Dosimetric Evaluation of Volumetric Modulated Radiotherapy Versus Intensity Modulated Radiotheray in Nasopharyngeal Cancers

Varun Kumar *

Corresponding Author: Varun Kumar, Oncologist.

Copy Right: © 2022 Varun Kumar, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: August 18, 2022

Published Date: September 01, 2022

Introduction                                                   

Head-and-neck cancer (HNC) accounts for 6% of all malignancies, and almost half of the patients present with a locally advanced stage(1). Among all types of HNC, nasopharyngeal Carcinoma (NPC) is endemic in Southern China and parts of Southeast Asia. Head and neck squamous cell carcinoma displays a clear radiation dose-response relationship. This implies that both the probability of tumor control and the risk of radiation-induced normal tissue damage increase with radiation dose. Therefore, treatment of NPC with radiation therapy is curative for many patients with localized disease. However, treatment planning for NPC is challenging because of the complex anatomy, with bones, soft tissues and air cavities all in need of consideration. Organs at risk (OARs), like spinal cord, brain stem and salivary glands, are located very close to the target volume. In addition, the target volume is often an irregular concave shape.

Overview of IMRT

Over the last decade, Intensity-Modulated Radiation Therapy (IMRT) has been implemented for routine clinical use. IMRT combines several intensity-modulated beams to provide improved dose homogeneity and highly conformal dose distributions(2), allowing for improved sparing of normal tissues for many tumor sites. A considerable amount of research has demonstrated the advantages of IMRT. Studies have concluded that IMRT allows more conformal dose coverage of the tumor, especially in situations where the tumor is in close proximity to critical normal tissues, thereby sparing the surrounding normal tissues(3). They have also pointed out that a highly conformal dose distribution is essential to reduce the dose to normal tissues, thus late radiation-induced toxicities can be minimized. Besides, dose escalation becomes possible, which can potentially improve local tumor control. For each daily fraction, IMRT can give higher dose to the gross tumor volume, resulting in a more effective biological dose.

Overview of VMAT

More recently, there has been an increasing interest in using arc delivery of radiation for treatment of cancers. As introduced by Takahashi(4), the principle of simple conformal arc therapy is to spread the entrance dose shaped to the projected tumor outline over many angles. The rotational centre is in the tumor so that the high dose is focused there with a steep fall-off outside the tumor. VMAT consists of a single arc or multiple arcs modulated technique which was released for clinical use in April 2008(5). In VMAT, multileaf collimator (MLC) positions, dose rates and gantry speeds can be dynamically varied during the delivery of radiation over one arc, typically taking 70–90 seconds(6). VMAT enables IMRT like dose distributions to be delivered using a single rotation or multiple rotations of the gantry. VMAT aims to achieve several objectives at once: (i) improve OARs and healthy tissue sparing compared to other IMRT solutions; (ii) maintain or improve the same degree of target coverage; (iii) reduce significantly the treatment time (beam on time) per fraction(7).

Advantages of VMAT over IMRT

For HNC, treatment planning comparisons between VMAT and IMRT have shown that RA offers equivalent or superior target coverage and greatly improves sparing of OARs(8). Concerning the beam on time, Verbakel et al.(7) indicated that the delivery of a double-arc plan requires less than 3 minutes. This was in contrast to a typical IMRT sliding window delivery for seven fields, which required 8–12 minutes. The reduction in delivery time can lower the risk of intra-fraction movement. In addition, a shorter delivery time is more patient-friendly and enables an increase in patient throughput or implementation of more on-line imaging technologies. Moreover, a shorter fraction delivery time can prevent the chance of reducing local tumor control due to sub-lethal damage repair. The improved local tumor control is essential for long-term survival(9). Another important advantage is the efficient use of monitor units (MUs), as VMAT only requires 40% of the number of MUs compared with 7-fields sliding window IMRT plans(7). Collimator transmission and scatter radiation from the linear accelerator contribute dose to healthy organs that are not in proximity to the target volume, and the dose can induce secondary malignancy. Since the amount of scattered radiation generated is a linear function of the number of MUs(10), the chance of having secondary tumors due to scattered doses can be reduced by using VMAT.

Justification for the study

Investigations have shown that arc-based solutions associated with intensity modulation are particularly promising in terms of physical dose calculations(6). It is therefore of clinical interest to assess the application of new arc modulation techniques. VMAT has already been investigated for prostate, rectum, intracranial and cervix uteri cancers(11)(12). These clinical cases are relatively simple. So, further studies on more complex cases, like NPC, will be an ideal benchmark for assessment of the effectiveness of VMAT in a broader clinical perspective.

In the light of recent developments and the potential advantages of VMAT, this study aimed to compare VMAT technique with IMRT technique, and to examine the potential clinical application of VMAT for NPC patients. Among the HNC patients, NPCs were selected because the treatment planning techniques are more demanding than for other HNCs, due to large and irregular planning target volumes (PTVs) and the large number of adjacent sensitive structures(7). Moreover, extensive studies on treatment planning and dosimetric comparison of VMAT technique with conventional IMRT technique for NPC have seldom been reported.

Aims and Objectives

This study aimed to perform a dosimetric comparison between conventional IMRT techniques and VMAT techniques in order to assess whether the latter is more beneficial for treatment of NPC. The study sought to compare dose homogeneity, degree of conformity and tumor control probability (TCP) in order to assess the degree of target coverage. For assessing OARs and normal tissue sparing, the doses to OARs and their normal tissue complication probability (NTCP) were compared. The number of MUs and treatment delivery times were also compared for VMAT plans and IMRT plans. It is hypothesized that treatment planning by VMAT technique would improve dose homogeneity and degree of conformity in the PTVs, deliver less dose to OARs, require less treatment time.

1. Organs at risk sparing based on DVH analysis.

2.  Plan quality parameters:

1. Physical parameters:

• Homogeneity index.
• Conformity index.
• Planned target volume coverage.
• Monitor units.
• Treatment time (beam on to beam off time).

  b) Biological parameters:

• Normal tissue complication probability (NTCP).
• Tumor control probability (TCP).
• Equivalent uniform dose (EUD).

Epidemiology

The term nasopharyngeal carcinoma (NPC) is used here as a surrogate for nasopharyngeal cancers (International Classification of Diseases, 10th revision [ICD-10] code C11), given that carcinomas represent the vast majority of nasopharyngeal tumors. There were an estimated 84,400 incident cases of NPC and 51,600 deaths in 2012, representing about 0.7% of the global cancer burden, and the disease may be considered one of the rarer cancer forms globally, ranking as the 24th most frequently diagnosed cancer form worldwide and 22nd within the developing world. The global statistics by world region reveal the distinct features of its descriptive epidemiology, however, and the contrasting geographical and ethnic variations in the distribution of incidence worldwide. NPC is more frequent in males than females in both the developing and developed world, with incidence rates commonly 2 to 3 times higher in males in higher resource countries, with male-to female rate ratios often considerably higher in developing regions .The geographical disparities in the burden of NPC in relation to resources are noteworthy, with an estimated 92% of new cases occurring within economically developing countries. According to world area, incidence rates are highest in South-Eastern Asia, in both sexes, with the disease being the sixth most common among males in the region. Indeed in global terms, the 3 highest national incidence rates are estimated in Malaysia, Indonesia, and Singapore, where rates are high among the Chinese and Malay populations. Elsewhere in Asia, high incidence rates are observed in a number of provinces in South-Eastern China, including Guangdong and Hong Kong, and in other parts of Southern Asia (the Philippines and Thailand). Rates are also elevated in Polynesia, Southern Africa, and Northern Africa, particularly within the latter region in Tunisia and Algeria. Other populations where NPC is relatively frequent include the Inuit populations of Alaska, Greenland, and North Canada, as well as Chinese and Filipinos living in the United States. Rates of this malignancy tend to be considerably lower in most populations living elsewhere within the Americas, Europe, Africa, and Central and Eastern Asia. A bimodal age distribution is observed in low-risk populations. The first peak incidence arises between 15 to 25 years of age, with the second peak at 50 to 59 years of age. In high risk Populations, the peak incidence occurs in the fourth and fifth decades of life. Both genders have a similar age distribution. However, the male-to-female incidence ratio is 2:1 to 3:1(13).

Indians, comprising about one-sixth of the world population with large family sizes and high levels of endogamy, provide a unique resource for dissecting complex disease etiology and pathogenesis. Historically, the Indian population is a conglomeration of multiple cultures and races. The evolutionary history of India entails migrations from central Asia and South China, resulting in a rich tapestry of socio-cultural, linguistic, and biological diversity. Broadly, Indians belong to the Austro-Asiatic, Tibeto-Burman, Indo-European, and Dravidian language families. Linguistically, the North-eastern region is distinguished by a preponderance of the Tibeto-Burman languages, and the population here is thought to comprise migrating peoples from East and Southeast Asia, who are presumed to have brought with them the risk for NPC to this region. 

Despite the high incidence of oral cancer in India, NPC is uncommon in most regions. For instance, in Mumbai, West India, the incidence is cited as 0.71% for all cancers. These low rates are comparable to those commonly quoted for other Caucasoid populations of 0.5 to 2.0/100 000. There are 23 Population-Based Cancer Registries (PBCR) in India under the network of National Cancer Registry Programme of the Indian Council of Medical Research(14).

Pathogenesis and Aetiology

The cause of NPC is most likely multifactorial. Current epidemiologic and experimental data suggest at least three major causal factors: viral, genetic, and 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. Using real-time polymerase chain reaction technology, Lo was able to detect circulating EBV deoxyribonucleic acid (DNA) in 96% of NPC patients in Hong Kong(15). 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 among Chinese NPC patients and control subjects. There is a significant increase of HLA-A2 and HLA-B-SIN2 in Chinese patients. 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 States 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 dust, 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. Dimethylnitrosamine, a carcinogen found in salted fish, has been shown to induce carcinoma in the upper respiratory tract of rats(16).

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). Each of the lateral walls contains the eustachian tube orifice, which is surrounded by the torus tubarius, a prominence in the cartilaginous portion of the tube. Behind the torus tubarius is a recess called the Rosenmuller fossa. The lateral walls, including the Rosenmuller 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. 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. 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. 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, Rosenmuller 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 Rouviere; 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.

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.

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 Rouviere.

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.

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. In 1991 the WHO reclassified NPC into the following histologic subtypes: (1) keratinizing squamous cell carcinoma, (2a) nonkeratinizing carcinoma, and (2b) undifferentiated carcinoma. 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. 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(17). Other common symptoms include epistaxis, decreased hearing, nasal obstruction, pain, and cranial nerve deficits. Cervical lymphadenopathy is present in 87% of patients. 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. The bones, lungs, and liver are the most common distant metastatic sites.

Routes of Spread

Local Extension

Anterior

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 Rosenmuller 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.

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. 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.

Lymphatic Spread

Lymphatic spread to the ipsilateral nodes is common and is present in 85% to 90% of cases(18). Bilateral spread occurs in approximately 50% of cases. Metastasis to the contralateral nodes only is uncommon. 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. 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.

 Haematogenous 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. An 80% incidence rate has been reported in a small autopsy series. The incidence of distant metastasis is highest in patients with advanced neck node metastasis, particularly in the low neck. 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 anaesthesia in the outpatient clinic. Biopsy with direct visualization under general anaesthesia 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: Rosenmuller 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 pre-treatment diagnostic evaluations are recommended:

1.         Complete history and physical examination, including a fiberoptic endoscope 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.         EBV-specific serologic tests, immunoglobulin A (IgA) anti-viral capsule antigen (VCA) titers, serum EBV DNA levels.

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

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

7.         Pretreatment dental evaluation and initiation of dental prophylaxis

8.         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. 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(19). 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. 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.MRI and CT scans can also detect lymph node metastasis that may not be evident on clinical examination. CT scan is superior to MRI in the detection of early bone invasion. 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.

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(20). 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.

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. Elevated IgA antibody titers have been reported in more than 90% of untreated patients with NPC from Hong Kong, East Africa, and California. 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.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(21). 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.

Staging Classification

Various staging systems have been formulated for NPC. 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. Figure 7 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. 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. Those with parapharyngeal space involvement are at higher risk for local and regional recurrence, as well as a high rate of distant metastases. Cranial nerve involvement has been shown to carry a worse prognosis than base of the skull involvement 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. Because of these limitations, modifications of both Ho's and AJCC classification have been proposed and are shown in Figure 7. 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. 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. With regard to N staging, because retropharyngeal nodes are the first echelons of nodal metastases, retropharyngeal lymph node involvement independent of laterality and without cervical lymph node involvement has been proposed as stage N1. The adequacy of these new modified staging classifications will require further clinical confirmation(22).

Treatment Overview

Standard Therapeutic Approaches

Because of the anatomic location proximity to critical structures surgical exposure and tumor resections with sufficient margins have been very challenging. Primary surgical intervention was rare after the 1950s for these reasons, with surgical interventions employed mainly for biopsy to gain histologic confirmation and salvage therapy for persistent or recurrent cancer.

Primary treatment since has typically employed radiotherapy (RT) alone and, more recently, in combination with chemotherapy. 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. To achieve the best therapeutic ratio, every single step in the RT procedures (localization of gross tumor and target volumes, immobilization, optimization of dose fractionation, determination of treatment techniques, and precision in RT delivery) is important.

Nasopharyngeal carcinoma is generally regarded to be a highly chemosensitive disease. While radiotherapy alone is the standard treatment for stage I NPC, concurrent CRT with or without adjuvant chemotherapy is the current standard for locally advanced disease (stage III–VB) based on multiple randomized, controlled trials and meta-analysis. Although there is less evidence for CRT in intermediate stage (2010 AJCC stage II) disease, it is recommended that such patients be treated with CRT in light of pooled data from two phase III trials and a more recent phase III trial from Chen et al. In more detail, Chen et al. demonstrated that Chinese stage II NPC patients (equivalent to AJCC II-III; only 13% of the study’s patients are AJCC 2010 stage III) that received concurrent chemoradiotherapy resulted in a 5-year OS benefit compared to radiation alone (94.5% vs. 85.8%, p = .007), with improved distant control (94.8% vs. 83.9%, p = .007). Multivariate analyses found that number of chemotherapy cycles was the only independent factor associated with improved OS, progression free survival, and distant control. With the addition of chemotherapy, an increase in acute side effects was observed, but no significant increase in late effects was reported. 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. Radiotherapy was delivered at 1.8 to 2 Gy per fraction per day, 5 days a week, to a total dose of 70 Gy.

Prognostic Factors

The extent of local invasion, regional lymphatic spread, and distant metastasis, as reflected by the TNM staging, is the most important prognostic factor. In general, advanced T-category is associated with worse local control and overall survival. Advanced N-category predicts increased risk of distant metastasis and worse survival. Presence of distant metastasis (M1) upon presentation usually indicates poor prognosis, and treatment has conventionally been palliative in nature. The association of bone erosion, cranial nerve palsy, and lower nodal level with poorer survival is largely undisputed. However, the prognostic significance of parapharyngeal extension has been a topic of controversy. Another prognostic factor to consider is the gross volume of the primary tumor (GTV-P). Sze et al. showed that those with GTV-P of <15 cm3 had significantly higher L-FFR than those with a value of ≥15 cm3 (97% vs. 82% at 3 years; p < 0.01). Most series found significantly better prognosis for females and younger patients. Histology to be an independent prognostic factor, many found nonkeratinizing and undifferentiated carcinomas (formerly known as lymphoepitheliomas) to be more radiosensitive and offer better prognosis than keratinizing squamous cell carcinoma. Of note, regarding ethnicity as a prognostic factor, a study by Corry et al. showed no prognostic difference between ethnic Asian and non-Asian patients with nonkeratinizing carcinoma.

Radiotherapy Technique

Linear accelerator (LINAC)

The first microwave electron linear accelerator (8 MV) for medical use became operational in 1953 at the Radiation Research Center of the Medical Research Council at Hammersmith Hospital in London. The design for an isocentric gantry mount for the accelerator first was conceived by P. Howard-Flanders. Shortly thereafter, Ginzton et al at Stanford developed a 6-MV isocentric medical linear accelerator (linac). Since then there have been continued advances in accelerator design and construction, and today medical linear accelerators (referred to as linacs) account for most of the operational megavoltage treatment units in clinical use.

Figure 8A is a block diagram of a high-energy, bent-beam medical linear accelerator showing the major components. The linac uses electromagnetic waves of frequencies in the S-band microwave region (2,856 megahertz [MHz]) to generate an electric field. The microwave radiation is propagated through a device called an accelerator structure and the electrons injected into the structure are accelerated by the electric field in a straight line. The accelerator structure consists of a stack of cylindrical metal cavities having an axial hole through which the accelerated electrons pass. The accelerator structure's electric field produced by the microwaves can be either a traveling wave or standing wave design. In a traveling wave design, the electrons travel with the electric field as the field propagates through the structure with time, somewhat in the manner of a surfboarder riding the crest of an ocean wave. In a standing wave accelerator, the reflected microwave power is used to produce a standing wave electric field. In that case, the microwave power is coupled into the accelerator structure by side-coupling cavities, rather than through the accelerator structure's axial cavity apertures.

The accelerator structure in low-energy (4 to 6 MV) linacs most often is mounted vertically in the treatment head collinear along with the components associated with producing, controlling, and monitoring the x-ray beam (Fig. 8B, left). High-energy (15 to 18 MV) linacs use a horizontally mounted accelerator structure with a beam-bending magnet system (Fig. 8B, right). Accelerator structure technology now makes possible multiple high-dose rate photon beams of widely separated energies.

Other important components of a linac are the modulator, microwave power sources, electron gun, and the beam-handling components. The modulator is the source of pulsed DC (direct current) power, which is needed for the production of microwave power. Pulsed DC power is also supplied to the electron gun (a hot-wire filament that serves as the source of the accelerated electrons). The electrons are bunched before acceleration by a device called a buncher. The electron beam thus consists of pulses of bunched electrons in the form of a narrow pencil beam. The magnetron is a device that serves as both the source of the microwaves and as a power amplifier. The klystron is a device used to amplify the microwave power that is generated from a separate microwave source (RF Driver). The microwave power coming from the magnetron or klystron is transported to the accelerator structure by a metallic pipe called a waveguide. A device called the circulator is used to isolate the klystron/magnetron from the reflected microwave power. Other important components in a linac are located in the treatment head. These include the x-ray target, fixed primary collimator, scattering foils, flattening filter, monitor ion chamber, movable secondary collimator jaws, light field localizer, and optical distance indicator. In addition, the treatment head contains a significant amount of shielding material to minimize leakage radiation.

At the exit window of the accelerator structure, the high-energy electrons emerge in the form of a pencil beam of about 2 to 3 mm in diameter. In a low-energy (4 to 6 MeV) linac, the accelerated electrons proceed in a straight line and strike an x-ray target, when in photon mode, producing bremsstrahlung x-rays. In high-energy linacs, because the accelerator structure is much longer and is placed horizontally or at some angle with respect to the horizontal, the electrons must be bent through a suitable angle, usually 90 or 270 degrees between the accelerator structure and the target. This is enabled by the beam transport system, which consists of an achromatic focusing and bending magnet, as well as steering and focusing coils.

The primary collimator is a fixed collimator located just below the x-ray target and used to collimate the x-ray beam in the direction of the patient treatment and reduces the leakage radiation from the x-ray source. The angular distribution of the bremsstrahlung x-rays produced by megavoltage electrons incident on a target is forward-peaked. To make the x-ray beam intensity uniform across the field, a conical metal flattening filter is inserted in the beam. Filters have been constructed of lead, tungsten, uranium, steel, and aluminum (or some combination of these), depending on x-ray energy. The flattened x-ray beam then passes through a monitor ionization chamber. In most cases, this system consists of several transmission-type parallel-plate ionization chambers, which cover the entire beam. These ion chambers are used to monitor the field symmetry, dose rate, and the integrated dose per monitor unit.

After passing through the monitor chamber, the beam can be further collimated by continuously movable x-ray collimators, consisting of two pairs of lead or tungsten jaws, which provide rectangular field sizes ranging from zero to typically 40 × 40 cm at a distance of 100 cm. The field size is defined by a light localizer and a mirror assembly. Independent jaw capability is available on modern units. This flexibility allows simplified patient positioning and improved safety by avoiding overlapping field abutments without the necessity of using heavy beam-splitting blocks. Independent jaw technology in conjunction with computer control of the dose rate can be used to create a wedge-shaped isodose pattern.

Most modern medical accelerators come with multileaf collimator (MLC) (Fig.8C) systems. The leaf settings for each field are computer controlled. Modern treatment planning systems have the ability to configure MLC shaped fields and the patient's MLC configuration files are sent via a local area network to the linac's MLC computer.

In the electron mode, the accelerator's beam current is reduced 1,000-fold and the x-ray target is retracted. An electron-scattering foil is moved into place on the beam center line so that the accelerated pencil electron beam strikes