Chapter 32 Nasopharyngeal Carcinoma
Etiology and Epidemiology
Nasopharyngeal carcinoma is an uncommon tumor in the United States, where the incidence is approximately 0.2 to 0.5 cases per 100,000 people.2 In comparison, the incidence is considerably greater in southern China and Hong Kong (25 to 50 cases per 100,000 people) and among the Inuit residing in Alaska and Greenland (15 to 20 cases per 100,000 people). The incidence of nasopharyngeal cancer is also higher in other parts of Southeast Asia (Taiwan, Vietnam, and Thailand), the Philippines, and Malaysia and in some Mediterranean and North African populations (8 to 12 per 100,000 people). These areas of increased incidence of nasopharyngeal cancer are considered endemic areas, and the incidence outside endemic areas is much lower and more often associated with tobacco use.
Several geographic-specific etiologic factors have been implicated in the incidence variations throughout the world. The high consumption of salted fish in southern China and Hong Kong has been implicated as a possible etiologic factor for nasopharyngeal carcinoma in these areas.3,4 It has been suggested that various macromolecular lignins associated with these foods in southern China (and perhaps other areas such as Alaska) may activate EBV,5 which has also been identified as a probable etiologic factor in nasopharyngeal carcinoma.6,7 Studies by Bouvier and colleagues5 involved the fractionation of harissa, a homemade spice mixture used in Tunisia on various foods, including salted fish. Harissa was separated into various macromolecular fractions by column chromatography. The lignin-containing complexes extracted from harissa induced the EBV promoter in Raji cells.5 The possibility that these environmental factors are important in the etiology of nasopharyngeal carcinomas is further supported by the finding that incidence rates decrease for successive generations of people who originally emigrated from southern China to California.8
Other potential environmental etiologic factors that have been associated with nasopharyngeal carcinoma include alcohol consumption and exposure to dust, fumes, formaldehyde, and cigarette smoke.9,10 Cigarette smoke and alcohol have long been associated with many other head and neck carcinomas, but their association with nasopharyngeal carcinoma has been controversial. Some studies have suggested that alcohol consumption and cigarette usage were not associated with nasopharyngeal carcinoma.9–11 Nam and associates10 conducted a case-control study using a National Mortality Follow-Back Survey based on death certificates and found that cigarette smoking and alcohol consumption are independent statistically significant risk factors for nasopharyngeal carcinoma. The increased risk of nasopharyngeal carcinoma with heavy smoking (adjusted for alcohol consumption) was threefold, and an excess risk of 80% was demonstrated for heavy alcohol consumption (adjusted for cigarette usage).
Prevention and Early Detection
The nasopharynx cannot be visualized externally, and tumors of this area often present after they have eroded into a vital structure and produced a presenting symptom. The association of EBV and nasopharyngeal cancer has led some investigators to hypothesize that serologic screening (EBV titer) may be useful in certain high-risk populations to identify groups of patients who might benefit from frequent nasopharyngeal examinations.12 In a study from China of 338,868 patients who underwent serologic screening for EBV titer, 9367 persons had immunoglobulin (Ig) A antibodies to EBV. Of these 9367 patients, 306 were positive for IgA to EBV early antigen. Nasopharyngeal cancer was detected in 113 of the 9367 patients (1.2%) and in 63 of the 306 (20.5%) who were positive for IgA to EBV early antigen. Most of the tumors (>85%) were early-stage lesions. Serologic EBV IgA screening is currently being used in endemic areas.
In addition to EBV serologic screening as a means of early detection and possible prevention of advanced-stage disease, several environmental and genetic predisposing factors are being explored as possible markers that could identify groups of patients at high risk for nasopharyngeal cancer.13 Real-time polymerase chain reaction (PCR) techniques show promise as screening tools for nasopharyngeal cancer.14 EBV DNA detection, in particular detection of EBV nuclear antigen, eliminates many false-positive results and improves the sensitivity and specificity of EBV IgA serologic screening.15 A retrospective analysis of blood samples from patients with disease relapse from previous clinical trials indicates that EBV nuclear antigen screening by PCR would have led to earlier detection of distant failure but, because of the quality of current imaging, would not have significantly affected detection of local recurrences.16 Real-time PCR screening for EBV latent membrane protein 1 (LMP1) in nasopharyngeal swabs has also been shown to be a promising screening tool for high-risk populations, with a sensitivity of 87% and specificity of 98%.17 These techniques are likely to replace serum IgA screening in endemic areas and have a promising role in screening for relapse in EBV-positive patients.18 The further study of other environmental and genetic markers may lead to the identification of patient populations that could benefit from screening or chemoprevention.13
Chemoprevention has been tested extensively in patients with a prior diagnosis of head or neck malignant tumors because second primary tumors in the respiratory and digestive tracts are common in that population.19–22 Hong and others19,20 conducted a prevention trial for patients with head and neck carcinoma after curative surgery or radiotherapy, or both. Patients were randomly assigned to receive 1 year of 13-cis-retinoic acid (isotretinoin) as a chemoprevention agent (see Khuri and associates13 for a discussion of the biologic factors) or placebo. The treated group had significantly fewer second primary tumors (4%) than the placebo group (24%) (p = .005); however, there was no difference in rates of survival or incidence of relapse between the two groups. In addition, the chemopreventive effect appeared to abate after 3 years; the incidence of second primary tumors was similar in the two groups after 3 years. Acute toxicity was significant.19
The results of the trial by Hong and colleagues19 were not confirmed by a controlled trial of 316 patients by Bolla and associates,21 in which patients were randomly assigned to 2 years of etretinate (a retinoic acid similar to isotretinoin) at a maintenance dosage of 25 mg/day. Subsequently, a large intergroup effort was mounted, and 1302 patients with previously treated head and neck malignant tumors were randomly assigned to receive 3 years of isotretinoin or placebo.22 Because of unacceptable toxicity seen with higher doses of isotretinoin (100 to 200 mg/m2 [≈150 to 400 mg total]) in prior studies, the dosage was decreased to 30 mg/day in this trial. No difference was seen in the occurrence of second primary tumors (4.6% in both arms), which was the primary endpoint of the study.23 A decrease in local recurrence was seen, however, and 13-cis-retinoic acid remains a topic of investigation.
The issue of whether retinoids or other chemopreventive agents should be used in the setting of premalignant lesions of the oral cavity has been considered, and many trials have suggested that retinoids can induce considerable responses in oral leukoplakia.24,25 Toxicity has been a limiting issue in these trials, however. It will be important to determine whether these chemoprevention strategies, developed for leukoplakia, can be extrapolated to prevention of nasopharyngeal cancer in subgroups of patients at high risk for such malignant tumors.
Blockade of cyclooxygenase-2 (COX-2) has also shown some promise as a chemopreventive strategy, and COX-2 inhibitors were recently the topic of investigation for various malignant tumors, including head and neck cancers.26 A phase II study at Fox Chase Cancer Center evaluated a 3-month course of celecoxib in patients with biopsy-proven dysplastic or hyperplastic leukoplakia, with results pending (NCT00101335). In another pilot randomized study of celecoxib in oral premalignant lesions conducted by the M.D. Anderson Cancer Center (MDACC), doses of 100 mg and 200 mg twice daily were shown to be ineffective in controlling these lesions.27 Most recent COX-2 inhibitor cancer prevention trials have been closed, except in very high risk settings such as familial polyposis, because of the increased rate of cardiovascular events seen in a few of the celecoxib and rofecoxib prevention trials.
Pathology
Malignant tumors of the nasopharyngeal area are generally carcinomas (90%), with lymphomas making up approximately 5% of lesions.28 Histologic classification of carcinomas continues to evolve as we find out more about the biologic characteristics of these tumors. The most current pathologic classification of nasopharyngeal carcinomas by the World Health Organization (WHO) includes three major categories: keratinizing squamous cell carcinoma (formerly, WHO type I), nonkeratinizing squamous cell carcinoma (including differentiated, or former WHO type II lesions, and undifferentiated, or former WHO type III lesions), as well as recently described basaloid squamous cell carcinoma.29
On histologic testing, keratinizing squamous cell carcinomas appear to be well differentiated with intercellular bridges. These lesions make up approximately 20% of carcinomas.29,30 Differentiated nonkeratinizing carcinomas, representing 30% to 40% of nasopharyngeal carcinomas, lack well-defined squamous cell characteristics but continue to show a “pavement stone pattern” characteristic of squamous cell histology.29 Undifferentiated nonkeratinizing carcinomas, comprising 40% to 50% of carcinomas, also formerly known as lymphoepitheliomas, are characterized by a lymphoplasmacytic infiltrate.29 On cytologic testing, the cells appear uniform, with round to oval nuclei and prominent nucleoli. The frequency of the different histologic types varies with geographic area. In the United States, the majority of nasopharyngeal carcinomas have keratinizing squamous cell histologic findings, whereas in Asia, the undifferentiated histologic type is by far the most common (Table 32-1).
Anatomy and Pathways of Spread
The nasopharynx is a musculofascial tube that connects the nasal cavity and oropharynx. The anatomic borders of the nasopharynx are (1) the anterior border, consisting of the posterior nasal apertures and nasal septum; (2) the posterior border, the pharyngeal mucosa; (3) the superior border, the pharyngeal mucosa and body of the sphenoid; and (4) the inferior border, the oropharynx. The lateral wall of the nasopharynx contains the pharyngeal opening of the auditory tube. The medial cartilaginous extension of the auditory tube forms a protrusion from the lateral wall of the nasopharynx at the superior and posterior aspects of the opening of the auditory tube. This protrusion, with its overlying mucosa, creates the torus tubarius. Just posterior to the torus tubarius lies the pharyngeal fossa, or the fossa of Rosenmüller, which is formed by the junction of the lateral and posterior walls of the nasopharynx (Fig. 32-1A to D).
The sensory innervation is shown in Figure 32-1D. The maxillary division of the trigeminal nerve supplies the upper nasopharynx, the posterior part of the nasal cavity, and most of the palate and upper gums of the oral cavity. The general sensory branches of the lingual and pharyngeal branches of the glossopharyngeal nerve supply the sensory innervation of the lower part of the nasopharynx, the posterior third of the tongue, and part of the soft palate and oropharynx.
Understanding the anatomic relationships of the nasopharynx and adjacent structures is important to correctly diagnose patients with nasopharyngeal carcinoma. The importance of superior extension into the sphenoid bone of the base of the skull is exemplified by the fact that cranial nerves can be involved at presentation. The frequency of involvement of cranial nerves has been described in two large series.31,32 Cranial nerves V and VI are the most commonly involved. These nerves traverse the sphenoid bone and can be involved when tumors erode superiorly through bone. Tumors of the nasopharynx can also gain access to the cranial nerves of the base of the skull by eroding superiorly through the foramen lacerum, which is bordered superiorly by the internal carotid artery (Fig. 32-1B).
Lateral extension of nasopharyngeal carcinomas can lead to erosion of the medial opening of the auditory tube and the medial pterygoid plate and can involve cranial nerves IX, X, XI, and XII (Fig. 32-1B and C). Lateral extension can lead to involvement of the carotid artery and internal jugular vein.
Lymph node involvement is common; 65% to 80% of patients present with clinically involved cervical neck nodes. The level VA and level II lymph nodes are commonly involved. The recently published frequency of involvement of these areas in two large series31,32 is presented later in the Clinical Manifestations section.
Biologic Characteristics and Molecular Biology
The potential etiologic link between EBV and nasopharyngeal carcinoma was first described more than 30 years ago6; however, recent advances in molecular biology have shed further light on this association. Earlier work focused on the serologic response to EBV and showed elevated levels of IgA and IgG antibodies to the viral capsid antigen and a replication protein called early antigen in patients with nasopharyngeal carcinoma. Other studies have demonstrated the presence of EBV DNA and encoded proteins directly in the nasopharyngeal carcinoma tissue samples.33 Latent infection of cells with EBV, initially studied in B lymphocytes, is associated with regulated expression of several viral genes, including latent membrane proteins (LMPs) 1, 2A, and 2B, six EBV nuclear antigens (EBNAs) 1, 2, 3A to C, and LP, and two small noncoding nuclear RNAs (EBERs).34 Some of the molecular mechanisms by which expression of these genes can lead to transformation have been elucidated. For example, LMP1 induces expression of epidermal growth factor receptor (EGFR) and may therefore influence cellular growth. A restricted pattern of these EBV antigens is present in nasopharyngeal cancer cells, which may in part explain why immunotherapy directed against these antigens has been more successful in other EBV-associated diseases.35 Allogeneic cytotoxic T cells to various EBV antigens have been developed and show some promise for treating locally recurrent nasopharyngeal carcinoma.36
Several studies have suggested that serologic responses to EBV may be more specific for the nonkeratinizing carcinoma (former WHO types II and III).37 This, however, was not confirmed by another group.38 Using the Southern blot technique to detect the viral DNA, Raab-Traub and others39 showed the presence of EBV in all former histologic variants of nasopharyngeal carcinoma, but the EBV copy number was lowest in keratinizing squamous cell carcinomas. The presence of EBV in keratinizing squamous cell carcinoma has been consistently detected by other groups.40–43 The differences in the rate of EBV detection by different investigators may stem from variability in the sensitivity of different assays. Alternatively, it may reflect differences in the sampled populations. The detection rate of EBV infection in keratinizing squamous cell nasopharyngeal carcinoma is highest in endemic areas.
Understanding the molecular basis of EBV-induced carcinogenesis and the role of the immune system response in this process will likely have a direct bearing on clinical practice. An association between decreasing antibody titers and response to therapy suggested that antibody titers could be used to assess a patient’s prognosis.44 Quantification of EBV DNA levels in pretreatment and postradiotherapy plasma samples from patients in Hong Kong has been shown to correlate with outcome,45 and, therefore, could prove to be a useful tool in risk stratification and planning of therapeutic interventions in high-risk areas.
In addition to environmental factors, the potential association of various genetic factors and nasopharyngeal cancer is a topic of current investigation. Earlier work implicated a disease susceptibility gene linked to the human leukocyte antigen (HLA) region, which has been associated with the increased incidence of nasopharyngeal carcinoma in southern China.46 Simons and associates47 originally described an association in Chinese patients with nasopharyngeal carcinoma and the HLA-A2 antigen with a deficit of the second antigen at the second locus (B locus). Later, Simons and co-workers48 reported on 110 Chinese patients in Singapore with nasopharyngeal carcinoma and hypothesized that the new B-locus antigen (Sin 2) may be associated with the tumor. It remains unclear whether specific HLA alleles may influence development of nasopharyngeal carcinoma directly, possibly by affecting the immune reaction to EBV, or whether, and perhaps more likely, the genetic susceptibility to nasopharyngeal carcinoma is encoded by a locus in close linkage disequilibrium. Various other genetic and epigenetic alterations have been reported in nasopharyngeal carcinoma. Deletions of the short arm of chromosome 3 (3p25, 3p14)29 and of chromosome 9 (9p21-22)49 are the most common cytogenetic changes. Candidate genes in these and other locations of interest are being identified. These findings may lead to a greater understanding of the genetic basis of nasopharyngeal carcinomas and the interplay of environmental factors with these genetic factors.
Clinical Manifestations, Patient Evaluation, and Staging
As mentioned, nasopharyngeal carcinoma is rare in the United States and, therefore, is not often suspected as a possible cause of a patient’s early symptoms. In addition, the list of possible early symptoms of nasopharyngeal carcinomas includes many symptoms that could have more common causes. In a series of 378 patients from the MDACC,32 the presenting symptoms included a neck mass in 41%; hearing loss, ear drainage, or otalgia in 27%; nasal bleeding or obstruction in 21%; cranial nerve deficits in 8%; and other nonspecific symptoms in 8%. Investigators from Washington University noted that the typical presentation involved multiple symptoms.31 In this series of 143 patients, presenting symptoms included otitis in 43%, throat pain in 39%, nasal obstruction in 37%, a neck mass in 35%, nasal bleeding in 29%, cranial nerve involvement in 24%, and trismus or other symptoms in 5%.
Similar to these data, most series have shown that neck masses, obstructive ear symptoms, and cranial nerve deficits are common presenting symptoms for nasopharyngeal carcinoma. In the Washington University series,31 66% of patients were found to have ipsilateral neck masses and 28% had contralateral neck masses on examination, although only 35% of patients had reported a neck mass as the reason for seeking medical advice. Of the patients with clinically involved neck disease, 60% had enlarged ipsilateral level II lymph nodes and 32% had enlarged ipsilateral level V lymph nodes. The most frequently involved cranial nerves in the series were cranial nerve VI in 15% of patients, V in 7.7%, and VIII, X, and XII in 5.6% of patients each.
In the series from the MDACC,32 the level VA lymph nodes were most commonly enlarged (54% of patients), followed by the level II nodes (49% of patients). The level III and lower level VA/upper level VB groups were involved in 24% and 22% of patients, respectively. The level IV lymph nodes, level VB lymph nodes, and supraclavicular lymph nodes were involved in 10%, 13%, and 10% of patients, respectively. Similar to the series from Washington University, cranial nerve VI was the most frequently involved nerve (6% of cases).
Patient Evaluation
The initial evaluation of patients with nasopharyngeal carcinoma should include a history and physical examination, with special attention to the level of nodal involvement (if any) (Fig. 32-2). It is helpful to diagram or digitally photograph the clinically involved lymph nodes in the neck because it can be helpful when the radiotherapy boost is considered.
CT and MRI of the head and neck are useful in the evaluation of both erosion of tumor into the bony structures of the base of the skull and retropharyngeal and cervical lymphadenopathy. Although the same information is often provided by CT and MRI, some investigations have suggested that MRI may be more useful in delineating soft tissue invasion outside the nasopharynx and the extent of retropharyngeal lymph node involvement,50 whereas CT may be most useful in delineating skull base erosion.51,52,53 Given the level of anatomic information required for the current T staging system, MRI is becoming the imaging study of choice in the evaluation of nasopharyngeal tumors.
Positron emission tomography (PET) can be useful for staging54,55 as well as for post-therapy management where other imaging is unclear. PET/CT, which provides additional anatomic information, is more commonly used now and may be helpful for radiotherapy planning.
The completion of the diagnostic evaluation involves acquiring routine complete blood counts, a chemistry panel, and a chest radiograph (see Fig. 32-2). Further evaluation of possible metastases should be done on the basis of the clinical presentation of the patient.
Staging
After a pathologic assessment has been made, the workup or evaluation leads to a clinical stage (Table 32-2). Clinical staging has been a matter of controversy, and the prognostic significance of the various TNM staging criteria remains under investigation. Several staging systems have been in use throughout the world. The most commonly used systems in North America and Europe are those of the American Joint Committee on Cancer (AJCC)56 and the International Union Against Cancer (Union Internationale Contre le Cancer [UICC]),57 which have become essentially analogous. In Asia, where nasopharyngeal carcinoma is endemic, the Ho58 classification system was initially developed in Hong Kong. In addition, in 1992, Chinese physicians adopted an independent system similar to the Ho system.59 All four systems, shown in Table 32-2, have limitations and continue to evolve, with researchers often drawing on each others’ experience. Updated versions of the Chinese system and the AJCC system were released in 200860,61 and 2010,62 respectively. The AJCC/UICC remains the most commonly used system in the English literature.
A well-recognized advantage of the Ho classification system lies in its approach to lymph node metastasis, namely, use of lymph node location in N-stage assignment and a more even distribution of nodal disease in stage grouping58,63 (see Table 32-2). Nodal involvement appears in stage II, and supraclavicular nodal metastasis, which is known to carry a worse prognosis, is represented in a separate stage IV category (see Table 32-2). The 1992 AJCC system used lymph node size and laterality in N-stage assignment, both of which carry some prognostic significance. However, only some patients with N1 disease were included in stage III, and most patients with nodal involvement were grouped into stage IV, together with patients with metastatic disease. Modifications to the AJCC classification implemented in 199764 and maintained in 200265 and 201062 have incorporated lymph node location into N-category assignment, designating involvement of the supraclavicular fossa, as originally defined by the Ho system, as N3 disease, and have placed all N3M0 lesions in a separate stage IVA grouping. In addition, stage groupings were changed to provide a more even stage distribution. These changes improved risk stratification of the 1997 AJCC classification in comparison to both the prior version of the AJCC system and the 1978 Ho system.66,67
Important changes to the most recent AJCC system targeted T-category assignment. Invasion into the soft tissues of the nasopharynx was used in the 1997 and 2002 AJCC classification to segregate T1 and T2 lesions, but studies have shown that this carries no prognostic significance.68–70 The parapharyngeal involvement used to segregate T2a and T2b lesions does,71,72,73 however, and therefore the new 2010 AJCC system segregates lesions with parapharyngeal involvement into the T2 subgroup, whereas all tumors either confined to the nasopharynx or extending into surrounding subsites but without parapharyngeal involvement are now in the T1 subgroup. Furthermore, cranial nerve involvement carries a significantly worse prognosis than base-of-skull involvement,31,69,74–76 but both were aspects of the T4 subgroup in the 1997 and 2002 AJCC systems and of the T3 subgroup in the Ho system. In the 2003 and 2010 versions, akin to the 2008 Chinese classification system, base-of-skull involvement has been downstaged to T3. Furthermore, data are emerging that extensive cranial nerve involvement, orbit involvement, and intracranial extension are associated with worse outcomes within the T4 subgroup.67,76 Therefore, some of the proposed modifications to the AJCC system include a separation of the T4 subgroup into two categories. T4a would include tumors with involvement of the masticator space (infratemporal fossae), asymptomatic radiographic cranial nerve involvement, and involvement of the hypopharynx. T4b would include tumors with intracranial extension, orbital involvement, and symptomatic cranial nerve palsies. However, more data need to be collected to validate this proposed modification.
With respect to N-category classification, the seventh edition of the AJCC staging manual for the first time includes disease that has spread to the retropharyngeal lymph nodes in staging, placing it in the N1 category. On MRI evaluation, these nodes are involved in 83% of patients with nasopharyngeal carcinoma compared with 74% involvement of the level II to IV nodes, and are considered to be the first echelon of nodal spread.77 Therefore, their inclusion into the staging system is expected to improve the prognostic accuracy.78,79
Primary Therapy
Traditionally, the nasopharyngeal area has not been easy to examine without fiberoptic technology and has been difficult to approach surgically. Surgical exposure of the area and resection of tumors with adequate tumor margins have long been challenging.80 For these reasons, primary surgical intervention fell out of favor in the 1950s; primary treatment has generally consisted of radiotherapy alone and, more recently, radiotherapy plus concurrent chemotherapy.
Single-Modality Therapy
Although histologic presentations of nasopharyngeal tumors vary throughout the world, with more undifferentiated tumors found in southern China and Hong Kong, the 10-year survival rates for patients treated with radiation therapy alone in the United States (MDACC),32 Denmark,81 and Hong Kong82 are similar, at 34%, 37%, and 43%, respectively (see Table 32-1). The rate from the Hong Kong study may be somewhat inflated because many patients had early-stage disease (node-negative disease in 39%) and few patients with the keratinizing histology (0.3%) were present in the series.82 However, elevation of EBV titers has been correlated with a poor prognosis,34 and higher titers would be expected in Hong Kong, an endemic area. The North American and European populations have a greater percentage of patients with keratinizing (WHO type I) histologic findings than with nonkeratinizing histologic findings (WHO types II and III), however, and the prognosis for the former has been poorer than for the latter.68 Therefore comparison of groups from various parts of the world is difficult, and our understanding of the role of EBV and histologic classifications is incomplete. Still, some general statements can be made.
The MDACC series elucidated the long-term outcome in a large population of patients treated with radiotherapy alone.32 Using the 1992 AJCC staging system (see Table 32-2), researchers found that advanced T category, squamous histologic typing, and cranial nerve deficits were predictive of poor prognosis for local control in univariate and multivariate analyses. Five-year local control rates for T1, T2, T3, and T4 categories were 93%, 79%, 68%, and 53%, respectively. Similar results were observed in other, smaller series.31,83–86
Combined-Modality Therapy
Irradiation Plus Chemotherapy
The randomized trial of Sanchiz and associates87 served as an introduction for using chemotherapy in nasopharyngeal cancer. However, only a small number of patients with nasopharyngeal cancer were included.
Brizel and co-workers88 reported a small randomized trial comparing twice-daily irradiation (1.25 to 75 Gy) to twice-daily irradiation (1.25 to 70 Gy) with concurrent cisplatin and 5-fluorouracil (5-FU) treatment. This trial included 121 patients with locally advanced (T3 and T4) squamous cell carcinomas of all head and neck sites (including some nasopharyngeal carcinomas). With a median follow-up of 41 months, the locoregional control rate at 3 years was 70% for the combined-modality arm versus 44% for the irradiation alone arm (p = .01). The overall survival (OS) at 3 years was 55% for the combined-modality arm versus 34% for the irradiation alone arm (p = .07). Mucositis appeared to be more prevalent in the combined-modality arm; 45% of patients required feeding tubes compared with 28% in the irradiation alone arm. However, the severe late complications of soft tissue necrosis or osteoradionecrosis were uncommon, with similar numbers in both arms (three patients in the irradiation group and five in the combined-modality group).
Several groups have conducted phase III trials specific to nasopharyngeal primary tumors (instead of a wide array of head and neck cancers). The trial design compared chemotherapy plus irradiation versus irradiation alone* (Table 32-3).
The intergroup study 0099 showed a dramatic improvement in survival rates with combined-modality treatment.1 The trial was closed at a planned interim analysis (October, 1995) after review of the preliminary results by the Data Safety and Monitoring Committee for the Southwest Oncology Group. The results are shown in Table 32-3. Patients treated with standard irradiation received 70 Gy to gross disease in daily fractions of 1.8 to 2 Gy. Patients enrolled in the combined-modality arm received 100 mg/m2 of cisplatin on days 1, 22, and 43 of irradiation, and cisplatin (80 mg/m2) and 5-FU (1000 mg/m2) on days 1 to 4 every 3 weeks for three courses after irradiation. A marked statistically significant improvement in both disease-free survival (DFS) and OS in the combined-modality arm was documented at both initial analysis and in the final update of the trial published in 2001.93 The 5-year OS for patients with the keratinizing squamous cell carcinoma histologic type (WHO type I) was 37%; the differentiated nonkeratinizing histologic type (WHO type II), 55%; and the undifferentiated nonkeratinizing histologic type (WHO type III), 60%.
Although the first reported results from a chemoradiation trial conducted in an endemic area were disappointing,91 the recently published final update94 as well as four additional independent trials conducted in Taiwan,89 Hong Kong,92,98 and Singapore96 all confirmed an advantage to cisplatin-based chemoradiation (see Table 32-3). A randomized trial from Hong Kong of concurrent weekly cisplatin chemotherapy (40 mg/m2), without adjuvant or neoadjuvant therapy, versus irradiation demonstrated a significant improvement in progression-free survival (PFS) at a median follow-up of 2.71 years91 and in OS at a median follow-up of 5.5 years (hazard ratio [HR], 0.51; p = .013)94 for a subset of patients with T3 to T4 disease. A trial conducted by Lin and colleagues89 in Taiwan randomized 284 patients to irradiation alone versus irradiation with two cycles of concurrent cisplatin (20 mg/m2/day) and 5-FU (400 mg/m2/day) by continuous infusion given over a course of 4 days. In this trial, combined-modality treatment was associated with a significant survival advantage. The differences in the degree of benefit derived from the combined-modality treatment in these two studies may stem from the different staging systems used to define entry criteria (AJCC system in the Lin study vs. Ho system in the Chan et al study91), different histologic makeup of the tumors (73.2% differentiated nonkeratinizing carcinoma in the Lin study vs. 93.7% undifferentiated carcinoma in the Chan study), or different chemotherapy and/or radiotherapy schedules. The role for concurrent chemotherapy in the management of nasopharyngeal carcinoma has been further supported by two other trials comparing concurrent and adjuvant chemotherapy with irradiation alone92,96 (see Table 32-3).
Many additional trials have been performed exploring combination chemotherapy and radiotherapy for nasopharyngeal carcinoma.59,90,95,99 So far, no benefit was shown to neoadjuvant or adjuvant chemotherapy in any of the randomized trials. Likewise, a recent meta-analysis using combined individual data from eight randomized trials enrolling 1753 patients showed no OS benefit with either neoadjuvant or adjuvant chemotherapy, although a meaningful treatment effect was seen for concurrent chemoradiation.100 However, the question remains whether addition of induction and/or adjuvant chemotherapy to concurrent chemotherapy may provide an additional advantage. Two ongoing trials are aimed at answering that question. A trial by the Nasopharyngeal Cancer Study Group of Hong Kong is designed to compare induction versus adjuvant chemotherapy with cisplatin and 5-FU in combination with concurrent chemoradiation (NCT00379262). A multicenter phase III trial opened by the Taiwan National Health Research Institutes is designed to compare a cisplatin-based multiagent induction regimen (mitomycin, epirubicin, cisplatin, 5-FU, and leucovorin) followed by concurrent chemoradiation with chemoradiation alone (NCT00201396). Both studies are expected to be completed by 2013.
In addition to evaluating the best sequencing for chemotherapy and irradiation, investigators are also examining the role for other chemotherapeutic agents in treatment of nasopharyngeal carcinoma. A recent study explored the efficacy of weekly carboplatin in the setting of concurrent chemoradiation for patients with locally advanced disease.101 At a median time of 26 months, OS and DFS were similar in the cisplatin and carboplatin groups, with less toxicity noted in the latter group. Therefore treatment with carboplatin is reasonable when use of cisplatin is precluded by patient comorbidities.
Setting the precedent, several landmark randomized controlled phase III studies have demonstrated that taxanes in the neoadjuvant setting greatly improve outcomes in other head and neck carcinomas.102,103 Phase II studies of patients with locally advanced nasopharyngeal cancer have already shown favorable results with paclitaxel, both in the neoadjuvant setting followed by concurrent therapy with platins or as a part of a concurrent regimen.104–106 To further address this question, a phase III trial was opened in 2009 by the international Groupe Oncologie Radiotherapie Tete et Cou (GORTEC), randomizing patients with nasopharyngeal carcinoma to receive induction chemotherapy with docetaxel, cisplatin, and 5-FU followed by concurrent chemoradiation with cisplatin or cisplatin-based concurrent chemoradiation alone (NCT00828386).
Molecular therapies are also under investigation. Although one trial showed a benefit to the use of cetuximab in other head and neck cancers,107 it remains to be seen whether these data will be confirmed for squamous cell carcinomas of the head and neck in general108 or for nasopharyngeal carcinoma in particular.
