar with all of these surgical approaches. The operation performed must be tailored to the areas involved by the tumor and may involve a combination of approaches, thus allowing maximal exposure while minimizing associated morbidity.
Neck - Regional failure
Radical neck dissection can be used to treat recurrent or residual disease in the neck after radiation treatment with a good probability of regional control. Wei et al reported a regional control rate of 66% after radical neck dissection.[59] On serial sectioning of the entire radical neck dissection specimen, 27.5% of the specimen was found to have tumors lying in close proximity to, or even infiltrating, the spinal accessory nerve. Based on this finding, Wei et al recommended radical neck dissection as the salvage procedure of choice.[59] If the retropharyngeal or parapharyngeal space is involved, neck dissection is extended to include this region.
A detailed assessment of the extent of tumor involvement is extremely important. Most surgeons consider the involvement of the cavernous sinus as a contraindication for surgery. A clear appreciation of the tumor in relation to the internal carotid artery is essential. Metastatic workup must be performed to exclude distant metastases.
Fee describes a transpalatal, transmaxillary, and transcervical approach.[24] This approach to the nasopharynx provides excellent exposure to both sides of the nasopharynx with minimal morbidity to the patient. Isolation and protection of the internal carotid artery through the transcervical approach allow resection of the lateral nasopharyngeal wall with minimal risk to the internal carotid artery and the cranial nerves. Disease that extends to the pterygomaxillary space can be exposed via a transmaxillary approach through the posterior wall of the maxillary sinus. Then, the clivus and vertebral body bone are drilled with a large cutting burr. Fee reported on his experience with 33 patients who had recurrent NPC and were monitored for 2-17 years after nasopharyngectomy. A 5-year local control rate of 67% with a 5-year disease-free survival rate of 52% and an OS rate of 60% were achieved.
Fisch describes the infratemporal fossa approach, and Gross and Panje describe the lateral temporal approach.[61, 62] Both approaches provide excellent exposure of tumors that extend into the infratemporal fossa and the parapharyngeal space. A major disadvantage of these approaches is that entry into the nasopharynx is performed on the side of the lesion, making complete excision difficult if the tumor extends to the contralateral nasopharynx. Furthermore, the morbidity following this approach is significant and may include sensorineural hearing loss, cerebrospinal fluid (CSF) leak, unilateral laryngeal paralysis, and facial nerve deficit.
Wei et al suggested a new idea for exposure of the nasopharynx through the maxillary swing (facial translocation).[63] This approach involves a Weber-Fergusson incision. After achieving the necessary bone cuts, the entire osteocutaneous complex is swung laterally to provide exposure of disease in the ipsilateralpterygomaxillary and paranasopharyngeal space. However, the control of the internal carotid artery is less than optimal. Wei reported a local control rate of 42% at 3.5 years.[63]
Biller and Krespi describe the transcervico-mandibulo-palatal approach. This approach provides a wide-field exposure of the nasopharynx and excellent protection of the internal carotid artery. Morton et al reported a 67% local control rate at 2 years with this approach.[64] King et al reported on a series of 31 patients who were treated with a variety of surgical approaches followed by postoperative radiation.[65] They reported a 5-year survival rate of 47% with a 5-year disease-free survival rate of 42%.
With the increasing interest in minimally invasive surgery in the field of head and neck, endoscopic approach for resection of recurrent nasopharyngeal carcinoma has been described. Chen et al. reported on a series of 6 patients with recurrent T1 or T2a disease who underwent endoscopic nasopharyngectomy with a local control rate of 83% at a mean follow-up duration of 29 months.[25]
Finally, the introduction of the da Vinci robot provided another technological advancement that enables surgeons to reach and operate in areas such as the nasopharynx, which are difficult to access. Tsang et al[66] reported on 12 patients who underwent robotic nasopharyngectomy with 2-year local control rate of 86% and 2-year OS of 83%.
The nasopharyngeal defect is covered with a split-thickness skin graft. The graft is held in place with packing. A 14F Foley catheter is then placed through the nose, and the balloon is inflated to keep the packing in place. Bilateral or unilateral myringotomy and tube placement are performed at the end of the surgery. The Foley catheter is usually removed on the third postoperative day, and the nasopharyngeal packing is removed on the 10th postoperative day. The patient is instructed to irrigate the nasopharynx with normal saline until healing is complete.
Unlike other head and neck cancers, NPC is known for its continued risk of late recurrences, and long-term follow-up care is required. Although most recurrences occur within 5 years, 5-15% of recurrences may manifest between the 5th and 10th year. Therefore, patients with NPC should be monitored for at least 10 years after treatment. Some authors have suggested that a 10-year, rather than the 5-year, survival rate is needed to assess the effectiveness of a particular treatment of NPC.
Recent advances in imaging capabilities (which more accurately define tumor volumes) and improved radiotherapy have helped in improving the locoregional control rate while, at the same time, reducing the complications associated with radiation therapy. However, in an attempt to improve locoregional control and survival rates, a higher radiation dose, a more radical fractionation schedule, and the addition of chemotherapy have, in some cases, increased the frequency and severity of complications.
Complications associated with radiation therapy to the nasopharynx and the neck can be classified according to the following organ systems:
Vascular system - Stenosis of common carotid artery or internal carotid artery (Cheng et al reported a 16% incidence of critical stenosis of either the common carotid artery or the internal carotid artery.[68] )
Although intensity-modulated radiation therapy (IMRT) is considered an improved means of radiation delivery, a cross-sectional cohort study by McDowell et al found that patients with NPC who underwent successful IMRT nonetheless suffered symptoms that impacted quality of life even years after treatment. Difficulties encountered frequently included hearing problems and also involved difficulties with dry mouth, mucus, swallowing/chewing, memory, and the teeth/gums. Moreover, hypothyroidism developed in 69% of the cohort. Patients demonstrated depression, anxiety, and fatigue rates of, respectively, 25%, 37%, and 28%, and these were significantly associated with quality of life.[69]
Surgery
Surgical complications can be divided into those associated with nasopharyngectomy and those associated with neck dissection. Because surgery is usually performed after a course of radical radiotherapy, complications from poor wound healing are commonly observed. These complications include palatal fistula, nasopharyngeal wound infection, osteonecrosis, osteomyelitis of cervical vertebrae or skull base, nonunion or malunion of osteotomy sites, and wound edge or flap necrosis. Other complications include damage to the internal carotid artery or the cranial nerves, dural violation at the skull base, and death.
The prognostic factors for patients with nasopharyngeal carcinoma (NPC) include the extent of the primary tumor (ie, skull base invasion, cranial nerve involvement, parapharyngeal infiltration), the level of the disease in the neck, the histologic subtype, the age and the sex of the patient, and the type and technique of radiotherapy. Survival rates are generally better in females than in males.
Some of the largest studies have reported a 5-year disease-free survival rate of 40-60% with primary radiation treatment. The 5-year overall survival (OS) rate is 85-95% for stage I NPC and 70-80% for stage II NPC treated with radiation alone. For stages III and IV NPC treated with radiation alone, the 5-year OS rate ranges from 24-80%, with better results generally occurring in patients from Southeast Asia. The Intergroup Study 0099 demonstrated that North American patients with advanced NPC benefited from concurrent chemotherapy with an improved 5-year OS rate of 67% compared with the 5-year OS rate of 37% for patients treated with radiation alone.
WHO type 3 NPC or undifferentiated carcinoma has the most favorable prognosis because of its high degree of radiosensitivity. The 5-year OS rate is 60-80%. In contrast, WHO type 1 NPC has the worst prognosis, with a 5-year OS rate of 20-40% because of its low radiosensitivity.
Unlike other head and neck carcinomas, some NPCs have a long, protracted course. Some patients can live with their recurrent disease for many years before succumbing to the disorder.
A literature review by Liao et al indicated that in patients with NPC, overexpression of matrix metalloproteinase-9 correlates with a poor prognosis for overall survival and disease-free survival.[70]
Several areas continue to be debated regarding the management of nasopharyngeal carcinoma (NPC).
The role of chemotherapy in advanced nasopharyngeal carcinoma
Unfortunately, the literature is conflicting regarding the role of chemotherapy in the management of advanced NPC. This discrepancy in the literature may result from differences in the proportion of NPC WHO types, the types of chemotherapeutic agents, and delivery schedules in these various clinical trials. The significant improvement in survival with the addition of chemotherapy reported from the Intergroup Study may be because of the large proportion of patients with type 1 NPC in this study and the concurrent use of chemotherapy. Other large clinical trials, most notably from Asia, include a large proportion of patients with type 2 or 3 NPC who received chemotherapy in the neoadjuvant or adjuvant fashion. These trials failed to demonstrate improvement in overall survival (OS) with the addition of chemotherapy.
Several clinical trials from Asia that incorporated the use of concurrent chemoradiotherapy for locoregionally advanced NPC did show statistically significant improvement in OS. However, results are still conflicting. Using the same regimen as the one used in Intergroup Study 0099, Lee et al reported no statistically significant difference in 3-year OS in patients treated with chemoradiotherapy (76%) versus patients treated with radiation alone (77%). Nonetheless, the locoregional control rate in the chemoradiation group (93%) is statistically significantly better than the radiation alone group (82%).
Most recently, a report from the Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) reviewed individual patient data from 8 well-designed, randomized trials comparing chemotherapy plus radiotherapy with radiotherapy alone in locally advanced NPC. A total of 1753 patients were included in this review. The authors found that the addition of chemotherapy improved 5-year OS from 56% to 62% (absolute survival benefit, 6%) and improved EFS from 42% to 52% (absolute benefit, 10%). The authors concluded that the addition of chemotherapy to standard radiotherapy provides a small but significant survival benefit in patients with nasopharyngeal carcinoma. This benefit is essentially observed when chemotherapy is administered concomitantly with radiotherapy. The role of induction chemotherapy and adjuvant chemotherapy is more questionable.
Treatment recommendations for type and schedule of chemotherapeutic agents
Even if the decision is made to add chemotherapy to the treatment, the type and the schedule of chemotherapeutic agents must be determined. The goal is to determine the optimal timing and regimen, thereby maximizing the effectiveness of the treatment while minimizing the adverse effects. Numerous clinical trials to address this issue are ongoing.
Conventional versus altered fractionation, stereotactic radiation boost, and brachytherapy
The goal of these therapies is to find the optimal radiation regimen, thereby maximizing the effectiveness of this treatment while minimizing the adverse effects. The general recommendation for treatment of a primary tumor is a radiation dosage of at least 66 Gy. Stereotactic radiotherapy and brachytherapy may be used to boost dosage as well as to minimize surrounding tissue damage. Various clinical trials that involve different radiation regimens have been reported, and many more clinical trials are ongoing.
Salvage nasopharyngectomy or re-irradiation for local recurrence
The choice of therapy for local recurrence is another area of ongoing controversy. Fee concluded that the results of surgical resection are probably only slightly better than retreatment with radiotherapy. However, Fee believes that surgery is associated with fewer long-term complications when compared with re-irradiation. With the continued improvement in radiation delivery techniques such as intensity-modulated radiation therapy (IMRT) and stereotactic boost, complications associated with re-irradiation may decrease.
The best approach for performing nasopharyngectomy
None of the surgical approaches for resection of recurrent NPC is ideal. Because of the nature of the disease process, which involves an extremely complex anatomical region, the surgeon needs to be familiar with all of the surgical approaches. The operation must be tailored to the areas involved by the tumor and may involve a combination of approaches, thus allowing maximal exposure while minimizing associated morbidity.
Guidelines for the treatment of nasopharyngeal carcinoma (NPC), issued by the American College of Radiology (ACR) in 2015, include the following recommendations[71] :
Nasopharyngectomy, stereotactic radiation therapy (SRT), intensity-modulated radiation therapy (IMRT), or IMRT with concurrent chemotherapy are all acceptable treatments for locally recurrent NPC in the absence of distant disease
Patients who had poor tolerance to initial concurrent therapy for locally advanced NPC may omit or receive adjuvant chemotherapy, provided that it is administered in a timely manner and there is good recovery from the toxicity
Patients with locally advanced and bulky, invasive NPC are typically treated with concurrent chemoradiation, although sequential or adjuvant approaches are also acceptable
Patients with an isolated bone focus of metastatic disease may achieve lengthy progression-free survival when treated with definitive concurrent chemoradiation to the primary site, as well as definitive radiation or stereotactic body radiation therapy to the metastatic bone disease
A platinum doublet is the standard systemic regimen for recurrent or metastatic NPC
Ho-Sheng Lin, MD, FACS, Professor and Interim Chair, Department of Otolaryngology-Head and Neck Surgery, Faculty, Sleep Fellowship Program, Divison of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine; Chief, Section of Otolaryngology, Department of Surgery, John D Dingell Veterans Affairs Medical Center
Disclosure: Received consulting fee from Intuitive Surgical for proctoring; consultant for Checkpoint Surgical.
Coauthor(s)
Willard E Fee, Jr, MD, Edward C and Amy H Sewall Professor Emeritus, Chairman Emeritus, Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Nader Sadeghi, MD, FRCSC, Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, McGill University Faculty of Medicine; Chief Otolaryngologist, MUHC; Director, McGill Head and Neck Cancer Program, Royal Victoria Hospital, Canada
Disclosure: Nothing to disclose.
Chief Editor
Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Additional Contributors
Benoit J Gosselin, MD, FRCSC, Associate Professor of Surgery, Dartmouth Medical School; Director, Comprehensive Head and Neck Oncology Program, Norris Cotton Cancer Center; Staff Otolaryngologist, Division of Otolaryngology-Head and Neck Surgery, Dartmouth-Hitchcock Medical Center
Al-Sarraf M, LeBlanc M, Giri PG. Superiority of 5-year survival with chemoradiotherapy vs. radiotherapy in patients with locally advanced nasopharyngeal cancer. Intergroup 0099 phase III study: final report abstract. Proc Am Soc Clin Oncol. 2001. 20:227a.
Panje WR, Gross CE. Treatment of tumor of the nasopharynx: surgical therapy. Thawley SE, Panje WR. Comprehensive Management of Head and Neck Tumors. Philadelphia, Pa: WH Sauders Co; 1987. 1: 662-683.
[Guideline] Saba NF, Salama JK, Beitler JJ, et al. Nasopharyngeal carcinoma. American College of Radiology. Available at https://acsearch.acr.org/docs/3094110/Narrative/. 2015; Accessed: Oct 7, 2016.
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