Cancer of the Nasopharynx

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27 Cancer of the Nasopharynx

Nancy Lee, MD, A. Dimitrios Colevas, MD, Karen K. Fu, MD

Epidemiology

Nasopharyngeal carcinoma (NPC) is uncommon in most parts of the world. The incidence is highest among people from southern China, particularly those originating from Kwantung Province, followed by the Chinese mixed populations of Southeast Asia and indigenous populations in Alaska.¹^,² It is of intermediate incidence in North Africa and in the Philippines and it is rare among whites and Japanese. The age-adjusted incidence rate (per 100,000 population per year) ranges from 28.8 in Hong Kong, 17.2 in indigenous populations in Alaska, 16.8 in Singapore, 4.6 in the Philippines, 2.8 in Algeria, and 0.6 in the United States and Japan.³^,⁴ The peak incidence occurs in the fourth and fifth decade of life, and the male/female ratio is 2 : 1 to 3 : 1.

Causal Factors

The cause of NPC is most likely multifactorial. Current epidemiologic and experimental data suggest at least three major causal factors: (1) viral, (2) genetic, and (3) environmental. Epstein-Barr virus (EBV) has long been associated with NPC. Antibody titers to EBV have been found to be elevated in NPC patients regardless of their ethnic and geographic origin. The EBV genome has been demonstrated by nucleic acid hybridization in biopsies from NPC. Recent studies show that EBV nuclear antigen was expressed in nearly all cases and that latent membrane protein was expressed in approximately two-thirds of cases of EBV-positive NPCs.⁵ Using real-time polymerase chain reaction technology, Lo⁶ was able to detect circulating EBV deoxyribonucleic acid (DNA) in 96% of NPC patients in Hong Kong. The high incidence of NPC among southern Chinese and southeast Asian populations of southern Chinese descent suggests a genetically determined susceptibility. Highly significant differences in histocompatibility human leukocyte antigen (HLA) patterns have been found between Chinese NPC patients and control subjects. There is a significant increase of HLA-A2 and HLA-B-SIN2 in Chinese patients.⁷ However, the high-risk HLA pattern is not present in all NPC patients and such a pattern is present in some individuals with no NPC. The decreased incidence of NPC in successive generations of Chinese-born populations in the United States⁸ suggests a role for environmental factors in the causal factors of this disease. Various environmental factors such as poor ventilation, occupational exposures to smoke or dusts, and diet have been implicated. The ingestion of salted fish during early childhood has been suggested as the most important environmental factor among the southern Chinese with NPC.^2,^9,¹⁰ Dimethylnitrosamine, a carcinogen found in salted fish, has been shown to induce carcinoma in the upper respiratory tract of rats.⁹

Anatomy

The nasopharynx is a roughly cuboidal open chamber located below the base of the skull and behind the nasal cavity. It measures 4 to 5.5 cm in its widest transverse diameter, 2.5 to 3.5 cm in its anterior-posterior diameter, and approximately 4 cm in height.

Anteriorly, the nasopharynx is in continuity with the nasal cavity through the posterior choanae, which are separated by the nasal septum. The posterior wall lies at the level of the first two cervical vertebrae and is continuous with the roof. The roof is formed by the basisphenoid, basiocciput, and the anterior arch of the atlas. The lymphoid tissue in this area forms the pharyngeal tonsil (adenoids) (Fig. 27-1). Each of the lateral walls contains the eustachian tube orifice, which is surrounded by the torus tubarius (see Fig. 27-1), a prominence in the cartilaginous portion of the tube. Behind the torus tubarius is a recess called the Rosenmüller fossa (see Fig. 27-1 and 27-2). The lateral walls, including the Rosenmüller fossa, are the most common sites of origin of NPC. The floor of the nasopharynx consists of the upper surface of the soft palate and communicates with the oropharynx via the pharyngeal isthmus. The isthmus is bounded by the uvula anteriorly, the palatopharyngeal arches laterally, and the posterior pharyngeal wall posteriorly.

FIGURE 27-1 • Mid-sagittal section of the head showing the nasopharynx and related structures.

(From MacComb WS, Fletcher GH: Cancer of the head and neck, Baltimore, 1967, Williams & Wilkins, p 154.)

FIGURE 27-2 • Normal computed tomography (CT) and magnetic resonance imaging (MRI) images of the nasopharynx. A, Axial postcontrast CT scan obtained through the midnasopharynx. Just posterior to the medial pterygoid plate (PP) is a small recess representing the orifice of the eustachian tube (E). Posterior to this and separating the fossa of Rosenmüller (R) from the eustachian orifice is a protuberance that extends in the nasopharyngeal airway, the torus tubarius (T). Lateral to the pterygoid plates is the lateral pterygoid muscle (P). Note the normal asymmetry of the fossa of Rosenmüller (double white arrows), which can occasionally simulate early carcinoma. Also of importance is the symmetrical parapharyngeal space, which contains branches of the internal maxillary artery and small veins of the pterygoid plexus. The parapharyngeal space separates the deep lobe of the parotid gland from the soft tissues of the nasopharynx and serves as a landmark for deep invasion from carcinoma of the nasopharynx. B, Axial “proton density”—weighted MRI scan through the nasopharynx showing soft tissue contrast achieved with MRI scanning in this region. Note the higher-signal-intensity mucosal adenoidal tissue, which is easily separated from the underlying musculature of the deep pharyngeal soft tissues. Also note the musculature of the masticator space, including the masseter muscle, deep head of the temporalis muscle, lateral and medial pterygoid muscles, as well as the tensor veli and levator veli palatini muscles. Note the symmetric convex appearance of the longest capitis muscles (L) positioned directly behind the mucosa of the nasopharynx and Rosenmüller’s fossa (R). Posterior and lateral to the torus tubarius (T) is the parapharyngeal space (P), containing fat and separating the deep structures from the deep lobe of the parotid gland. C, Coronal T2-weighted MRI scan showing the intimate relationship of the superior recess of the nasopharynx to the skull base, the torus tubarius (T), the levator veli palatini muscle (double arrows), the medial pterygoid muscle (M), the lateral pterygoid (LP) muscle, the mandible, and the masseter muscle. Positioned in the midline are the tongue and soft palate.

The posterior wall of the nasopharynx is made up of four anatomic layers: the mucous membrane of the pharynx; the pharyngeal aponeurosis; the superior constrictor muscle of the pharynx; and the buccopharyngeal fascia, which is loosely connected with the adjacent prevertebral fascia. The muscular wall of the nasopharynx is incomplete. In the upper nasopharynx, the lateral walls consist of only two layers: the mucous membrane and the pharyngeal aponeurosis. This area of muscular deficiency is called the sinus of Morgagni, through which the cartilaginous part of the eustachian tube enters the pharyngeal wall along with the levator veli palatini muscle.

The pharyngeal fascia of the posterior and lateral walls of the nasopharynx is attached to the pharyngeal tubercle on the basiocciput just in front of the foramen magnum. It extends laterally on each side to the ridge on the undersurface of the petrous pyramid, just in front of the carotid canal and anteriorly to the apex of the petrous portion of the temporal bone, and then to the posterior border of the medial pterygoid plate. This fascia is continuous with the fibrous tissue occupying the foramen lacerum, which is separated from the middle cranial fossa only by fibrocartilaginous tissue. Five other foramina are adjacent to the wall of the nasopharynx: the foramen ovale, the foramen spongiosum, the carotid canal, the jugular foramen, and the hypoglossal canal (Fig. 27-3). The foramen lacerum and the foramen ovale constitute the petrosphenoidal crossway, providing an easy pathway into the cranium, and are in close anatomic relationship to the cavernous sinus and hence the II, III, IV, and VI cranial nerves, and the trigeminal ganglion of the fifth nerve and its branches.

FIGURE 27-3 • Basal view of the skull showing the bony attachments of the nasopharyngeal wall. The bony foramina of the base of the skull are shown on the right and the structures occupying these foramina appear on the left.

(From MacComb WS, Fletcher GH: Cancer of the head and neck, Baltimore, 1967, Williams & Wilkins, p 155.)

Anterior to the eustachian tube, the lateral wall of the nasopharynx is in close relation with the maxillopharyngeal space, which is limited laterally by the ascending ramus of the mandible. In this space is the mandibular nerve descending from the foramen ovale. Posterior to the eustachian tube, Rosenmüller fossa is in close relationship with the lateral pharyngeal or retroparotidian space. The lateral pharyngeal or retroparotidian space is limited anteriorly by the parotid gland and the styloid process and its muscles, posteriorly by the transverse process of the first cervical vertebra, and laterally by the sternocleidomastoid muscle. It contains the lateral pharyngeal nodes, including the lateral retropharyngeal node of Rouvière; the internal carotid artery; the internal jugular vein; and the glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves, as well as the cervical sympathetic nerves as they emerge from the base of skull (Fig. 27-4).

FIGURE 27-4 • Poststyloid portion of the lateral pharyngeal space and its contents.

(From MacComb WS, Fletcher GH: Cancer of the head and neck, Baltimore, 1967, Williams & Wilkins, p 157.)

Blood supply to the nasopharynx is provided by one direct and two indirect branches of the external carotid artery. They are (1) the ascending pharyngeal artery and two branches of the maxillary artery, (2) the artery of the pterygoid canal (vidian artery), and (3) the sphenopalatine artery. Venous drainage is via the pharyngeal plexus, which communicates with the pterygoid plexus above and drains into the internal jugular vein below. The pharyngeal plexus also communicates with the veins of the orbit through the inferior ophthalmic vein. Nerve supply to the nasopharynx is primarily derived from branches of the glossopharyngeal (IX), the vagus (X), and the sympathetic nerves, although the maxillary (V2) branch of the trigeminal (V) nerve supplies the sensory innervation of the anterior portion of the roof and floor of the nasopharynx and the motor innervation of the tensor veli palatini.

Lymphatic Drainage

The nasopharynx has a rich lymphatic plexus, particularly in the roof and in the posterior and lateral walls. The lymphatics from the nasopharynx have three major pathways (Fig. 27-5):

1 One path is through the lateral pharyngeal wall to the lateral pharyngeal (parapharyngeal) nodes in the lateral pharyngeal or retroparotid space. The uppermost of this group of nodes is the lateral retropharyngeal node of Rouvière (see Fig. 27-5).

2 From these lateral pharyngeal nodes, efferent channels pass to the jugular chain, especially to the jugulodigastric (subdigastric) nodes. Some lymphatic channels may bypass the lateral pharyngeal wall and drain directly to the jugulodigastric node.

3 Another path is by direct channel to the deep nodes of the posterior triangle, the spinal accessory nodes. The uppermost node of this chain lies beneath the sternocleidomastoid muscle at the tip of the mastoid process.

FIGURE 27-5 • Major lymphatic drainage of the nasopharynx.

(From MacComb WS, Fletcher GH: Cancer of the head and neck, Baltimore, 1967, Williams & Wilkins, p 158.)

From these primary groups of nodes, further extensions proceed down the jugular chain to the mid and lower jugular nodes and down the spinal chain to the mid and lower posterior cervical nodes in the posterior triangle. Lymphatic channels crossing the midline account for contralateral or bilateral involvement. Rarely, carcinoma of the nasopharynx may spread to the submaxillary and submental nodes. Spread to the parotid nodes can occur via the lymphatics of the eustachian tube.

Pathologic Conditions

The majority of malignant nasopharyngeal tumors (80% to 99%) arise from the epithelium and should be considered as variants of squamous cell carcinoma. According to the most commonly used World Health Organization (WHO) classifications, carcinomas of the nasopharynx are classified into three histologic types: (1) squamous cell carcinoma, (2) nonkeratinizing carcinoma, and (3) undifferentiated carcinoma.¹¹ In 1991 the WHO reclassified NPC into the following histologic subtypes: (1) keratinizing squamous cell carcinoma, (2a) nonkeratinizing carcinoma, and (2b) undifferentiated carcinoma.¹² The histologic distinctions among these three types are by no means sharp. Some lesions share intermediate features and some are histologic hybrids. The term lymphoepithelial carcinoma or lymphoepithelioma is used to describe nonkeratinizing and undifferentiated NPCs in which numerous lymphocytes are found among the tumor cells. The distribution of WHO histopathologic types varies with geography, race, and national origin.¹³ Asians have the highest proportion of WHO types 2 and 3. In Hong Kong, approximately 3% are type 1, 9% are type 2, and 88% are type 3.¹⁴ In North America, approximately 20% of NPCs are type 1, 10% are type 2, and 70% are type 3.¹⁵ WHO type 1 includes 75% of the U.S. NPC cases and are found most often in U.S.-born, non-Hispanic whites. WHO types 2 and 3 compose the remaining 25% and are more common in Asians. Other uncommon malignant tumors found in the nasopharynx include adenocarcinoma, lymphoma, plasmacytoma, melanoma, and sarcomas.

In the 2010 AJCC staging manual, WHO reclassified NPC into 3 subcategories: keratinizing squamous cell carcinoma (former WHO Type I) and nonkeratinizing carcinoma, which is subdivided into differentiated (former WHO Type II or 2a) versus undifferentiated (former WHO Type III or 2b). A recently described new subcategory called basaloid squamous cell carcinoma was also added to the classification of NPC.

Clinical Presentation

A neck mass is the most frequent presenting symptom and sign in carcinoma of the nasopharynx.¹⁶ Other common symptoms include epistaxis, decreased hearing, nasal obstruction, pain, and cranial nerve deficits. Cervical lymphadenopathy is present in 87% of patients.¹⁷ Typically, a mass is visible in the upper posterior neck and palpable beneath the superior aspect of the sternocleidomastoid muscle at the tip of the mastoid. This is due to metastasis in the parapharyngeal or superior posterior cervical nodes of the spinal accessory chain or both. Bilateral cervical lymph node metastases occur in approximately 50% of cases. The most frequently involved nodes are the upper posterior cervical, parapharyngeal, and jugulodigastric nodes. The midjugular and midposterior cervical nodes are the next most commonly involved, followed by the lower jugular and supraclavicular nodes. The submental nodes and occipital nodes are occasionally involved, usually in the presence of massive cervical lymphadenopathy in the more commonly involved neck sites. Rarely, patients present with metastatic preauricular nodes. Nasal voice occurs as a consequence of nasal obstruction, loss of nasopharyngeal resonance, and mechanical interference with normal movement of the soft palate. Nasal discharge, epistaxis, and coughing up of blood-tinged sputum from postnasal drip are symptoms due to local tumor effect. Impaired hearing of the conductive type, usually unilateral with or without tinnitus and serous otitis media, occurs as a result of obstruction, usually by compression rather than direct extension, of the eustachian tube orifice by the primary tumor.

Cranial nerve deficits can result from direct extension intracranially with compression of the II to VI cranial nerves as they emerge from the cranial vault at or near the base of skull orifices (the petrosphenoidal syndrome of Jacod) or from lateral retropharyngeal lymph node metastases in the retroparotid space with involvement of the IX to XII cranial nerves and the cervical sympathetic nerve (the syndrome of the retroparotid space of Villaret). The cranial nerves V and VI are most frequently involved, whereas cranial nerves I, VII, and VIII are rarely involved.

Syndromes from nerve compression seen in NPC include the following: the petrosphenoidal syndrome of unilateral neuralgia of the trigeminal (V) type, unilateral ptosis (III), complete ophthalmoplegia (III, IV, and V) and amaurosis (II). The syndrome of retroparotid space of difficulty in swallowing (IX and X); perversion of taste in the posterior third of the tongue (IX); hyperesthesias, hypoesthesias, or anesthesias of the mucous membrane of the soft palate, pharynx, and larynx; respiratory and salivary problems (X); hemiparesis of the soft palate; paralysis and atrophy of the trapezius and sternocleidomastoid muscles (XI); and unilateral paralysis and atrophy of the tongue (XII). This may be accompanied or preceded by Horner syndrome resulting from compression of the cervical sympathetic nerve.

Pain is often caused by the compression of the trigeminal nerve or its branches and from invasion of the bones of the skull. Facial pain and occipital and temporal headaches are most common. Pain in lifting the head and extending the neck can occur as a consequence of posterior invasion of the prevertebral muscles.

Sore throat occurs secondary to tumor extension into the oropharyngeal wall. Trismus results from invasion of the pterygoid muscles or involvement of the motor branches of the fifth nerve. Proptosis occurs with posterior orbital invasion.

Distant metastasis at presentation is detected in approximately 3% of cases.¹⁸ The bones, lungs, and liver are the most common distant metastatic sites.

Routes of Spread

Local Extension

Anteriorly, direct extension into the nasal cavity is common. Invasion into the lateral wall of the nasal cavity may lead to destruction of the pterygoid plates. Invasion of the posterior ethmoid and maxillary sinuses is less common. Orbital invasion can occur in advanced disease.

Superior and Posterior

Superiorly and posteriorly, the tumor can directly invade the base of the skull, the sphenoid sinus, and the clivus. The foramen lacerum, located directly above Rosenmüller fossa, is a weak spot in the base of the skull, through which the tumor can gain access into the cavernous sinus and the middle cranial fossa and invade cranial nerves II to VI. Tumor may also invade through the foramen ovale into the middle cranial fossa, the petrous part of the temporal bone, and the cavernous sinus. Invasion of the prevertebral (longus capitus) muscles posteriorly is commonly seen on magnetic resonance imaging (MRI) scans (Fig. 27-6).

FIGURE 27-6 • Magnetic resonance imaging (MRI) scans of a patient with T₄-N₂ carcinoma of the nasopharynx: A, Transaxial postcontrast T1-weighted MRI scan with fat saturation demonstrating an invasive carcinoma (T) of the left fossa of Rosenmüller. Note that the carcinoma extends into the left longest capitis muscle and into the left hypoglossal canal (H). B, Coronal postcontrast T1-weighted image with fat saturation demonstrating multiple bilateral lymph nodes, the largest of which is located in the upper left posterior cervical chain. C, Axial fast-spin-echo T2-weighted MRI scan through the neck demonstrating bilateral enlarged, inhomogeneous lymphadenopathy. Note the foci of high signal intensity within the lymph nodes, indicating malignant invasion (arrows).

Inferior

Inferiorly, extension into the oropharynx is not uncommon. It may involve the tonsillar pillars, the tonsillar fossae, and the lateral and posterior oropharyngeal walls. Invasion of the C1 vertebra posteriorly and inferiorly occurs in advanced disease. Direct invasion of the soft palate is uncommon.

Lateral

Lateral spread into the lateral parapharyngeal space and invasion of the levator and tensor veli palatini muscles occur early and are commonly seen on MRI scans (see Fig. 27-6 and Fig. 27-7). Invasion of the pterygoid muscles occurs in more advanced disease. Direct tumor extension or lateral retropharyngeal lymph node metastasis in the parapharyngeal space can lead to compression or invasion of cranial nerve XII as it exits through the hypoglossal canal, cranial nerves IX to XI as they emerge from the jugular foramen and the cervical sympathetic nerves. Compression or direct invasion of the internal carotid artery can also occur in advanced disease. Through the eustachian tube, tumor can directly invade the middle ear.

FIGURE 27-7 • Magnetic resonance imaging (MRI) scans of a patient with T₄N₀ carcinoma of the nasopharynx. A, Sagittal T1-weighted MRI scan demonstrates abnormal soft tissue (arrows) in the region of the left cavernous sinus extending from the upper nasopharynx. B, Axial postcontrast T1-weighted image following fat saturation demonstrating an invasive carcinoma that extends across midline to involve both Rosenmüller’s fossae (arrows). C, Coronal T1-weighted postcontrast MRI scan demonstrating the invasive carcinoma of the nasopharynx (black arrows) with extension through the foramen ovale along the course of the third division of the fifth cranial nerve into the cavernous sinus (white arrows). D, Axial postcontrast T1-weighted image through the cavernous sinus demonstrating an enhancing tumor that has expanded the left cavernous sinus (arrows) as it courses along the third division of the fifth cranial nerve.

Lymphatic Spread

Lymphatic spread to the ipsilateral nodes is common and is present in 85% to 90% of cases.¹⁷ Bilateral spread occurs in approximately 50% of cases. Metastasis to the contralateral nodes only is uncommon. The distribution of clinically palpable nodes at diagnosis is shown in Fig. 27-8. Spread to the lateral and posterior retropharyngeal lymph nodes occurs early and is frequently seen on MRI or computed tomography (CT) scans, although the nodes are not palpable (Fig. 27-9). Metastasis to the jugulodigastric and superior posterior cervical nodes is also common. From these first echelon nodes, further metastasis to the midjugular and posterior cervical, lower jugular, and posterior cervical and supraclavicular nodes can occur. Occasionally, spread to the submental and occipital nodes occurs as a result of lymphatic obstruction caused by extensive cervical lymphadenopathy. Metastasis to the mediastinal lymph nodes may occur when supraclavicular lymphadenopathy is present, and occasionally there is metastasis to the axillary nodes as well. Distant lymph node metastasis is often reported in autopsy series, but is rarely apparent clinically at diagnosis.

FIGURE 27-8 • Distribution of clinically palpable cervical lymph nodes at diagnosis.

(From Fletcher GH: Textbook of radiotherapy, ed 3, Philadelphia, 1980, Lea & Febiger, p 260.)

FIGURE 27-9 • Axial T2-weighted MRI scan through the midnasopharynx showing the presence of a metastatic right lateral retropharyngeal lymph node (N). Note its location lateral and posterior to the tumor (T) in the right fossa of Rosenmüller.

Hematogeneous Spread

Distant metastasis is present in 3% of the cases at diagnosis and may occur in 18% to 50% or more of cases during the course of the disease.¹⁹^–²³ An 80% incidence rate has been reported in a small autopsy series.²⁴ The incidence of distant metastasis is highest in patients with advanced neck node metastasis,^19,²⁵^–²⁷particularly in the low neck.²⁸^,²⁹ Bone is the most common distant metastatic site followed by the lungs and liver.

Diagnostic and Staging Studies

Diagnosis of NPC is established by biopsy of a primary tumor in the nasopharynx, which usually can be done under local anesthesia in the outpatient clinic. Biopsy with direct visualization under general anesthesia may be necessary to obtain a positive tissue diagnosis when the tumor is not visible or when the patient cannot cooperate. Not infrequently the tumor is submucosal and not visible. In cases suspicious for a nasopharyngeal primary tumor, but without a visible tumor, random biopsies should be taken from the most commonly involved sites: Rosenmüller fossa on each of the lateral walls and the superior posterior wall of the nasopharynx. Fine needle aspiration of a neck mass may establish the presence of metastatic NPC in cervical lymph nodes. This may precede biopsy of the nasopharynx when the primary tumor is not clinically detectable.

The following pretreatment diagnostic evaluations are recommended:

1 Complete history and physical examination, including a fiberoptic endoscopy examination

2 MRI (preferred) or CT scan of the nasopharynx, paranasal sinuses, base of the skull, nasal cavity, and the neck

3 Posterior-anterior and lateral chest x-ray

4 Complete blood count, urinalysis, and liver function tests

5 EBV-specific serologic tests, immunoglobulin A (IgA) anti-viral capsule antigen (VCA) titers, serum EBV DNA levels

6 Bone scan in patients with advanced locoregional disease, symptoms suggestive of bone metastasis, or an elevated serum alkaline phosphatase

7 CT scan of the chest and abdomen in patients with abnormal liver function tests or clinical suspicion of lung or liver metastasis

8 Pretreatment dental evaluation and initiation of dental prophylaxis

9 Positron emission tomography (PET) scan to evaluate full extent of disease

The nasopharynx is best visualized with a fiberoptic endoscope. However, when the nasal cavity is completely obstructed because of tumor extension, the tumor may be visualized through indirect mirror examination or with a flexible fiberoptic endoscope. Complete physical examination should include careful palpation of the neck, cranial nerve examination, percussion and auscultation of the chest, palpation of the abdomen for possible liver involvement, and percussion of the spine and bones for possible bone metastasis.

Both MRI and CT scans are useful in diagnostic imaging of the nasopharynx, as well as in radiotherapy treatment planning. However, MRI is the imaging technique of choice in the staging evaluation of NPC.³⁰^–³² Because the current T classification system requires a search for tumor invasion into the soft tissue, such as parapharyngeal space, and bony structures, MRI may be necessary for proper staging because CT has limitations in accurately defining the tumor extent in these regions.³³ MRI is capable of multiplanar display of tumor extent and is superior to CT scans in delineating muscle, other soft tissue involvement, and evaluating the skull base (see Fig. 27-6, Fig. 27-7, and Fig. 27-10).³³^–³⁵ In post-treatment follow-up examinations, it has the ability to differentiate radiation fibrosis from persistent or recurrent tumor based on T2-weighted signal intensities and with gadolinium enhancement and fat suppression.³⁶ MRI and CT scans can also detect lymph node metastasis that may not be evident on clinical examination³⁷ (see Fig. 27-9). CT scan is superior to MRI in the detection of early bone invasion.³²^,³⁴ CT scan with bone windows is useful to demonstrate the extent of invasion of the base of the skull or cervical vertebrae, although MRI is preferable. The major limitation of CT is its poor tissue differentiation, which may be problematic in the evaluation of patients after radiotherapy.³⁵

FIGURE 27-10 • MRI scans of a patient with early stage carcinoma of the nasopharynx. A, Sagittal T1-weighted MRI scan. A soft tissue mass can be visualized in the upper nasopharynx (arrows). Note the soft tissue mass does not invade the normal high-signal-intensity marrow of the clivus (C). B, Axial T2-weighted MRI scan. Expansion of the left fossa of Rosenmüller by a high-signal-intensity mass can be identified (arrows). While normal asymmetry of the adenoidal tissue may be seen, it will not result in mass effect as is seen here. This is the earliest appearance of nasopharyngeal carcinoma confined to the mucosa of the nasopharynx. C, Coronal T1-weighted MRI scan following contrast administration. The mass within the left upper recess of the nasopharynx (arrow) is visualized. However, it has little in the way of signal intensity difference from surrounding normal mucosa. There is no invasion of the skull base or the cavernous sinus.

PET CT scanning has been used more frequently recently in the staging of nasopharyngeal cancer patients. Preliminary data suggest that the standardized uptake value (SUV) may be predictive for failure at distant sites.³⁸^,³⁹ PET CT is now commonly used in lieu of conventional staging with CT, bone scans, and ultrasound studies, and appears to be at least as sensitive, but large comparative studies of these staging modalities are not available.⁴⁰^,⁴¹

The close association between EBV and NPC, regardless of geographic and ethnic background, has provided a tumor marker for the diagnosis of this disease. Both IgA anti-VCA and IgG anti-early antigen (EA) antibodies are sensitive for the diagnosis of NPC, although IgA anti-VCA is more specific.¹⁵ Elevated IgA antibody titers have been reported in more than 90% of untreated patients with NPC from Hong Kong, East Africa, and California.⁴²^–⁴⁴ Positive IgA anti-VCA and IgG anti-EA serologies are primarily associated with WHO type 2 and type 3 NPC. Elevated IgA anti-VCA antibody titers were detected in 82%, and IgG anti-EA antibody titers were detected in 86% of patients with nonkeratinizing carcinoma and undifferentiated carcinomas, but in only 16% and 35%, respectively, of patients with squamous cell carcinomas in a North American study.¹⁵ Elevated serum IgA anti-VCA antibodies may be demonstrated in patients months before the onset of symptoms and may serve as a screening test in high-risk patients.⁴⁵^,⁴⁶ Quantification of plasma EBV DNA can be useful at baseline as it appears to add to the prediction of outcome and levels over time can be used as a post-treatment surveillance tool.⁴⁷^,⁴⁸

Staging Classification

Various staging systems have been formulated for NPC.^9,⁴⁹^–⁵⁵ The most widely used systems in the English literature are the American Joint Committee on Cancer (AJCC), Union International Cancer Centre (UICC), and Ho systems. The latest versions of the AJCC and UICC (2002) systems are virtually identical. Table 27-1 shows the AJCC and Ho systems currently in use. Each system has its limitations. In the AJCC and UICC systems, the designation of T1 or T2, which is based on the extent of involvement within the nasopharynx, is not meaningful and carries no prognostic significance.⁵³^,⁵⁶ In the 2002 version of the AJCC staging system with regard to T2 lesions, it is divided into with or without parapharyngeal involvement, which has prognostic significance.⁵⁷ Those with parapharyngeal space involvement are at higher risk for local and regional recurrence, as well as a high rate of distant metastases.⁵⁸ Cranial nerve involvement has been shown to carry a worse prognosis than base of the skull involvement^27,^28,^51,⁵⁹; however, both are included in the T4 classification in the AJCC (2002) and the UICC systems and the T3 in Ho’s system. With respect to N-stage classification, the Ho system, which is based on the level or location of neck node involvement, appears to be superior to the AJCC and the UICC system, which are based on size, number, and laterality of the lymph nodes involved.^10,^28,⁵³ Because of these limitations, modifications of both Ho’s and AJCC classification have been proposed and are shown in Table 27-1. Retrospective comparison of the 1997 or the 2002 AJCC with the 1988 AJCC classification in patients staged with CT or MRI scans suggest a more even stage distribution and better correlation with prognosis with the 1997 or the 2002 AJCC classification.⁶⁰ In the 2010 AJCC staging manual, T1 patients include those who have disease confined to the nasopharynx, or tumor extending to oropharynx and/or nasal cavity without parapharyngeal extension. Tumor with parapharyngeal extension is now staged as T2. There is no longer a subdivision between T2a and T2b disease. The former T2a disease is now down staged as T1 disease in this new staging system.⁶¹ With regard to N staging, because retropharyngeal nodes are the first echelons of nodal metastases,⁶² retropharyngeal lymph node involvement independent of laterality and without cervical lymph node involvement has been proposed as stage N1.⁶¹ The adequacy of these new modified staging classifications will require further clinical confirmation.

Table 27-1 Classification of Nasopharyngeal Carcinoma

Standard Therapeutic Approaches

Because of the anatomic location and the propensity for early bilateral lymph node metastases and involvement of the lateral retropharyngeal node of Rouvière, which usually is unresectable surgically, NPC is primarily managed with radiotherapy. Cervical lymph node metastases from NPC, even when they are bulky, are very radioresponsive and curable locoregionally. Radiotherapy, consisting of external beam irradiation or brachytherapy or both, is the mainstay of treatment for locally recurrent disease. In patients with distant metastasis, radiotherapy can offer significant palliation.

Although surgery is not used in the treatment of the primary tumor, radical neck dissection is the treatment of choice for resectable neck disease that is persistent or recurrent after radiotherapy.⁶³^,⁶⁴ Surgery has also been used to salvage selected patients with locally recurrent disease.⁶⁵^–⁶⁸

Concurrent chemoradiotherapy using cisplatin (CDDP)-based chemotherapy is the current standard for patients with NPC with stage III or IV (nonmetastatic) disease. Because of the known chemosensitivity of NPC, a series of randomized controlled trials of chemoradiotherapy versus radiotherapy conducted in the 1990s and early 2000s demonstrated that in patients with advanced local or regional disease, the addition of concurrent chemotherapy to radiation was associated with a statistically significant and clinically meaningful survival advantage.⁶⁹^–⁷¹ Notably, a phase III trial by the Head and Neck Intergroup in the United States compared radiotherapy alone with radiotherapy plus concurrent and adjuvant chemotherapy for stage III and IV disease.⁶⁹ Chemotherapy consisted of CDDP 100 mg/m² every 3 weeks during radiotherapy and CDDP 80 mg/m² plus 5-fluorouracil (5-FU) infusion 1000 mg/m²/day, for 4 days every 4 weeks after the completion of radiotherapy. Radiotherapy was delivered at 1.8 to 2 Gy per fraction per day, 5 days a week, to a total dose of 70 Gy. An update of the Intergroup trial⁷² showed that at 5 years, the overall survival was 37% versus 67% (P < 0.001) and progression-free survival was 29% versus 58% in favor of the combined modality arm (P < 0.001). Significant differences were found in the overall survival and progression-free survival between the histologic types for all patients treated. The overall survival was 37% for WHO I, 55% for WHO II, and 60% for WHO III (P < 0.001). A smaller subsequent trial suggested that even in patients with advanced local disease but minimal nodal disease (T_3-4N_0-1), local control increased with the use of combined chemotherapy and accelerated fractionation radiation versus conventional radiation alone.⁷³ A substantial reduction in both locoregional recurrence and metastatic disease in the combined treatment arms versus radiation alone has been observed in these combined modality trials.

In all of the randomized controlled trials, the chemotherapy combined CDDP-based chemotherapy with radiation, with CDDP dosing plans including 40 mg/m² weekly to 100 mg/m² every 3 weeks to 20 mg/m²/day for 4 days with concurrent 5-FU infusion every 3 weeks.

A common theme to all of these chemotherapy regimens is that in all cases the cumulative dose of concurrent CDDP exceeded 180 mg/m². However, in the U.S. Intergroup trial, although three cycles of 100 mg/m² of CDDP during radiotherapy were intended, only 63% of the patients received all three cycles. In the trial by Chan et al. in which CDDP was administered weekly to an anticipated total of 240 mg/m²95% of the patients were compliant with the plan.⁷⁴ It appears that weekly dosing is more tolerable and in many cases dosing beyond a cumulative dose of 200-240 mg/m² is not feasible. In addition, of the three randomized controlled trials discussed, only one, the U.S. Intergroup study, administered adjuvant CDDP and 5-FU. Only approximately half of the patients were able to receive all three cycles, and one-third of the patients randomized to that arm received no adjuvant treatment. Therefore, because all three randomized trials showed an overall survival advantage for patients with advanced disease, it is not clear that adjuvant CDDP and 5-FU has benefit beyond concurrent chemoradiation, nor is it clear that administration of CDDP and 5-FU after chemoradiation is feasible.

A recent study directly compared CDDP versus carboplatin (AUC 5) in the curative setting in 206 patients with NPC who were receiving concurrent radiation.⁷⁵ In this study, the standard U.S. Intergroup regimen of concurrent plus adjuvant chemoradiation was compared with an identical radiation plan with concurrent AUC 5 100 mg/m² weekly instead of CDDP, and AUC 5 instead of CDDP in the adjuvant setting.⁷⁵ There was no difference in overall survival or disease-free survival. Toxicity was markedly less in the AUC 5 arm, and more than twice as many patients in the AUC 5 arm (62% versus 26%) completed all intended chemotherapy treatment. Therefore, although CDDP is still considered the standard, substitution of AUC 5 in patients who are ineligible for CDDP because of renal or neurologic compromise is an alternative treatment approach and warrants further study.

Chemotherapy has been used as induction or neoadjuvant therapy before radiotherapy or as an adjuvant after radiotherapy in the treatment of advanced NPC.⁷⁶^–⁸⁰ Thus far, prospective randomized trials comparing neoadjuvant or adjuvant chemotherapy combined with radiotherapy to radiotherapy alone have not shown a survival benefit, despite diminution of metastatic relapse rates.⁸¹^–⁸³ In addition, several meta-analyses did not show a benefit of neoadjuvant chemotherapy in the treatment of NPC.⁸⁴^–⁸⁶ However, some investigators argue that most of these trials either used treatment regimens regarded as outmoded today or that were underpowered, particularly with respect to induction chemotherapy. There are ongoing large randomized controlled trials designed to definitively answer the question concerning the possible benefit of the addition of CDDP and 5-FU induction chemotherapy to concurrent chemoradiation in patients with NPC. Lee et al.⁸⁷ of the Hong Kong Nasopharyngeal Cancer Study Group are conducting a trial comparing induction chemotherapy with CDDP and 5-FU versus adjuvant chemotherapy with CDDP and 5-FU in the setting of concurrent chemoradiation as a backbone. This trial, which opened in September 2006, is planning to enroll 798 patients with an estimated completion date of September 2013. Feng et al.,⁸⁸ of the Taiwan National Health Research Institutes, opened in 2003 a multicenter phase III trial comparing induction chemotherapy with mitomycin, epirubicin, CDDP, fluorouracil, and leucovorin followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in stage IV NPC. This is based on the results of a phase II trial showing a 5-year overall survival of 70% and a 5-year distant metastasis rate of 81% with the induction chemotherapy.⁸⁹ This trial plans to enroll 480 patients and is expected to be completed in 2013. Therefore, the question of the role of induction plus concurrent chemoradiation using CDDP-based chemotherapy in patients with NPC, although still open, will hopefully be answered in the next 5 years by these two randomized trials, at least for the specific chemotherapy regimens described previously.

Chemotherapy alone or combined with reirradiation is also used in the palliation of recurrent or metastatic disease. Complete response rates of 15% to 44% have been achieved with combination chemotherapy in recurrent or metastatic NPC.^76,^78,^81,⁹⁰ In general, recurrent NPC is uniformly more responsive to reirradiation when compared with recurrent disease arising from other head and neck cancer sites.⁹¹^,⁹²

Intensity-Modulated Radiation Therapy

Intensity-modulated radiation therapy (IMRT) has replaced conventional radiotherapy in the treatment of NPC in an increasing number of institutions in the United States as well as throughout the world. With this technique, the intensity of the radiation beams can be modulated so that a high dose can be delivered to the tumor with an improved target volume coverage while significantly reducing the dose to the surrounding normal tissues.⁹³^–⁹⁸ Since the initial publication⁹⁹ along with the update on the use of IMRT for NPC from the University of California–San Francisco (UCSF),⁹⁷ several institutions have also implemented this technique as well as reported excellent treatment outcomes.¹⁰⁰^–¹⁰⁶ The following describes the simulation and CT treatment planning procedures.

Simulation and Treatment Planning Computed Tomography Procedures

The patient’s head position should be hyperextended at the initial simulation so that there is adequate separation between the primary and retropharyngeal and the upper neck nodes.⁹⁷ The tip of the uvula and the base of the occiput should be on a plane parallel to the beam axis. The head, neck, and shoulders are immobilized using a thermoplastic mask with the neck supported on a carbon-fiber head support⁹⁴^,¹⁰⁷ (Fig. 27-11). A pair of orthogonal radiographs are taken for isocenter localization at the initial simulation. The isocenter on the initial simulation film is placed at the anticipated treatment isocenter. Treatment planning CT scans are then obtained. In the region that contains the primary gross tumor volume (GTV), CT scan slice thickness should be 3 mm or less. The regions above and below the primary tumor target volume may be scanned with slice thickness of 5 mm.

FIGURE 27-11 • Head, neck, and shoulder immobilization using a thermoplastic mask with the neck supported on a Timo (S-type, MED-TEC).

Treatment Volume

The treatment volume should encompass the GTV as well as regions of microscopic disease and potential spread of disease, known as the clinical target volume (CTV). The GTV is determined by clinical examination as well as by MRI, CT, and PET scans. All patients should have a pretreatment MRI scan for precise target volume delineation unless medically contraindicated. Whenever possible, fusion of the diagnostic MRI or PET images and the treatment planning CT images should be performed to accurately delineate the GTV and the surrounding critical normal structures, particularly in regions near the skull base. The GTV should include the primary tumor in the nasopharynx, gross retropharyngeal lymphadenopathy, and gross nodal disease. Any lymph nodes larger than 1 cm or that have a necrotic center are considered gross nodal disease. A gross disease CTV should be defined as the GTV plus an additional margin of 5 mm to 1 cm surrounding all gross disease. This is also known as the CTV gross disease. The margin can be reduced to as small as 1 mm in regions near the brainstem or spinal cord. The high-risk subclinical CTV encompasses the GTV plus all potential areas of microscopic spread of disease. This volume should include at least the entire nasopharynx, retropharyngeal lymph nodal regions, clivus, skull base, pterygoid fossae, parapharyngeal space, sphenoid sinus, posterior one-third to half of the nasal cavity, and posterior one-third to half of the maxillary sinuses. This CTV high-risk subclinical should also include the following lymph nodal groups that are at risk of potential microscopic spread of disease: bilateral upper deep jugular (junctional, parapharyngeal), submandibular, subdigastric (judulodigastic), midjugular, posterior cervical, and retropharyngeal lymph nodes. In patients with clinically N0 neck, it is not necessary to include level I nodal regions. The planning target volume (PTV) is defined by adding a circumferential margin of typically 3 mm to 5 mm to all the CTVs to accommodate potential patient motion and set-up errors. The PTV margin can be reduced to as small as 1 mm in regions near critical normal structures such as the brainstem or spinal cord.

Two different IMRT approaches are currently being used: extended-whole field (EWF) IMRT technique or a split-field (SF) IMRT technique (see the following sections for detailed explanations). If an EWF IMRT technique is contemplated, a low-risk subclinical CTV should also be defined that encompasses bilateral lower neck and supraclavicular nodal regions. This is also known as the CTV low-risk subclinical. If there is gross nodal disease in the low neck, the entire low neck should be included in the high-risk subclinical CTV. If an SF IMRT technique is contemplated, a separate low-anterior neck field (anterior-posterior) can be used to match the IMRT fields, particularly if there is no gross nodal involvement in the low neck. The match typically occurs at just above the arytenoids as the larynx can be spared and shielded under the midline block in the low anterior neck fields.

The lymph node groups at risk are outlined on the treatment planning CT scans according to image-based nodal classification.¹⁰⁸^–¹¹¹ The surrounding critical normal structures, including the brainstem, spinal cord, optic nerves, chiasm, parotid glands, pituitary, temporomandibular (TM) joints, middle and inner ears, and skin should also be outlined on the treatment planning CT scans.

Treatment Planning and Delivery

Various treatment planning systems are available commercially.¹¹²^–¹¹⁵ At the Memorial Sloan-Kettering Cancer Center (MSKCC), an in-house treatment planning software is used to plan treatment for all patients undergoing IMRT.¹¹⁶^,¹¹⁷ Treatment is delivered using linear accelerators equipped with a computer-controlled auto-sequence multileaf collimator (MLC) system using a step-and-shoot approach, a multivane dynamic MLC (MIMiC), or a dynamic MLC system using a sliding window approach, or helical tomotherapy.¹¹⁵^,¹¹⁸ Detailed descriptions of the treatment planning and delivery methods are provided in Chapter 10.

In general, treatment planning is performed with inverse-planning. However, in centers where the expertise is not available, forward planning can also be done.¹¹⁹ Examples of a 10-field forward plan, an inverse peacock plan delivered using the MIMiC collimator, and an inverse corvus plan delivered using MLC are shown in Fig. 27-12, Fig. 27-13, and Fig. 27-14. An example of an MSKCC IMRT plan delivered with the dynamic MLC system using a sliding window approach is shown in Fig. 27-15.

FIGURE 27-12 • Isodose curves of a 10-field forward intensity-modulated radiotherapy plan for a patient with T1N1 carcinoma of the nasopharynx displayed on the axial (A), coronal (B), and sagittal (C) planes through the centroid of the primary tumor and the Dose Volume Histogram (D) for the relevant structures.

(From Lee N, Xia P, Quivey JM, et al: Intensity-Modulated Radiotherapy in the Treatment of Nasopharyngeal Carcinoma: An Update of the UCSF Experience. Int J Radiat Oncol Biol Phys. 53:15, 2002.)

FIGURE 27-13 • Isodose curves of an inverse IMRT plan delivered using multivane dynamic multi-leaf collimator (MIMiC) for a patient with T4N1 carcinoma of the nasopharynx displayed on the axial (A), coronal (B), and sagittal (C) planes through the centroid of the primary tumor and the Dose Volume Histogram for the relevant structures (D). The gross tumor volume is shown in red and the clinical target volume is shown in orange.

(From Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF Experience, Int J Radiat Oncol Biol Phys 53:16, 2002.)

FIGURE 27-14 • Isodose curves of an inverse IMRT plan using nine coplanar gantry angles delivered with conventional MLC for a patient with T3N0 carcinoma of the nasopharynx displayed on the (A) axial, (B) coronal, and (C) sagittal planes through the centroid of the primary tumor and the Dose Volume Histogram for the relevant structures (D). The GTV is shown in red and the CTV is shown in magenta.

(From Lee N, Xia P, Fischbein N, et al: Intensity-modulated radiotherapy for head and neck cancer: the UCSF Experience focusing on target, Int J Radiat Oncol Biol Phys 57[1]:49–60, 2003.)

FIGURE 27-15 • An example of a nasopharyngeal cancer patients treated with IMRT delivered with the dynamic MLC system using a sliding window approach.

With increasing use of IMRT in the clinic, questions regarding the optimal treatment technique have been raised. One issue is whether patients should undergo a EWF IMRT technique in which the entire target volume is encompassed in the IMRT plan, or a SF IMRT technique in which the target volumes superior to the vocal cords are treated with an IMRT plan whereas the lower neck nodes are treated with a conventional low-anterior neck field.^107,^120,¹²¹ Debates among radiation oncologists on which IMRT technique is optimal have been on-going. Because of concerns of potential failures at the matchline resulting from underdose or complications resulting from overdose, many centers have implemented EWF IMRT even when no clinically involved lymph nodes are apparent in the region of the matchline. These concerns could be caused by the treatment delivery system that is used at centers where a perfect match between the IMRT fields and the low-anterior neck field is not possible. However, with this technique, an unnecessary dose of radiation is delivered to the normal glottic larynx.¹²² With the SF IMRT technique, dose to the vocal cords is minimal because they are shielded under the midline Cerrobend block or the MLC. Thus far, no IMRT matchline failures or complications have been reported with the SF IMRT technique.⁹⁹

Beam Energy

Megavoltage x-ray beams of 6 MV or greater are typically used for IMRT for NPC. X-rays with energy greater than 6 MV should not be used for the irradiation of the cervical lymph nodes.

Dose and Fractionation

The prescribed dose is 70 Gy to the PTV of the CTV gross nodes, 59.4 Gy to the PTV of the CTV high-risk subclinical in 33 one-a-day fractions. For the low neck, if SF IMRT is used, a dose of 50.4 Gy at 1.8 Gy/fraction/day is typically prescribed. However, if the low neck is included in the IMRT fields and is considered at low risk for nodal involvement, the PTV of the CTV low risk subclinical typically receives 54 Gy at 1.64 Gy/fraction/day.

Dose-volume histograms are generated for all target volumes and critical normal structures. Guidelines for the dose constraints to normal tissues are as follows:

Brainstem	≤54 Gy	60 Gy to 1% of PTV
Optic nerves	≤54 Gy	60 Gy to 1% of PTV
Optic chiasm	≤54 Gy
Spinal cord	≤45 Gy	50 Gy to 1 cc of PTV
Mandible	≤70 Gy	75 Gy to 1 cc of PTV
Temporal lobes	≤60 Gy	65 Gy to 1% of PTV
Parotid glands	≤ Mean dose of 26 Gy
Oral cavity	≤ Mean dose of 40 Gy

These dose constraints include all scattered and transmitted doses.

Brachytherapy

Brachytherapy with intracavitary insertions ¹²³^–¹³¹ or interstitial implants¹³²^–¹³⁵ has been used as a boost treatment of T1 to T3 carcinoma of the nasopharynx after external-beam irradiation or in the treatment of recurrent disease, either alone or in combination with external-beam irradiation. Because of the rapid falloff of dose with an increase in the distance from the radioactive source, brachytherapy is not suitable for treatment of tumors with intracranial extension. However, since the introduction of IMRT as primary treatment for NPC with excellent local control, the use of brachtherapy as a boost treatment after definitive IMRT has markedly diminished. Various applicators and techniques have been used for the delivery of intracavitary brachytherapy for carcinoma of the nasopharynx.¹²⁵^–¹²⁷ ^,129 ^,131 ^,136 In the past, intracavitary brachytherapy was delivered using low-dose-rate techniques. More recently, remote afterloading, fractionated high-dose-rate techniques on an outpatient basis are more commonly used.¹³⁶ In a modification of the technique described by Levendag et al.,¹³⁷ the mucosa of the nasal cavity and the nasopharynx is first sprayed with a decongestant (0.05% oxymetazoline hydrochloride) and anesthetized with 5% cocaine hydrochloride applied topically with cotton swabs. The soft palate is anesthetized with a spray of benzocaine, tetracaine hydrochloride, butamben, and benzalkonium chloride (Cetacaine). Two 5-French pediatric feeding tubes with an outer diameter of 1.65 mm and an inner diameter of 1.09 mm, respectively, are then introduced into the nasopharynx and withdrawn through the mouth to serve as guide tubes for the Rotterdam nasopharynx applicator. The applicator is then guided intraorally over the pediatric feeding tubes into the nasopharynx and the nasal cavity by pulling the nasal portion of the pediatric feeding tubes. Placement of the applicator into the nasopharynx is facilitated by gentle pushing of the oral portion of the pediatric feeding tubes intraorally with a pair of forceps. After the applicator is positioned in the nasopharynx and the nasal cavity, the pediatric feeding tubes are withdrawn, and the applicator is secured in place with a plastic clamp placed over the external portion of the applicator outside the nose (Fig. 27-16). Dummy iridium-192 sources in afterloading catheters are then inserted into each of the tubes of the applicator. After lead markers are placed on the contralateral outer canthus and tragus, a pair of ortho gonal anterior-posterior and lateral localization x-ray films with the dummy sources in place are obtained (Fig. 27-17). The points of interest, including the nasopharynx, base of skull, node of Rouvière, pituitary, optic chiasm, spinal cord, and the palate points, are marked on the localization films.¹³⁶ Treatment planning and optimization is then performed with a computer software program (Plato brachytherapy afterloading planning system). A dose of 5 to 6 Gy in two fractions, 5 to 6 hours apart, is prescribed at the isodose curve that passes through the nasopharynx points as a boost treatment for T1 to T2 lesions after 65 Gy of external-beam radiotherapy. The dose for reirradiation of recurrent tumors depends on the previous dose of external-beam radiotherapy. After treatment planning, afterloading catheters are then inserted into the applicator and connected to a remote-controlled, high-dose-rate afterloading machine for treatment delivery. After completion of treatments, the nose clamp and the afterloading catheters are removed. Two 5-French pediatric feeding tubes are reinserted into the applicator and the applicator is withdrawn through the mouth by pushing it into the nose while gently pulling on the feeding tubes exiting the mouth.

FIGURE 27-16 • A, A patient with the Rotterdam nasopharynx applicator in place. The afterloading catheters are connected to a remote-controlled high-dose-rate afterloading machine (microSelectron HDR, Nucletron-Oldeft Nucletron). B, Close-up view of the Rotterdam nasopharynx applicator secured in place with a plastic clamp placed over the external portion of the applicator just outside the nose.

FIGURE 27-17 • A, Lateral and B, anterior-posterior localization films of an intracavitary brachytherapy boost using the Rotterdam Nasopharynx Applicator with the dummy sources inserted.

Several approaches have been used for permanent interstitial implantation of carcinoma of the nasopharynx at different institutions. They include the transnasal approach ¹³³ and the transoral approach¹³² for lesions in the middle and low posterior wall, implantation of iodine-125 seeds through a transpalatal flap for lesions in the superior or high posterior wall, and the split-palate approach with gold-198 seeds.¹³⁸

Complications

In the past, because of the large treatment volume and high dose required for NPC in most patients, various complications occurred after conventional radiotherapy.¹³⁹ The overall complication rate ranged from 31% to 66%.^21,^27,^140,¹⁴¹ Severe complication rates of 6% to 15% and fatal complication rates of 1% to 3% have been reported.^21,^27,^140,¹⁴¹ The complication rates are increased with concurrent chemotherapy^141,¹⁴² or coexisting medical conditions such as diabetes or hypertension. However, using modern three-dimensional conformal radiotherapy techniques, including IMRT, these complication rates have decreased.^96,^97,¹⁰⁰^–¹⁰² Xerostomia was by far the most common sequela with conventional radiotherapy. Most patients experience some degree of dry mouth permanently. Dental problems, a consequence of decreased saliva and altered salivary consistency, occurred in 4% to 17% of patients treated with conventional radiotherapy.²¹^,¹⁴¹ Dental prophylaxis with topical fluorides and good dental care before, during, and after radiotherapy can reduce the incidence of dental caries. However, since the introduction of IMRT, most patients recover their salivary gland function more rapidly and in many cases, completely.^96,^97,¹⁰⁰^–¹⁰² Two recent randomized trials have shown the superiority of IMRT over conventional radiotherapy for early-stage nasopharyngeal carcinoma in terms of improved salivary function as well as patient quality of life.¹⁴³^,¹⁴⁴ With time, dental problems should diminish as patients are being treated with IMRT.

Chronic otitis media occurred in 3% to 18% and hearing loss in 6% to 8% of the patients treated with coventional radiotherapy techniques in the past.^21,^29,¹⁴¹ The incidence of hearing impairment was related to the dose to the inner ear and was significantly higher in patients who received more than 50 Gy to the cochlea.¹⁴⁵ Others have suggested that the mean dose to the cochlea should be kept under 48 Gy to minimize sensorineural hearing loss. More recently Honore et al. found that increasing patient age and decreased pretreatment hearing level were associated with increasing risk of sensorineural hearing loss.¹⁴⁶

In the past, trismus occurred as a result of fibrosis and contraction of pterygoid muscles or fibrosis of the TM joint in 5% to 10% of patients.^21,^29,¹⁴¹ Mandible exercise may prevent progression of the trismus and surgical intervention may be necessary occasionally to relieve severe trismus. Severe neck fibrosis usually resulted from the use of a large dose per fraction²⁹ and neck irradiation using anterior-posterior opposed fields,²¹ especially when compensators were not used. The use of doses less than or equal to 2 Gy/fraction and the use of a combination of photon and electron beam for treatment of posterior cervical nodes should reduce the incidence of this complication.

Soft tissue or bone necrosis or both have been described in 5% to 16%^21,^29,¹⁴¹ and brain necrosis in 2% to 3% of patients treated with coventional radiotherapy techniques in the past.²¹^,²⁹ Cranial nerve dysfunction, usually affecting cranial nerves IX to XII, and in particular the twelfth nerve, may result from soft tissue fibrosis along the course of the nerves and entrapment in the lateral retroparotid space. The incidence is approximately 1% to 6%.^21,^27,^29,¹⁴¹ Transverse radiation myelitis has been reported in 1% to 4% of patients.^21,^29,^141,¹⁴⁷ Improvement in tumor localization and treatment planning with the aid of CT and MRI scans and careful treatment techniques such as IMRT should prevent this devastating treatment complication. Because a portion of the orbit and sometimes the eye, especially in patients with advanced disease, is usually included in the treatment volume, optic nerve injury and radiation retinopathy with impairment of vision can occur in patients after radiotherapy for NPC when using conventional techniques.^21,^148,¹⁴⁹ Retinopathy has occurred after a dose of less than 50 Gy.¹⁴⁸^,¹⁴⁹ Optic nerve injury can occur after 50 Gy, and the incidence increases with increase of fraction size.¹⁴⁸ Limiting the fraction size to less than or equal to 2 Gy/fraction per day and a dose of 45 Gy to the retina and 54 Gy or less to the optic nerve should prevent this complication. Hypothalamic-pituitary or thyroid dysfunction or both can occur in 1% to 6% of long-term survivors.^29,^141,¹⁵⁰^–¹⁵³ The true incidence of endocrine dysfunction following radiotherapy of NPC may be higher as most patients have not been routinely evaluated for endocrine function during follow-up examinations. Because most of these endocrine dysfunctions can be corrected medically, periodic evaluation of the hypothalamic, pituitary, and thyroid function may be indicated in the follow-up examination of patients after radiotherapy for NPC.

Carotid stenosis has been reported in patients who undergo irradiation of the head and neck region. Interval from radiotherapy was a significant independent predictor for severe carotid stenosis. Some have recommended a routine duplex ultrasound screening test in these patients.¹⁵⁴

Results of Treatment

The local-regional control rates by radiotherapy in select conventional radiotherapy series are shown in Table 27-2 and Table 27-3. Control of the primary lesion using conventional radiotherapy varied with the T classification (see Table 27-2), ranging from 67% to 97% for T1 lesions, 54% to 94% for T2 lesions, 34% to 78% for T3 lesions, and 40% to 71% for T4 lesions.^20,^21,^27,^141,¹⁵⁵^–¹⁵⁷ Local control rate increased with increase in dose.^20,^27,^141,^156,¹⁵⁸ and field size.²⁰^,²¹ Interruption of treatment for 3 weeks or longer adversely affected local control.¹⁵⁶ Boost treatment with intracavitary brachytherapy if using non-IMRT treatment techniques¹²⁶ can also improve local control. Stereotactic radiosurgery boost after external-beam radiotherapy (both conventional and IMRT) has also improved local control.¹⁵⁹^,¹⁶⁰ Nonkeratinizing squamous cell carcinoma and undifferentiated carcinoma had better local control than keratinizing squamous cell carcinoma in T2 to T3 lesions but not in T1 or T4 lesions.^27,^69,⁸⁶ Control of cervical lymph node metastasis from carcinoma of the nasopharynx by conventional radiotherapy is excellent even with extensive disease in the neck (see Table 27-3). The control rate of cervical lymph node metastasis ranged from 82% to 100% for N0, 86% to 92% for N1, and 78% to 89% for N2 to N3 disease.^21,^27,¹⁴¹ Five-year survival rates ranged from 36% to 58% (Table 27-4).* The 5-year survival rate with conventional non-IMRT radiotherapy correlated with the T classification, as well as with the N classification (Table 27-5 and Table 27-6), being 60% to 76% for T1, 48% to 68% for T2, 27% to 55% for T3, and 0% to 29% for T4 lesions²¹^,¹⁵⁷; 42% to 78% for N0, 27% to 70% for N1, and 32% to 52% for N2 to N3 disease. The prognosis is poor when nodes in the lower neck or the supraclavicular fossa or both are involved.

Table 27-2 Carcinoma of the Nasopharynx: Control of the Primary Tumor According to 1992 AJCC T-Stage After Conventional Radiotherapy

Table 27-3 Carcinoma of the Nasopharynx: Control of Cervical Lymph Node Metastases According to 1992 AJCC N-Stage* After Conventional Radiotherapy

Table 27-4 Carcinoma of the Nasopharynx: 5-Year Survival After Conventional Radiotherapy (1992 AJCC Staging System)*

First Author	Patients, n	5-Yr Survival, %
Hoppe (1976)	82	57 (actuarial)
Mesic (1981)	251	52 (actuarial disease-free)
Chu (1985)	80	36 (actuarial)
Vikram (1984)	107	56 (actuarial)*
Wang (1990)	185	43 (absolute)
Bailet (1992)	103	58 (actuarial)

* Estimated from survival curve.

Table 27-5 Carcinoma of the Nasopharynx: 5-Year Survival After Conventional Radiotherapy According to 1992 AJCC T-Classification*

Table 27-6 Carcinoma of the Nasopharynx: 5-Year Survival After Conventional Radiotherapy According to 1992 AJCC N-Classification*

With IMRT, excellent local and regional control was achieved in 97% and 98% of the patients treated at UCSF, respectively (Fig. 27-18 and Fig. 27-19).⁹⁷ An unpublished update of the UCSF experience continued to show excellent local control of approximately 96%. However, distant metastases remained high; the distant metastases–free rate was 66% at 4 years (Fig. 27-20). The overall survival was 88% (Fig. 27-21). Similar to the UCSF experience, several other institutions also recently published results that continue to show local control rates ranging from 91% to 100% and regional control rates ranging from 92.3% to 98% (Table 27-7). Because of the excellent local control rates from UCSF, the Radiation Therapy Oncology Group (RTOG) conducted a phase II trial using IMRT with or without chemotherapy in the treatment of NPC in which patients with T2b or greater or node-positive disease also received concurrent CDDP followed by adjuvant CDDP and 5-FU chemotherapies. Preliminary results showed that IMRT is feasible in a multi-institutional setting that reproduced the excellent results (local control rate of 92.3%) from single institutions.¹⁶¹ Compliance with concurrent chemotherapy was significantly improved in comparison with the U.S. Intergroup trial in which 88% of the patients underwent three cycles of CDDP. Compliance to adjuvant chemotherapy was slightly decreased; only 46% of the patients received three cycles of CDDP and 5-FU. Although it is encouraging to see the reproducibility of excellent locoregional control rates from single institutions as well as from a cooperative phase II trial, the development of distant metastases after these combined modality treatments is still problematic (21%-34%), which ultimately resulted in patient death (see Table 27-7).^97,^100,^102,¹⁶⁰ Patients with NPC with vascular endothelial growth factor (VEGF) overexpression have a higher likelihood of recurrence, distant metastases, and decreased survival.¹⁶²^–¹⁶⁵ A recent report showed that overexpression of VEGF was seen in 67% of nasopharyngeal cases and higher expression of VEGF in EBV positive tumors was associated with a higher rate of recurrence, nodal positivity, and lower survival.¹⁶⁵ Another report showed that the pre- and post-treatment serum levels of cytokines and angiogenesis factors were predictive markers for outcome in patients with head and neck cancer. With a median follow-up of 37 months, patients were more likely to remain disease-free with the VEGF level decreased post-treatment compared with those who continued to have increased VEGF levels after treatment.¹⁶⁶ Given the available data on VEGF overexpression and increased propensity for distant failure in nasopharygneal carcinoma, it seems logical to test the addition of bevacizumab, a monoclonal antibody direacted against VEGF to the present treatment strategy for these patients. This is currently under investigation by the RTOG (protocol 0615).

FIGURE 27-18 • Kaplan-Meier estimate of local progression-free probability.

(From Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF Experience, Int J Radiat Oncol Biol Phys 53:17, 2002.)

FIGURE 27-19 • Kaplan-Meier estimate of regional progression-free probability.

(From Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF Experience, Int J Radiat Oncol Biol Phys 53:18, 2002.)

FIGURE 27-20 • Kaplan-Meier estimate of distant-metastasis-free probability.

(From Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF Experience, Int J Radiat Oncol Biol Phys 53:18, 2002.)

FIGURE 27-21 • Kaplan-Meier estimate of overall survival.

(From Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF Experience, Int J Radiat Oncol Biol Phys 53:18, 2002.)

Table 27-7 Carcinoma of the Nasopharynx: Control of Primary Tumor and Regional Lymph Nodes According to the 1997 AJCC T and N staging

In addition to stage, EBV DNA levels, serum VEGF levels, several other factors may influence prognosis: histologic type, age, sex, EBV-specific IgA antibody titer, tumor angiogenesis, HLA antigen pattern, and cell-mediated immune status. Lymphoepitheliomas and undifferentiated carcinomas have been reported to be more radiosensitive and associated with better prognosis than squamous cell carcinoma in some series.^20,^25,^141,^157,¹⁶⁷^–¹⁶⁹ Younger patients appear to have better 5-year survival rates than older patients.^9,^20,^27,¹⁷⁰ In Ho’s series, the difference in 5-year survival between patients younger than 40 years of age and those 40 years or older was statistically significant (57.8% versus 43.4%, P = 0.001).⁹ In a retrospective review of 119 patients younger than 30 years of age from the Children’s Cancer Study Group,¹⁷¹ the overall 5-year survival and relapse-free survival rates from diagnosis were 51% and 36%, respectively, and were not significantly different from other series of adult patients.

Better prognosis for women than men has been shown in some series, although the difference is not statistically significant in most series.^9,^20,^21,^155,¹⁷⁰

EBV antibody titer following treatment may be a significant prognostic factor.^42,^172,¹⁷³ In a multicenter follow-up study, increasing titers of IgA anti-EA antibodies in patients in apparent clinical remission 1 year after radiotherapy were highly significant for prediction of relapse.¹⁷³ In another study from Taiwan, 72% to 100% of the patients who developed recurrent NPC demonstrated elevated IgA, as well as IgG, anti-VCA antibody titers 1 year after radiotherapy, although during the first year following radiotherapy, some decrease and fluctuation of seropositive rates were observed in both the cured and recurrent patients.¹⁷² However, in one North American study, sequential measurements of various EBV antibody titers was not useful in post-treatment monitoring of patients.¹⁷⁴

Recently circulating EBV DNA concentration has been shown to be an independent prognostic indicator.¹⁷⁵ Pre-treatment EBV DNA correlated with disease stage, clinical outcome, and prognosis in patients with endemic NPC.^6,^175,¹⁷⁶ Post-treatment EBV DNA has even a stronger correlation with prognosis and has been used in some centers to monitor patients for recurrence after treatment.^47,^177,¹⁷⁸ Patients with distant failures had significantly higher pretreatment EBV DNA levels than those without distant failures.¹⁷⁹ A recently published phase II trial on 31 locoregionally advanced NPC patients who received neoadjuvant chemotherapy followed by concurrent chemoradiation, serum EBV DNA was obtained at baseline, weekly during therapy, 4 to 6 weeks after treatment, and every 2 months for 1 year after treatment.¹⁸⁰ Serum EBV DNA level was found to be increased significantly in 8 out of 9 patients who experienced treatment failure versus no evidence of disease if the patients did not have elevated serum EBV DNA levels. Elevated EBV DNA has been shown to predate clinical recurrence by 3 to 7 months.¹⁸⁰^–¹⁸²

Reirradiation of Recurrent Carcinoma

Significant palliation and occasional long-term survival can be achieved without excessive risk in patients with recurrent NPC.* Various radiation therapy modalities, including external beam irradiation, intracavitary brachytherapy, interstitial implantation, particle beam radiotherapy, and stereotactic radiosurgery have been used.^† More recently, IMRT has also been used with excellent preliminary outcome with control rates as high as 100% for recurrent NPC, namely, rT1-3 in one series.¹⁹⁰

The treatment technique and the dose of reirradiation depend on the extent of disease at recurrence and the dose of previous radiotherapy. Superficial recurrent disease limited to the nasopharynx may be treated with intracavitary brachytherapy or interstitial implant alone, or combined with hyperfractionated external-beam radiotherapy with or without concurrent chemotherapy. Given the late complications observed with reirradiation and when the tumor is not amenable to brachytherapy or stereotactic radiotherapy, external-beam radiotherapy using IMRT is preferred for recurrent NPC to minimize the late effects.¹⁹⁰^–¹⁹² Once-a-day fractionation using IMRT to 60 Gy can be used if a desirable plan is achieved with concurrent chemotherapy. High-dose brachytherapy or stereotatctic boost can be considered in patients with residual disease limited to the nasopharynx after external-beam radiotherapy.

Particle beam radiotherapy has a more favorable physical dose distribution than conventional photon irradiation, and heavily charged particle irradiation may have additional biologic advantages. Using heavily charged particle irradiation, a local control rate of 45% and a 5-year survival of 31% was achieved in a small series of patients with recurrent disease involving the base of the skull with or without cranial nerve deficits.¹⁸⁶

Results of reirradiation of select patients with recurrent NPC are shown in Table 27-8.* However, long-term local control, which depends on the extent of recurrent disease, was possible in only 14% to 60% of the patients retreated with conventional radiotherapy. Survival after retreatment appears to correlate with the time of recurrence after initial radiotherapy,^125,^130,¹⁸⁴ extent of recurrent disease, and dose of reirradiation.^125,^131,¹⁸⁵ Five-year actuarial survival was 13% in patients whose disease recurred 2 years or less after initial radiotherapy and 66% in those with recurrence more than 2 years after initial treatment.¹²⁵ Five-year actuarial survival was 38% for stage T1 to T2 and 15% for stage T3 to T4 disease at recurrence.¹²⁵ It was 45% with doses greater than or equal to 60 Gy and 0% with doses less than 60 Gy, although most of the patients who received lower doses had more advanced recurrent disease.¹²⁵