Head and Neck Cancer

EPIDEMIOLOGY

The incidence of head and neck squamous cancer is more than 500,000 cases per year worldwide, and 40,000 to 50,000 cases per year in the United States, where it comprises approximately 3% to 5% of all new cancers and 2% of all cancer deaths (1). Most patients are older than 50 years, and incidence increases with age; the male-to-female ratio is 2.5:1. The age-adjusted incidence is higher among black men, and, stage-for-stage, survival among African Americans is lower overall than in whites (1 and references therein). Death rates have been decreasing since at least 1975, with rates declining more rapidly in the last decade (1). Ninety percent of these cancers involves squamous cell histology. The most common sites are the oral cavity, pharynx, larynx, and hypopharynx. Nasal cavity and paranasal sinus cancers, salivary gland malignancies, and various sarcomas, lymphomas, and melanoma are less common.

RISK FACTORS

Heavy alcohol consumption increases the risk of developing squamous head and neck cancer two-fold to sixfold, whereas smoking increases the risk 5- to 25-fold, depending on gender, race, and the amount of smoking. Both factors together increase the risk 15- to 40-fold. Smokeless tobacco and snuff are associated with oral cavity cancers. Case-control studies show that the relative risk for developing erythroplasia or cancer in tissues in contact with snuff powder (cheek and gum) is nearly 50-fold (2). In many parts of Asia and some parts of Africa, chewing betel with or without tobacco and slaked lime is associated with premalignant lesions and oral squamous cancers (3,4).

Multifocal mucosal abnormalities have been described in patients with head and neck cancer (“field cancerization”) (5). There is a 2% to 6% risk per year for a second head and neck, lung, or esophageal cancer in patients with a history of cancer in this area. Those who continue to smoke have the highest risk. Second primary cancers represent a major risk factor for death among survivors of an initial squamous carcinoma of the head and neck (6,7,8).

Epstein-Barr virus (EBV) has been detected in virtually all nonkeratinizing and undifferentiated nasopharyngeal cancers but less consistently in squamous nasopharyngeal cancers (9). Cancers of the oropharynx and tonsil can be associated with human papillomavirus (HPV) infection (10,11,12). The incidence of HPV-associated cancers is more common in nonsmokers and seems to be increasing in several countries.

Disorders of DNA repair (e.g., Fanconi anemia) as well as organ transplantation with immunosuppression are associated with increased risk of squamous head and neck cancer (13).

PREVENTION AND CHEMOPREVENTION

The most important recommendation for prevention of head and neck cancer is to avoid smoking and to limit alcohol intake. Premalignant lesions occurring in the oral cavity, pharynx, and larynx may manifest as leukoplakia (a white patch that does not scrape off and that has no other obvious cause)

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or erythroplakia (friable reddish or specked lesions) (Table 1.1). The risk of leukoplakias without dysplasia progressing to cancer is about 4%. However, up to 40% of severe dysplasias or erythroplasias progress to cancer. Retinoids can reversibly improve premalignant histology. However, randomized, placebo-controlled clinical trials in patients with curatively treated head and neck squamous cell carcinoma failed to find any benefit for 13-cis-retinoic acid, retinyl palmitate, N-acetyl-cysteine (NAC), or the combination of retinyl palmitate and NAC in preventing second primary cancers or in improving survival (14,15).

TABLE 1.1. Premalignant lesions

Leukoplakia Erythroplakia Dysplasia Clinical features White patch or plaque occurring in surface of mucous membrane that does not rub off, once other oral diseases are ruled out Bright red velvety plaques that cannot be characterized clinically or pathologically as being due to any other condition Can present as leukoplakia, erythroplakia, or without obvious macroscopic findings Probability of progression to malignant lesions 4% 15%-30% of dysplastic lesions 15%-30% Histopathology Hyperkeratosis associated with variable histologic findings; rarely contain dysplasia or carcinoma (invasive or in situ carcinoma found in only 6% of cases) Mild to moderate dysplasia in 10% of patients; severe dysplasia, in situ or invasive carcinoma in 90% of cases True histologic diagnosis: pleomorphic changes, increased number of nucleoli, prominent nucleoli Source: From McFarland M, Abaza NA, El-Mofty S. In: Damjanov I, Linder J, eds. Anderson’s pathology. St. Louis: Mosby, 1996, with permission.

Presently, there is no effective chemoprevention for patients at risk for head and neck squamous cancer. An NCI study of PPAR agonists for prevention of oral premalignant lesions is underway at this writing, but final results are pending. Other avenues of research are also being pursued (16). Chemoprevention outside a clinical trial is not recommended and is potentially harmful (17,18,19).

ANATOMY

A simplified depiction of extracranial head and neck anatomy is presented in Fig. 1.1.

The patterns of lymphatic drainage divide the neck into several levels (Fig. 1.2). Level I comprises the submental or submandibular nodes; level II (upper jugular lymph nodes) extends from the skull base to the hyoid bone; level III (middle jugular lymph nodes) is the area between the hyoid bone and the lower border of the cricoid cartilage; level IV (lower jugular lymph nodes) is the area between the cricoid cartilage and the clavicle; level V is the posterior triangle; level VI is the anterior compartment from the hyoid bone to the suprasternal notch, bounded on each side by the medial carotid sheath; and level VII is the area of the superior mediastinum. Masses more than 3 cm in greatest dimension can be groups of nodes or a single node, with the tumor extending into the soft tissues (20). Knowledge of the lymphatic drainage of the neck assists in locating a primary tumor when a palpable lymph node is the initial presentation, enabling the surgeon or radiation oncologist to plan appropriate treatment of both primary and neck diseases.

STAGING

Clinical staging is based on physical examination and imaging tests. The staging systems put forth by the American Joint Committee for Cancer (AJCC) (Table 1.2) and the Union Internationale Contre

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le Cancer (UICC) (tumor, node, metastasis [TNM]) are used. The AJCC classification (20) emphasizes resectability status by dividing advanced disease stages into stage IVA (resectable), stage IVB (unresectable), and stage IVC (distant metastatic disease).

Fig. 1.1. Sagittal section of the upper aerodigestive tract. [Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, sixth edition (2002) published by Springer-Verlag, New York.]

Fig. 1.2. Diagram of the neck showing levels of lymph nodes. Level I, submandibular; level II, high jugular; level III, midjugular; level IV, low jugular; level V, posterior jugular; level VI, tracheoesophageal; level VIII, superior mediastinal, is not shown. [Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, sixth edition (2002) published by Springer-Verlag, New York.]

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TABLE 1.2. TNM staging of head and neck tumors

Definition of TNM Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ Nasopharynx T1 Tumor confined to the nasopharynx T2 Tumor extends to soft tissue T2a Tumor extends to the oropharynx and/or nasal cavity without parapharyngeal extensiona T2b Any tumor with parapharyngeal extensiona T3 Tumor involves bony structures and/or paranasal sinuses T4 Tumor with intracanial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space Oropharynx T1 Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension T3 Tumor more than 4 cm in greatest dimension T4a Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible T4b Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery Hypopharynx T1 Tumor limited to one subsite of hypopharynx and 2 cm or less in greatest dimension T2 Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx T3 Tumor more than 4 cm in greatest dimension or with fixation of hemilarynx T4a Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissueb T4b Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures Regional lymph nodes (N) Nasopharynx The distribution and the prognostic impact of regional lymph node spread from nasopharynx cancer, particularly of the undifferentiated type, are different from those of other head and neck mucosal cancers and justify the use of a different N classification scheme. NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossac N2 Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossac N3 Metastasis in a lymph node(s):c 6 cm and/or to supraclavicular fossa N3a Greater than 6 cm in dimension N3b Extension to the supraclavicular fossad Oropharynx and hypopharynx NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension. N2a Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node more than 6 cm in greatest dimension Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping: Nasopharynx Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIA T2a N0 M0 Stage IIB T1 N1 M0 T2 N1 M0 T2a N1 M0 T2b N0 M0 T2b N1 M0 Stage III T1 N2 M0 T2a N2 M0 T2b N2 M0 T3 N0 M0 T3 N1 M0 T3 N2 M0 Stage IVA T4 N0 M0 T4 N1 M0 T4 N2 M0 Stage IVB Any T N3 M0 Stage IVC Any T Any N M1 Stage grouping: Oropharynx, hypopharynx Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage IVA T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 Stage IVB T4b Any N M0 Any T N3 M0 State IVC Any T Any N M1 aParapharyngeal extension denotes posterolateral infiltration of tumor beyond the pharyngobasilar fascia. bCentral compartment of soft tissues includes prelaryngeal strap muscles and subcutaneous fat. cMidline nodes are considered ipsilateral nodes. dSupraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described by Ho. It is defined by three points: (a) the superior margin of the sternal end of the clavicle, (b) the superior margin of the lateral end of the clavicle, (c) the point where the neck meets the shoulder. Note that this would include the caudal portions of levels IV and V. All cases with lymph nodes (whole or part) in the fossa are considered N3b. Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, sixth edition (2002) published by Springer-Verlag, New York.

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TABLE 1.3. Common presenting signs and symptoms of head and neck cancer
Painless neck mass Odynophagia Dysphagia Hoarseness Hemoptysis Trismus Otalgia Otitis media Loose teeth Ill-fitting dentures Cranial nerve deficits Nonhealing oral ulcers

The T classification indicates the extent of the primary tumor. It differs for each site. For primary tumors of the oral cavity, hypopharynx, and oropharynx, lesions greater than 4 cm are classified as T3. Vocal cord paralysis with a larynx or hypopharynx primary indicates at least T3. Lesions with local invasion of adjacent structures indicate T4.

The N classification is uniform for all primary sites, except nasopharynx. For all primary sites except nasopharynx, any clinical lymph node involvement indicates at least stage III, and nodes larger than a single 3-cm ipsilateral node are classified as stage IV regardless of T stage.

The presence of distant metastasis (M1) indicates stage IVC disease. Mediastinal lymph node involvement is considered distant metastasis.

Tumor grade has not shown significant association with outcome and is not considered when staging head and neck cancers.

PRESENTATION

Signs and symptoms are usually secondary to mass effect and/or pain from primary tumor or involved lymph nodes and invasion of adjacent structures or nerves (Table 1.3). Adult patients with any of these symptoms for more than 4 weeks should be referred to an otolaryngologist. Delay in diagnosis is common for reasons such as patient delay or repeated courses of antibiotics for otitis media or sore throat. A lateralized firm cervical mass in an elderly smoker is highly suggestive of squamous cell carcinoma. For nasopharyngeal cancers, the most common presenting symptom is a neck mass, sometimes in the posterior triangle. In advanced lesions, cranial nerve abnormalities may be present.

With the exception of hypopharyngeal and nasopharyngeal cancers, distant metastases are uncommon at presentation. The most common sites of distant metastases are lung and bone; liver involvement is less common.

DIAGNOSIS

The history should include:

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  Tobacco exposure (pack years; amount chewed; and duration of habit, current or former)
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  Alcohol exposure (number of drinks per day)
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  Other risk factors mentioned earlier
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  Cancer history of patient and family
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  Signs and symptoms listed in Table 1.3
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  Thorough review of systems

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The head and neck physical examination should include the following:

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  Careful inspection of the scalp, ears, nose, and mouth
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  Palpation of the neck and mouth, assessment of tongue mobility, determination of restrictions in the ability to open the mouth (trismus), and bimanual palpation of the base of the tongue and floor of the mouth
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  Mirror or flexible endoscopic examination of the nasal passages, nasopharynx, oropharynx, hypopharynx, and larynx
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  Special attention to the examination of cranial nerves

Abnormalities are suggested by asymmetry in the physical examination. Direct or indirect laryngoscopy should be strongly considered for symptoms of hoarseness or sore throat not cured by a single course of antibiotics.

Friability (easy bleeding), an indicator of an early malignant process or erythroplakia (see Table 1.1), is frequently associated with severe dysplasia or carcinoma in situ and the site should be biopsied. When neck mass is the first presentation, the primary site can be located and biopsied in approximately 80% of cases. If no primary site is obvious, tissue diagnosis can be obtained by fine needle aspiration (FNA) biopsy of the node, with sensitivity and specificity approaching 99%. A nondiagnostic FNA does not rule out the presence of tumor.

Computerized tomography (CT) scan remains the primary imaging study for evaluation of bone involvement and metastatic adenopathy. Magnetic resonance imaging (MRI) may complement the CT scan with greater resolution of soft tissue. Positron emission tomography (PET) scans combined with CT (PET/CT) are being used more frequently to detect tumors or nodes that are not obvious on other scans and for monitoring for disease recurrence in patients with advanced locoregional disease treated with concurrent chemotherapy and radiotherapy who have residual anatomical abnormalities on CT or MRI (21).

Diagnostic and staging laryngoscopy and nasopharyngoscopy should be performed to identify site of origin and extent of primary tumor and to obtain biopsies. With occult primary tumors, directed biopsies of the nasopharynx, tonsil, base of tongue, and pyriform sinus should be performed (Fig. 1.3). Bilateral tonsillectomy will sometimes reveal the source of an occult cancer. Esophagoscopy and bronchoscopy may be indicated for symptoms such as dysphagia, hoarseness, cough, or to search for occult primary.

Surgical biopsy of a neck mass before endoscopy is contraindicated if a squamous cell carcinoma is suspected. Studies show that open biopsy may worsen local control, increase the rate of distant metastases, and decrease overall survival rate, possibly by spreading the disease at the time of the biopsy. Finally, an open biopsy does not provide any information additional to that obtained from FNA, and laryngoscopy is still necessary for treatment planning.

WORKUP AND STAGING EVALUATION

After the diagnosis of cancer is established, the patient should be clinically staged by physical examination and radiologic studies, usually by CT scan and/or MRI of the primary tumor, neck, and chest. CT scan better defines the cortical bone and is better than MRI for evaluating metastatic adenopathy. MRI has superior soft tissue contrast, does not involve radiation, and may be better than CT scan for primary tumor staging. PET/CT scanning is indicated for staging patients with advanced head and neck cancers (21). A chest radiograph, chest CT scan, or PET/CT is indicated for all patients because of the risk of a second lung malignancy. Additional studies vary according to the clinical stage, symptoms, and primary site.

PROGNOSIS

The most important determinant of prognosis is stage at diagnosis. The 5-year survival for stage I patients exceeds 80% but is less than 40% in stages III and IV disease. Most patients have locally advanced disease involving one or several lymph nodes on one or both sides of the neck. The presence

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of a palpable lymph node in the neck generally decreases the survival rate by 50% compared to the same T stage without node involvement.

Fig. 1.3. Evaluation of cervical adenopathy when a primary cancer of the head and neck is suspected.

Most relapses occur locoregionally. Distant metastases are more commonly seen later in the course of the disease or as part of relapse after successful initial treatment, and predominantly involve lung, bone, and liver. The lifetime risk of developing a new cancer for a patient with head and neck cancer is 20% to 40% (6,8). After 3 years, development of a new cancer represents the greatest survival risk (Tables 1.4, 1.5 and 1.6).

SCREENING

Careful examination of the head and neck is warranted in individuals with risk factors or suggestive symptoms. Mucosal abnormalities and palpable neck masses should be biopsied (see the section on diagnosis).

The U.S. Preventive Task Force (http://www.ahrq.gov/clinic/uspstfix.htm) does not recommend regular screening for oral cancer in the general population but recommends counseling for cessation

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of tobacco use and limitation of alcohol intake. The American Cancer Society (www.cancer.org) recommends oral examination during physician or dental appointments. The oral examination should include inspection of all mucosal areas, assessment of range of motion of tongue, bimanual palpation of floor of mouth, palpation of the tongue, and assessment of dental health. Any of the complaints described earlier require evaluation, especially if symptoms persist for more than 4 weeks or after treatment for presumed infection.

TABLE 1.4. Head and neck cancer: Oral cavity

Site Epidemiology Natural history and common presenting symptoms Nodal involvement Prognosis (5-yr survival) Lip Risk factors are sun exposure and tobacco; 3,600 new cases a year; 10 to 40 times more common in white men than in black men or women (black or white) Exophytic mass or ulcerative lesion; more common in lower lip (92%); slow-growing tumors; pain and bleeding 5%-10% Midline tumors spread bilaterally Level I more common (submandibular and submental); upper lip lesions metastasize earlier: level I and also preauricular T1, 90% T2, 84% With lymph node involvement, 50% Alveolar ridge and retromolar trigone 10% of all oral cancers; M:F, 4:1 Exophytic mass or infiltrating tumor, may invade bone; bleeding, pain exacerbated by chewing, loose teeth, and ill-fitting dentures 30% (70% if T4) Levels I and II more common T1, 85% T2, 80% T3, 60% T4, 20% Floor of mouth 10%-15% of oral cancers, (occurrence 0.6/100,000); M:F, 3:1; median age, 60 yr Painful infiltrative lesions, may invade bone, muscles of floor of mouth and tongue T1, 12%; T2, 30%; T3, 47%; and T4, 53% Levels I and II more common By stage: I, 85%-90% II, 80% III, 66% IV, 32% Advanced stage, 30% Hard palate 0.4 cases/100,000 (5% of oral cavity); M:F, 8:1; 50% cases squamous, 50% salivary glands Deeply infiltrating or superficially spreading pain Less frequently: 6%-29% By stage: I, 75% II, 46% III, 36% IV, 11% Buccal mucosa 8% of oral cavity cancers in United States; women > men Exophytic more often, silent presentation; pain, bleeding, difficulty in chewing 10% at diagnosis 18%-77% all stages M:F, male-to-female ratio.

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TABLE 1.5. Head and neck cancer: Oropharynx and larynx

Site Epidemiology Natural history and common presenting symptoms Nodal involvement Prognosis (5-yr survival) Base of tongue 4,000 new cases annually in the United States; M:F ratio, 3 to 5:1. May be HPV-associated Advanced at presentation (silent location, aggressive behavior); pain, dysphagia, weight loss, and otalgia (from cranial nerve involvement); neck massis a frequent presentation All stages: 70% (T1) to 80% (T4) Levels II and III more common, also IV, V, and VI By stage: I, 60% II, 40% III, 30% IV, 15% Tonsil, tonsillar pillar, and soft palate Tobacco and alcohol are the most significant risk factors. HPV common Tonsillar fossa: more advanced at presentation: 75% stage III or IV, pain, dysphagia, weight loss, and neck mass Soft palate: more indolent, may present as erythroplakia Tonsillar pillar T2, 38% Tonsillar fossa T2, 68% (55% present with N2 or N3 disease) Tonsillar fossa, 93% (stage I) to 17% (stage IV) Soft palate, 85% (stage I) to 21% (stage IV) Posterior pharyngeal wall Advanced at diagnosis (silent location); pain, bleeding, and weight loss; neck mass is common initial symptom Clinically palpable nodes T1, 25% T2, 30% T3, 66% T4, 75% Bilateral involvement is common By stage: I, 75% II, 70% III, 42% IV, 27% Supraglottis 35% of laryngeal cancers Most arise in epiglottis; early lymph node involvement due to extensive lymphatic drainage; two-thirds of patients have nodal metastases at diagnosis Overall rate: T1, 63%; T2, 70%; T3, 79%; T4, 73% Levels II, III, and IV more common By stage: I, 70-100% II, 50-90% III, 45-70% IV, 20-60% Glottis Most common laryngeal cancer Most favorable prognosis; late lymph node involvement; usually well differentiated, but with infiltrative growth pattern; hoarseness is an early symptom; 70% have localized disease at diagnosis Sparse lymphatic drainage, early lesions rarely metastasize to lymph nodes. Clinically positive: T1, T2 Levels II, III, and IV more common T3, T4, 20%-25% 2% T1, 74-86% T2, 67-75% T3, 55 T4, 50 Subglottis Rare, 1%-8% of laryngeal cancers Poorly differentiated, infiltrative growth pattern unrestricted by tissue barriers; rarely causes hoarseness, may cause dyspnea from airway involvement; two-thirds of patients have metastatic disease at presentation 20%-30% overall Pretracheal and paratracheal nodes more commonly involved 26% overall M:F, male-to-female ratio.

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TABLE 1.6. Head and neck cancer: Hypopharynx, nasal cavity, paranasal sinuses, and nasopharynx

Site Epidemiology Natural history and common presenting symptoms Nodal involvement Prognosis (5-yr survival) Hypopharynx 2,500 new cases yearly in United States; etiology: tobacco, alcohol, and nutritional abnormalities Aggressive, diffuse local spread, early lymph node involvement; occult metastases to thyroid and paratracheal node chain; pain, neck stiffness (retropharyngeal nodes), otalgia (cranial nerve X), irritation, and mucus retention 50% present as neck mass; high risk of distant metastases Abundant lymphatic drainage Up to 60% have clinically positive lymph nodes at diagnosis Survival varies between sites within hypopharynx T1, T2, 40% T3-T4, 16%-37% Nasal cavity and paranasal sinuses Rare, 0.75/100,000 occurrence in United States Nasal cavity and maxillary sinus, four-fifths of all cases M:F, 2:1 Increased risk with exposure to furniture, shoe, textile industries; nickel, chromium, mustard gas, isopropyl alcohol, and radium Nonhealing ulcer, occasional bleeding, unilateral nasal obstruction, dental pain, loose teeth, ill-fitting dentures, trismus, diplopia, proptosis, epiphora, anosmia, and headache, depending on site of invasion Usually advanced at presentation 10%-20% clinically positive nodes Levels I and II more common 60% for all sites all stages, 30% for T4 Nasopharynx Rare (1/100,000) except in North Africa, Southeast Asia, and China, far northern hemisphere Associated with EBV, diet, genetic factors Most common initial presentation: neck mass Other presentations: otitis media, nasal obstruction, tinnitus, pain, and cranial nerve involvement Clinically positive: WHO I, 60% WHO II and III, 80%-90% T1, 37%-60% T2, 46%-68% T3, 16%-25% T4, 11%-40% M:F, male-to-female ratio; EBV, Epstein-Barr virus.

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TREATMENT

The management of patients with head and neck cancer is complex. The choice of treatment modality depends on the stage and site of disease. Patients with locally advanced disease should be evaluated by a multidisciplinary team including an otolaryngologist or head and neck surgical oncologist, radiation oncologist, medical oncologist, dentist, prosthodontist, nutritionist, speech and swallowing pathologist, and personnel involved in rehabilitation before treatment is initiated.

In general, either surgery or radiation is effective as single-modality therapy for patients with early-stage disease (stage I or II) for most sites. The choice of modality depends on local expertise, patient preference, and functional result. For 60% of patients with locally advanced disease (stages III, IV, and M0), combined-modality therapy is indicated.

Surgery

The nature of the surgical procedure is determined primarily by the size of the tumor and the structures involved.

Resectability depends on the experience of the surgeon and the rehabilitation team. In general, a tumor is unresectable if the surgeon believes that all gross tumor cannot be removed or that local and distant control will not be achieved after surgery even with adjuvant radiation therapy. Generally, involvement of the skull base, pterygoid, and deep neck musculature and of the major vessels portends a poor outcome with surgery as a primary modality.

T1 and T2 lesions of the oral cavity, oropharynx, and hypopharynx may be amenable to wide local excision with a 2 cm margin, and closed by primary or secondary intention, skin graft, or local tissue flap reconstruction. Carcinoma in situ, T1 and T2 lesions of the larynx may be treated by microlaryngoscopic mucosal excision, cordectomy, or one of the various external hemilaryngectomy or partial laryngectomy procedures that have been developed. Newer technology for transoral and transnasal endoscopic surgical approaches have been recently investigated for resection of T1, T2, and selected T3 carcinomas involving the larynx, paranasal, and skull base region. Extensive surgeries and those involving function of the tongue frequently require myocutaneous flaps or microvascular free flaps to achieve a more functional reconstruction. However, as will be discussed below, with the advent of primary therapy with concurrent chemoradiotherapy for advanced cancers of the larynx, nasopharynx, oropharynx, and hypopharynx, surgery is increasingly being used for treatment of advanced neck disease (N2, N3) and for salvage of nonresponding or recurrent tumors of the primary site.

Cervical lymph node dissections may be elective or therapeutic. Elective neck dissections are done at the time of surgery in patients with necks that are clinically negative when the risk of a positive lymph node is at least 30%. Therapeutic neck dissections are done for clinically obvious masses. Cervical lymph node dissections are classified as radical, modified radical, or selective. The radical dissection includes removal of all lymph nodes in the neck from levels I to V (see Fig. 1.2), including removal of the internal jugular vein, spinal accessory nerve, and sternocleidomastoid muscle. This surgery is now rarely performed because of excessive morbidity, especially loss of shoulder function. The modified radical dissection preserves one or more of the nonlymphatic structures. In selective neck dissections, only certain levels of lymph nodes are removed based on the specific lymphatic drainage from the primary site. With no palpable or CT scan evidence of clinical nodal involvement, nodal metastases will be present beyond the confines of an appropriate selective neck dissection less than 10% of the time. Sentinel lymph node dissection and PET scanning are currently being evaluated for use in diagnosing positive lymph nodes in patients with necks that are clinically negative.

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Radiation Therapy

Over the past two decades, radiation therapy has evolved from a primitive modality fraught with toxicity to a fine art that demands a keen appreciation of both tumor biology and radiation physics. The use of computed tomography for simulation and three-dimensional techniques for treatment planning facilitated greater accuracy in portal design based on an improved understanding of the radiographic extent of the tumor. Intensity-modulated radiation therapy techniques helped to reduce normal tissue toxicity while maintaining high doses to the target volume. The advantages of these advances have been demonstrated very eloquently in the management of head and neck cancer by an improvement in locoregional control (22,23,24) and a decrease in normal tissue toxicity (25,26,27,28). Brachytherapy offers similar advantages when performed by experienced physicians (29,30).

Early-stage (T1, T2, N0) disease responds well to single-modality treatment with either surgery or radiation therapy. Radiation therapy allows organ preservation—as evidenced by its role in the management of early-stage cancers of the glottis larynx and pharynx (31,32,33,34,35,36,37).

More advanced disease requires the integration of radiation therapy with other modalities. When surgery is the primary modality, as in the case of paranasal sinus or salivary gland tumors, postoperative radiation therapy or chemoradiation is generally preferred to the preoperative setting and is recommended for close or positive margins, T4 disease, perineural or lymphovascular invasion, large and/or multiple positive lymph nodes, extracapsular extension, and recurrent disease after an initial surgical procedure (38). Radiation therapy has been effectively combined with chemotherapy to allow organ preservation and improved survival in the management of advanced laryngeal and pharyngeal cancers.

Concomitant chemotherapy and radiation has proven more efficacious than sequential treatment, although there is some evidence that neoadjuvant chemotherapy followed by concomitant chemoradiation may be effective as well. There is now a growing body of evidence demonstrating an improvement in outcome by adding EGFR receptor inhibition to radiation with or without chemotherapy (39). Cooperative group multicenter trials are underway to study this concept.

Advances in diagnostic imaging have contributed to improvements in radiation therapy planning. Both PET and MRI allow better tumor delineation (40,41,42). Current technology allows fusion of the images from various imaging techniques on each patient so that the radiation oncologist may outline the tumor more accurately (43,44). Although target delineation for IMRT is currently time consuming and labor intensive, algorithms are being developed to automate this process (45).

Traditionally, radiation therapy has been delivered at 1.8 to 2 Gy once daily for a total of 50 to 70 Gy with successive field reductions based on risk assessment. IMRT allows the integration of all sites into a single plan with lower-risk areas receiving lower doses per fraction while higher-risk areas receive higher doses per fraction (46). Altered fractionation schemes have had mixed success (47,48). These include hyperfractionation (1.2-1.5 Gy twice or thrice daily) and the concomitant boost technique (1.8 Gy in the morning to the entire field followed by 1.5 Gy in the evening to a smaller field encompassing high-risk disease). With either schedule, it is essential to maintain 4 to 6 hours between fractions to allow normal tissue repair (47). Although altered fractionation improves outcome, this is offset by an increase in acute toxicity without any increase in long-term complications (47,48). The integration of chemotherapy with altered fraction schedules is under investigation (48,49).

Reirradiation without and with chemotherapy has been studied in patients with recurrent local and regional disease. Reirradiation has usually been studied in selected patients with relatively limited recurrent disease allowing conformal treatment. Response and short-term local control rates of 15% to 30% are observed, and longer term control of 1 to 2 years is observed in 10% to 20% (50,51).

Common severe acute radiation toxicity includes dermatitis, mucositis, loss of taste, xerostomia, dysphagia, and hair loss. Decreased hearing occurs less commonly. Dental evaluation and necessary extractions should be performed before radiation because dental extractions in a radiated mandible can lead to osteonecrosis (52). Dentulous patients should be given prophylactic fluoride. Patients receiving radiation are at high risk for tooth decay due to the xerostomia caused by injury to the salivary glands as well as mucosal damage. Radioprotectors such as amifostine and pilocarpine have not demonstrated a consistent ability to decrease xerostomia (53). IMRT techniques enabling the reduction of dose to the parotid glands have had more success (26,54). Similarly, permanent swallowing dysfunction can be avoided by decreasing the dose to the pharyngeal musculature (55,56,57). Prophylactic, pretreatment

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and posttreatment evaluations by a speech therapist also help in preventing and alleviating dysphagia in these patients.

Chemotherapy

Historically, chemotherapy was used for palliation without proven survival advantage in patients with locally recurrent or disseminated disease. Combination chemotherapy yields higher response rates but has increased toxicity when compared with single agents. The choice of single-agent or combination chemotherapy depends on the patient’s performance status. Single agents with more than 10% response activity are listed in Table 1.7 (58,59,60,61,62,63,64,65,66,67,68,69,70,71,72). Combination regimens have been developed to improve response rates (Table 1.8) (73,74). Prior to the use of taxane combinations, meta-analyses and randomized trials demonstrated improved response for cisplatin compared with methotrexate, improved response for cisplatin and 5-fluorouracil (5-FU) combination compared with single drugs, and improved response for cisplatin and 5-FU combination when compared with other regimens for treatment of recurrent or metastatic head and neck squamous cancer. In the metastatic or recurrent setting, the combination of cisplatin and infusional 5-FU produces a 70% response rate and a 27% complete remission (CR) rate in chemotherapy-naive patients (75), but the response rate is 30% to 35% in patients who have relapsed after radiation therapy (see Table 1.8) with less than 10% complete responses. A randomized trial of cisplatin and 5-FU versus carboplatin (300 mg/m2) and 5-FU versus weekly methotrexate in patients with recurrent or metastatic head and neck squamous cancer demonstrated response rates of 32%, 21%, and 10%, respectively. Median survival was not improved by combination chemotherapy (6.6, 5.0, and 5.6 months, respectively) (76).

TABLE 1.7. Active chemotherapeutic agents for metastatic/recurrent squamous cancer of the head and neck

Drug Dose Response rate Median survival Reference Comments Methotrexate 40-60 mg/m2/wk 16%-23.5% 6 mo 58,59,60 Better response rates reported in patients not exposed to chemoradiation or platinum Cisplatin 50 mg/m2 d1 and 8 or 80-100 mg/m2 q21-28d 8%-28.6% 6 mo 58, 60 Paclitaxel 250 mg/m2 over 24 h, with G-CSF (NOT recommended) 36%-40% 9.2 mo 61 80 mg/m2/wk 9.3% 235 d Docetaxel 80-100 mg/m2 OR q21d 30 mg/m2/wk 11%-42% 42% 8.4 mo 62,63,64,65 11% in platinum-refractory patients Pemetrexed 500 mg/m2 q21d 26% 7.3 mo 67 Irinotecan 75 mg/m2/wk × 2 q3wk or 14.2% 214 d 68 75-125 mg/m2/wk × 4 q5wk 26.3% Gemcitabine 800-1,250 mg/m2 weekly × 3 q4wk 13% 69 Vinorelbine 30 mg/m2/wk 7.5%-16% 32 wk 70, 71 Cetuximab 400 mg/m2 week 1250 mg/m2 weekly 10% 5-6 mo 72 Erlotinib 150-250 mg daily 4% 20% 1-year survival 72

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TABLE 1.8. Active combination chemotherapeutic regimens for recurrent/metastatic squamous cancer of the head and neck

Regimen Response rate Median survival Reference Comments Cisplatin 100 mg/m2 5-FU 1,000 mg/m2/d CI × 96 h q21d 32% 6.6 mo 73,74 277 patients No prior chemotherapy Doses modified <25% toxicity or lack of toxicity Cisplatin 75 mg/m2 Paclitaxel 175 mg/m2 (3 h infusion) q21d 28% 9 mo 30% 1-yr survival 74 No significant difference from cisplatin-5-FU in efficacy or quality of life; cisplatin and paclitaxel may have fewer toxicities compared to cisplatin and 5-FU

Carboplatin may be slightly less active than cisplatin for head and neck squamous cancer, but is preferred in patients at high risk for cisplatin toxicity, that is, those with renal dysfunction, neuropathy, or hearing loss (76).

Both docetaxel and paclitaxel have shown antitumor activity (61,62,63,64,65). For paclitaxel regimens given every 3 weeks, 3-hour infusions are probably the best balance between theoretically optimum exposure and tolerable toxicity (66). Docetaxel is usually administered at doses of 60 to 100 mg/m2 every 3 to 4 weeks. Weekly schedules are being evaluated (64). Taxane combinations, including paclitaxel with ifosfamide and cisplatin or carboplatin, and docetaxel with cisplatin and 5-FU (77,78,79), show promising response rates. Epidermal growth factor inhibitors, combined with chemotherapy, have also shown intriguing results (80,81).

The role of chemotherapy has expanded significantly because of the results of clinical trials incorporating chemotherapy in multimodality regimens for previously untreated disease.

Studies have evaluated the use of chemotherapy administered before (i.e., neoadjuvant or induction chemotherapy), during (i.e., concomitant chemotherapy), or after (i.e., adjuvant chemotherapy) radiation therapy or surgery.

Combined modality (chemoradiation) is indicated for patients with locally advanced disease that would require total laryngectomy if treated by surgery and who wish to preserve the larynx, for patients who are technically resectable but who are not medically fit enough for surgery, and for patients with technically unresectable locally advanced cancer. In the patient who presents with locally advanced tumor concomitant with distant metastasis, local control of the disease may prevent infectious and necrotic complications.

Induction Chemotherapy

Induction chemotherapy followed by definitive radiation therapy in patients responding to chemotherapy has been studied for organ preservation in patients with locally advanced cancers of the larynx and of the hypopharynx. The advantages of induction chemotherapy include reduction of tumor burden potentially allowing more effective local control with surgery or radiation, as well as organ preservation, though at the price of increased toxicity, cost, and length of treatment.

In stages III and IV larynx cancer, and hypopharynx cancer, no significant survival difference was demonstrated for chemotherapy followed by radiotherapy compared to surgery followed by radiotherapy (82,83), though two-thirds of surviving patients had larynx preservation. Surgical salvage was eventually necessary for about one-third of the patients with larynx cancer treated with chemotherapy and radiation, and therefore close follow-up is required in the event that salvage surgery is needed. For laryngeal cancer, concomitant cisplatin and radiation therapy has since been shown to lead to better local control and organ preservation, but not survival, compared to neoadjuvant chemotherapy followed by radiation or radiation alone (84).

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Recently, several investigators have studied combinations of taxanes, platinums, and fluorouracil as induction chemotherapy prior to radiation or to concomitant chemoradiation. A phase III study in stages III and IV cancers of the oral cavity, oropharynx, hypopharynx, and larynx demonstrated improved disease-free and overall survival after follow-up of 32.5 months, for patients receiving the triplet chemotherapy compared to cisplatin and fluorouracil for up to four courses prior to radiation alone (85). A second study used cisplatin and fluorouracil with or without paclitaxel for three courses, followed by chemoradiation with high-dose cisplatin on days 1, 22, and 43 if response was at least 80%. This trial also showed that complete response rate (the primary end point of the trial) was improved (33% vs. 14%) in the triplet arm. With a median follow-up of 23 months, survival data had not yet matured (86). A third phase 3 trial randomized unresectable or organ preservation patients to induction therapy with cisplatin and fluorouracil with or without docetaxel, followed by radiation with weekly carboplatin at AUC 1.5. With a median follow-up time of 42 months, treatment with the triple drug neoadjuvant therapy showed a 30% improvement in survival (79).

Presently, induction chemotherapy with a taxane, cisplatin, and 5-fluorouracil combination followed by radiation therapy can be considered as a reasonable treatment strategy, particularly in patients with unresectable cancers and good performance status. Data are awaited on trials that randomized patients to concomitant chemoradiation treatment with or without induction chemotherapy.

CONCOMITANT CHEMORADIATION

The rationale for concomitant chemoradiation is based on experimental evidence of synergism between chemotherapy and radiation that is theoretically mediated by interference of chemotherapy with multiple intracellular radiation-induced stress-response pathways involved in apoptosis, proliferation, and DNA repair (87). The finding that certain chemotherapeutic agents (e.g., cisplatin, 5-FU, taxanes, and hydroxyurea) can induce radiosensitivity and increase log cell kill from radiation supports this treatment strategy. Cisplatin, the most extensively evaluated drug in recent large randomized trials, has the advantage of not having mucositis as toxicity; although as a radiation enhancer, it does increase radiation-induced mucositis.

Recent meta-analyses and randomized clinical trials published before 2001 show that for locally advanced head and neck squamous cell carcinoma, concomitant chemoradiation produces a small but significant survival advantage of about 8% compared to radiation therapy alone (88,89,90). The U.S. intergroup compared concomitant cisplatin and radiation to split-course radiation with cisplatin and 5-FU to standard radiation alone in patients with unresectable head and neck squamous cancer and showed that concurrent cisplatin at 100 mg/m2 every 21 days with daily radiation significantly improved survival rates (91). A randomized trial of neoadjuvant cisplatin and 5-FU followed by radiation versus concurrent cisplatin and 5-FU with radiation in patients with unresectable head and neck cancer showed similar survival rates but improved locoregional control for the concomitant arm. This early study highlighted the importance of aggressive supportive care for concomitant regimens, including adequate fluid and electrolyte support (92). Concomitant platinum-based chemoradiation has become a standard therapy for patients with unresectable advanced head and neck cancer with good performance status.

Although no randomized phase 3 trial has been reported, results using taxanes with 5-FU and/or cisplatin show promising results as do regimens containing 5-FU and hydroxyurea with concomitant twice-daily radiation, with both chemotherapy and radiation administered together every other week (93). Agents that inhibit epidermal growth factor receptor (EGFR) signaling have been evaluated as radiation enhancers in head and neck squamous cancer. More than 90% of head and neck squamous cancers express EGFR (94), and increased expression has been correlated with poorer survival rates after radiation therapy (95,96). The EGFR inhibitory monoclonal antibody cetuximab has been shown to result in an enhancement of response and survival over radiation therapy (RT) alone, although more than 50% of the trial participants had oropharyngeal primary tumors, a type previously associated with greater responsiveness to RT (39). In contrast to trials comparing radiotherapy with or without chemotherapy, there was no reduction in distant metastases in the cetuximab arm. Clinical studies are ongoing with combinations of EGFR inhibitors, with radiation and with standard chemotherapy agents. Recent studies suggest that additional molecular alterations, in addition to EGFR, are likely to be important for response.

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These include activation of the prosurvival signal-activated transcription factors nuclear factor-kappaB, signal transduction and transcription-3 (STAT-3), and inactivation or mutation of tumor suppressor p53 (97), as well as epithelial-to-mesenchymal transition (98,99). Agents targeting some of these pathways such as bortezomib and quinacrine (NF-κB, p53) and STAT decoy are under investigation as a result of combinatorial activity observed with EGFR or standard chemotherapy agents in preclinical studies (100,101,102,103).

Elective lymph node dissection is often carried out after chemoradiation in patients with N2, N3, or multiple nodes at diagnosis, regardless of nodal response to chemoradiation, when complete response is obtained at the primary site. N2 or greater nodes often (about 20%) harbor tumor even if a clinically complete response is obtained in the neck with chemoradiation (104). Surgical salvage may be attempted if complete control is not achieved at the primary or locoregional site. Major complications with surgical salvage are found in about 52% of patients previously treated with organ-preserving regimens (105).

Because concomitant regimens are associated with increased toxicity compared with sequential chemoradiation, patients should be followed closely for dehydration, electrolyte abnormalities, and adequacy of nutritional intake. In some patients, placement of an enteral feeding tube during or prior to the start of concomitant chemoradiation is performed because the incidence of grade 3 or greater mucositis is 70% to 80%.

Adjuvant Chemotherapy

A large randomized study in resected patients with stage III or IV disease compared adjuvant radiation therapy with adjuvant chemotherapy followed by radiation. This trial showed improved local control and overall survival rates approaching statistical significance for a subset of patients treated with chemotherapy who were at high risk for local recurrence. Patients with low-risk disease (negative resection margins, one or no positive nodes, and no extracapsular spread of tumor) did not benefit from adjuvant chemotherapy (106).

Adjuvant concomitant cisplatin and radiation in patients at high risk for recurrence after surgery has been studied both in Europe and in the United States. Both studies found a possible benefit in disease-free and overall survival for patients receiving concomitant cisplatin and radiation, particularly in patients with positive margins or extracapsular extension of tumor (107).

SITE-SPECIFIC HEAD AND NECK TUMORS

Oral Cavity

The oral cavity includes the lip, anterior two-thirds of the tongue, floor of the mouth, buccal mucosa, gingiva, hard palate, and retromolar trigone. Approximately 20,000 new cases are diagnosed annually in the United States. Squamous cell carcinoma is the histologic type observed in most cases.

The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites are shown in Table 1.4. Early lesions (stages I and II) are treated with surgery or radiation therapy as single-modality therapy. For resectable locally advanced disease (stages III and IV, and M0), surgery followed by radiation therapy is indicated (Fig. 1.4). Definitive radiation therapy with or without chemotherapy is an option for patients with resectable disease at any stage who have high medical or surgical risk, or according to patients’ preference (based on discussions about quality of life, functional outcome, and toxicity profile of each treatment). Treatment for locally advanced and metastatic disease is discussed in subsequent text.

Oropharynx

The oropharynx includes the base of the tongue, tonsils, posterior pharyngeal wall, and the soft palate.

The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the oropharynx are shown in Table 1.5. Treatment may include primary

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surgery and postoperative radiotherapy. Increasingly, primary radiation therapy with chemotherapy is being used for stage III or IV disease as a result of superior organ preservation and swallowing when compared to surgical resection and reconstruction of the tongue base, reserving surgery for management of regional node metastases or for salvage of persistent disease. Randomized trials show that concurrent chemotherapy and radiotherapy significantly improve locoregional control and survival compared with radiotherapy (108). Increased complexity, toxicity, and need for close follow-up of this combined-modality approach mandates that the patient has adequate performance status and psychosocial resources.

Fig. 1.4. Treatment for head and neck squamous cell carcinomas (M0).

Larynx

Risk factors are a history of tobacco and/or alcohol intake. In addition, certain dietary factors and exposure to wood dust, nitrogen mustard, asbestos, and nickel have been implicated as etiologic factors. The male-to-female ratio for laryngeal cancer is 4.5:1, with a peak incidence in the sixth decade of life. This disease is 50% more common in African Americans than in whites and 100% more common in whites than in Hispanics and Asians. More than 95% of laryngeal cancers are squamous cell carcinomas.

Laryngeal cancers can be supraglottic, glottic, and/or subglottic. The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the larynx are shown in Table 1.5.

Early cancers not requiring laryngectomy (T1-T2 N0) are usually treated with radiation or microendoscopic surgery. If lymph nodes are involved, neck dissection and/or neck radiation is indicated.

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Locally advanced resectable tumors (T3-T4 or T2 N+) may be treated with surgery and adjuvant radiation if locoregional risk factors are present (i.e., close or positive margins, T4 tumor involving laryngeal-cricoid cartilage or hyoid bone, lymphatic or vascular or perineural involvement, vascular invasion, multiple positive nodes, extracapsular invasion, subglottic extension, or prior tracheostomy). An alternative is the use of combined radiation and chemotherapy. In 1991, the Veterans Administration Laryngeal Study Group trial established (82) that sequential chemotherapy with cisplatin and infusional 5-FU followed by radiation therapy in highly responsive patients resulted in equivalent survival and a larynx preservation rate of about 66% compared to treatment with surgery followed by radiation. A subsequent randomized phase 3 trial conducted in the United States comparing radiation therapy alone, sequential chemotherapy and radiation therapy, and concomitant cisplatin and radiation therapy for organ preservation in patients with locally advanced laryngeal cancer demonstrated that concurrent cisplatin (100 mg/m2 on days 1, 22, and 43) and radiation therapy resulted in better laryngectomy-free survival, larynx preservation rate, and local-regional control rate than either sequential (induction) cisplatin and 5-FU followed by radiation therapy or radiation therapy alone. Induction chemotherapy followed by radiotherapy was shown to have no advantage over radiotherapy alone. Survival rate was not significantly different for the three treatments, in part reflecting the ability to surgically salvage laryngeal cancer patients treated for organ preservation. It is of interest to note that patients who received any chemotherapy regardless of receiving radiotherapy or not had a lower metastatic rate at 2 years than did patients who received radiation alone (84). Patients with high-volume T4 disease (with destruction of larynx or massive extension of supraglottic laryngeal cancer to the base of tongue) are not likely to obtain functional laryngeal and swallowing preservation without aspiration, and should be treated with surgery followed by radiation therapy rather than by organ preservation therapy, if possible.

Speech rehabilitation is critically important for patients with advanced laryngeal cancer who are undergoing total laryngectomy. Phonation options include a mechanical electrolarynx, esophageal speech, and tracheoesophageal puncture. Most patients can obtain satisfactory communication through one of these techniques.

Patients whose lesions are unresectable or patients who are considered to have high surgical risks are candidates for definitive radiation therapy with chemotherapy if performance status is good. The treatment for a patient with metastatic disease is discussed later.

Hypopharynx

The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the hypopharynx are shown in Table 1.6.

Early cancers not requiring laryngectomy (most T1 N0-N1; small T2 N0) can be treated with surgery or radiation. Locally advanced resectable tumors (T3-T4 any N) may be treated with surgery followed by radiation or sequential or concomitant chemoradiation. In these cases, surgery involves total laryngectomy and partial or total pharyngectomy and neck dissection. Even with this radical surgery and the consequent functional impairment of the tumor, the survival prognosis is poor.

Combined-modality treatment with chemotherapy and radiation allows organ function preservation with chances of survival being equivalent to that after surgery. Patients who achieve a complete response at the primary site after two to three cycles of induction chemotherapy (see Table 1.6) receive definitive radiation, whereas those achieving less than complete response at the primary site undergo surgery. A large randomized trial is in progress comparing induction chemotherapy followed by radiation therapy to concomitant chemoradiation in patients with hypopharyngeal cancer. The outcome of this trial will provide more definitive information on the most efficacious therapy.

Patients who are prone to high surgical or medical risks can be treated with radiation. The management of metastatic disease is discussed later.

Nasal Cavity and Paranasal Sinuses

The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for carcinomas of the nasal cavity and paranasal sinuses are shown in Table 1.6.

Most tumors are squamous cell carcinomas and are usually slow growing with low incidence of metastasis.

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Carcinomas of the nasal cavity and paranasal sinuses are usually detected in patients in advanced stages because of the relatively silent tumor location. Treatment follows the same general guidelines as those for oral cancer. If feasible, surgery is the preferred primary management since response to radiation is often incomplete when bone is involved.

Nasopharynx

The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for nasopharyngeal cancer are shown in Table 1.6. It is rare in most parts of the world, with an incidence of less than 1 case per 100,000 population. However, it is endemic in certain areas, including North Africa, Southeast Asia, China, and the far northern hemisphere. EBV is strongly associated with nasopharyngeal carcinoma. This association has been demonstrated by serologic studies and by the detection of the viral genome in tumor samples. Diet (salt-cured fish and meat) and genetic susceptibility are other probable risk factors; tobacco and alcohol are not risk factors, except in a minority of cases.

The World Health Organization (WHO) classification divides nasopharyngeal carcinoma into three types: type I, keratinizing squamous cell carcinoma; type II, nonkeratinizing squamous cell carcinoma; and type III, undifferentiated carcinoma (20). Type II, the most common, is also sometimes referred to as lymphoepithelioma because of the characteristic exuberant lymphoid infiltrate accompanying malignant epithelial cells.

The most common initial presentation is a neck mass. Other presenting signs and symptoms are related to tumor growth, with resulting compression or infiltration of neighboring organs. These include serous otitis media, nasal obstruction, tinnitus, pain, and involvement of one or multiple cranial nerves.

Nasopharyngeal carcinoma has a high metastatic potential to regional nodes and distant sites. WHO type I has the greatest propensity for uncontrolled local tumor growth and the lowest propensity for metastatic spread (60% clinically positive nodes) compared with WHO type II and type III cancers (80-90% clinically positive nodes). Even though WHO type I cancer is associated with a lower incidence of lymphatic and distant metastases than are types II and III, its prognosis is worse because of a higher incidence of deaths from uncontrolled primary tumors and nodal metastases.

The prognoses for different stages of nasopharyngeal carcinoma are shown in Table 1.6.

General treatment guidelines are shown in Fig. 1.5. Surgery is usually not recommended because of anatomic considerations and the pattern of spread of the cancer via the retropharyngeal lymphatics. Radiation has been the standard treatment, with good results (local control rates: T1-T2, 70-90%; T3-T4, 30-65%), and remains the standard of care for early (stages I and II) cancer.

In a randomized trial in the United States, concurrent cisplatin (cisplatin 100 mg/m2 every 21-28 days) and daily radiation followed by three courses of adjuvant cisplatin and 5-FU was shown to improve overall survival (76% for concurrent chemoradiation vs. 46% for radiation therapy alone) (109). On the basis of this study, concurrent chemoradiation followed by adjuvant chemotherapy is considered standard treatment for locally advanced nonmetastatic (stages III and IV) nasopharyngeal cancer in the United States. Other drugs, such as taxanes, appear to have activity but have not been evaluated extensively.

Fig. 1.5. Treatment of nasopharyngeal carcinoma (M0).

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ADVANCED HEAD AND NECK TUMORS: UNRESECTABLE, RECURRENT, AND METASTATIC DISEASE

In patients with good performance status (ECOG 0-1), concurrent radiation and chemotherapy is considered standard treatment for patients with newly diagnosed locally advanced unresectable disease. In several recent trials, chemoradiation therapy was shown to improve the overall survival, disease-free survival, and/or local control when compared with radiation therapy alone. Several cisplatin or carboplatin-containing regimens and several standard and altered fractionation-radiation regimens have been evaluated. In patients with poor performance status, radiation alone is a reasonable option.

Local or regional recurrences can sometimes be salvaged by radiation therapy or surgery. In patients unable to undergo resection, reirradiation with a dose of 60 Gy with or without concomitant chemotherapy can achieve prolonged survivals in about 15% to 20% of highly selected patients (110). In nasopharyngeal carcinoma, a second course of radiation may be delivered. If salvage is not possible, palliative treatment will be guided by the performance status of the patient.

Single-agent or combination chemotherapy is indicated for palliation of patients with good performance status with local or distant recurrence and of those patients presenting with distant metastasis. Combination chemotherapy achieves higher response rates at the cost of increased toxicity when compared with single-agent chemotherapy. The most active agents are listed in Table 1.7. Cisplatin plus infusional 5-FU (see Table 1.8) or cisplatin with a taxane are the most commonly used combination-chemotherapy regimens. Weekly methotrexate or taxanes have also shown some activity in patients with advanced head and neck tumors. Targeted agents, such as erlotinib and cetuximab, may have some palliative effect (72) as single agents, and appear to be promising in combination with platinum-based regimens (111). The choice of single-agent or combination chemotherapy depends on preference and performance status of patients. Patients with good performance status, no prior chemotherapy for treatment of recurrent disease, and minimal tumor burden may benefit most from combination chemotherapy. A small subset of these patients may achieve durable complete response and prolonged survival. However, the median response duration to combination or single-agent chemotherapy is about 3 to 4 months.

The median survival for patients with locally recurrent or disseminated disease is 6 to 9 months, and only 20% to 30% are alive at 1 year. No therapy has been shown to affect survival rate. Therefore, whenever possible, patients should be encouraged to enroll in clinical trials that evaluate new agents or new combination regimens.

Cancer of Unknown Primary Site (of the Head and Neck)

The workup of a patient with a neck mass is shown in Fig. 1.3. Nasopharyngeal, oropharyngeal, and hypopharyngeal origins are most common. In 10% of cases, a primary tumor is not found, and the term “cancer of unknown primary site” is used.

Cervical lymph node involvement (except supraclavicular) by squamous carcinoma indicates a head and neck primary tumor. Unknown primary tumors of the head and neck are usually treated with neck dissection and radiation. The prognosis is roughly equivalent to cancers with the same N (nodal) status. Five-year survival ranges from 30% to 50% in patients treated definitively.

Salivary Gland Cancer

Salivary gland cancers make up about 3% of all head and neck cancers diagnosed in the United States yearly. Tobacco and alcohol consumption are not risk factors, except possibly in women. Ionizing radiation and certain occupational exposures (e.g., in workers in rubber and automotive industries, wood workers, and farm workers) have been associated with the development of salivary gland cancer.

The salivary glands are classified as major (parotid, submandibular, and sublingual) and minor (distributed along upper aerodigestive tract, predominantly in the oral and nasal cavities and the paranasal sinuses). About 75% of parotid gland neoplasms are benign, whereas about 75% of submandibular, sublingual, and minor salivary gland tumors are malignant.

Most salivary gland tumors are benign, and the most common histology is pleomorphic adenoma, which is characterized by slow growth and few symptoms, and is most frequently seen in the parotid gland. The most common presentation of benign salivary gland tumors is asymptomatic swelling of the lip, the parotid, or the submandibular or the sublingual gland. Persistent pain or neurologic involvement (mucosal or tongue numbness and facial nerve weakness) suggests malignant disease. The benign salivary gland tumors are listed in Table 1.3) .

TABLE 1.9. Salivary gland benign tumors
Pleomorphic adenoma (benign mixed tumor) Warthin tumor (papillary cystadenoma lymphomatosum) Monomorphic adenoma Benign lymphoepithelial lesion Oncocytoma Ductal papilloma Sebaceous lymphadenoma

The clinical characteristics and prognosis of specific malignant salivary gland tumors are shown in Table 1.10.

TABLE 1.10. Salivary gland malignant tumors: Clinical characteristics and prognosis

Histology Clinical characteristics Prognosis Mucoepidermoid carcinoma Most common malignant tumor in major salivary glands; most common in parotid glands (32%) Low grade: 76%-95% 5-yr survival Low grade: local problems, long history, cure with aggressive resection; rarely metastasizes High grade: 30%-50% 5-yr survival High grade: locally aggressive, invades nerves and vessels, and metastasizes early Adenocarcinoma 16% of parotid and 9% of submandibular malignant tumors 76%-85% 5-yr survival Grade correlates with survival 34%-71% 10-yr survival Squamous cell carcinoma Uncommon: 7% of parotid gland and 10% of submandibular gland malignant tumors 24% 5-yr survival 18% 10-yr survival Grade correlates with survival Squamous cell carcinoma of temple, auricular, and facial skin can metastasize to parotid nodes and can be confused with primary parotid tumor Acinic cell carcinoma <10% of all salivary gland malignant tumors 82% 5-yr survival 68% 10-yr survival Low grade with slow growth, infrequent facial nerve involvement, infrequent and late metastases (lungs) Regional metastasis in 5%-10% of patients Adenoid cystic carcinoma Most common malignant tumor in submandibular gland (41%), 11% of parotid gland 5-yr survival: 50%-90% 10-yr survival: 30%-67% High incidence of nerve invasion, which compromises local control 15-yr survival: 25% 40% of patients develop metastases; most common site of metastases is the lung. Patients may live many years with lung metastasis, but visceral or bone metastases indicate poor prognosis Malignant mixed tumor 14% of parotid gland and 12% of submandibular gland cancers 5-yr survival: 31%-65% 10 yr; 23%-30% May originate in previous pleomorphic adenoma Lymph node involvement in 25% of cases; 26%-32% of patients develop metastases

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Surgery is the mainstay of treatment for all localized stages of salivary gland tumors. Postoperative radiation is indicated for localized tumors of high-grade histology that are large, with close or positive margins, and/or positive regional lymph nodes. Radiation is the primary treatment for unresectable tumors. The role of chemotherapy is limited to the management of locally recurrent, unresectable disease or distant metastatic disease. There is no established standard chemotherapy for salivary gland cancer. Regimens employing cisplatin, carboplatin, anthracyclines, taxanes, cyclophosphamide, and 5-FU result in transient responses in 14% to 30% of patients with adenocarcinoma or mucoepidermoid carcinoma (112), but the effect on survival is unknown.

Molecular characterization of salivary gland tumors has included EGFR-dependent pathways, angiogenesis, cell cycle inhibition, and apoptosis that may eventually provide prognostic information and predict response to conventional chemotherapy as well as newer targeted treatments (). Targeted therapies, particularly inhibitors of EGFR, VEGF or its receptors, and Her-2/neu, have been tested in phase 2 clinical trials (). Larger trials are needed to confirm the activity of these new agents against salivary gland cancers either alone, or in combination with conventional chemotherapeutic agents that have previously been shown to be active in this disease. Patients with good performance status should be encouraged to enter clinical trials.

Follow-up

Curative treatment of patients with head and neck cancer should be followed by a comprehensive head and neck physical examination every 1 to 3 months during the first year after treatment, every 2 to 4 months during the second year, every 3 to 6 months from years 3 to 5, and every 6 to 12 months after year 5. The thyroid-stimulating hormone (TSH) level should be checked every 3 to 6 months if the thyroid is irradiated. Generally, thyroid hormone replacement therapy should begin when, and if, TSH remains stably elevated, before symptoms of hypothyroidism appear. Up to 50% of patients will develop hypothyroidism by 5 years after radiation therapy to the head and neck. Patients with nasopharyngeal tumors who were treated with radiation are at risk for pituitary failure .

The highest risk of relapse is during the first 3 years after treatment. After 3 years, a second primary tumor in the lung or head and neck is the most important cause of morbidity or mortality. Because of this risk, a semiannual chest radiograph is recommended. Some recurrences, as well as second primaries, can be treated with curative intent.

OTHER HEAD AND NECK TUMORS

Sarcoma

Soft tissue sarcomas of the head and neck are relatively rare. Of head and neck sarcomas, 80% are seen in adults and 20% are in children. These tumors are heterogeneous and can present in any head and neck site, commonly as a submucosal or subcutaneous painless mass. In the hypopharynx and nasopharynx, the presenting symptoms may be cranial nerve abnormalities or airway or swallowing difficulties. As in sarcomas at other sites, grade is an important prognostic indicator. High-grade, aggressive tumors such as malignant fibrous histiocytoma, angiosarcoma, osteogenic sarcoma, neurofibrosarcoma, and soft part sarcomas tend to be locally aggressive and spread along neurovascular structures, fascia, and bone. In addition to aggressive local behavior, there is a high risk for metastatic disease, particularly in lung, bone, central nervous system, and liver. Metastatic disease may occur without local lymph node involvement. Sarcomas may arise after radiation therapy, but this is very uncommon in the head and neck region. The prognosis for these secondary sarcomas may be worse than for primary sarcomas.

Treatment depends on stage, age of the patient, tumor type, location, and size. Wide margin en bloc resection is the goal, but may not be possible because of the proximity of vital structures. Adjuvant postoperative radiation and/or brachytherapy can improve local control in aggressive sarcomas. The major indications for adjuvant radiation are high-grade sarcomas or positive margins, lesions greater than 5 cm, and recurrent sarcoma. Elective neck radiation is not necessary because the incidence of occult positive lymph nodes is low. Soft tissue and possibly osteogenic sarcomas may benefit from adjuvant or neoadjuvant chemoradiation. Such patients should be referred to clinical trials when possible. Overall survival rate approaches 60% for patients with sarcomas of the head and neck (123,124).

Melanoma

Mucosal melanomas represent less than 1.5% of all melanomas. About 50% of mucosal melanomas occur in the head and neck, and more than 20% of melanomas that occur in the head and neck region are mucosal. The age of diagnosis is 60 to 80 years. The hard palate is the most common site. Nearly one-third of these tumors are amelanotic. The proportion of mucosal melanomas is higher in African American and Hispanic populations than in white populations. Although rare in the United States, mucosal melanomas are more frequent in Japan and in some parts of Africa. Mucosal melanomas may be multiple, may have satellite lesions, may invade angiolymphatics, and can metastasize. They behave more aggressively than skin melanomas. Lymph node metastasis is observed at presentation in up to 48% of patients. Surgery is the mainstay of treatment for local or locoregional disease. Prophylactic lymph node dissection is not recommended. Radiation, when used, is usually employed adjuvantly for positive margins or used palliatively for local recurrence or unresectability. Adjuvant use of radiation has not been shown to improve survival. Prophylactic nodal radiation is not recommended. Chemotherapy and immunotherapy have been studied, but the effect of these interventions on survival when used as palliation or as adjuvant therapy has not been defined. Patients should be encouraged to enter clinical trials where available. Mean overall 5-year survival is 17% (range 0-48%) ().

Novel Targeted Therapies and Future Directions

EGFR is overexpressed in most head and neck squamous cancers, and therapies targeting this receptor and its downstream pathways are currently under investigation. Increased expression of EGFR correlates with poorer prognosis in this cancer. Mechanisms of resistance to EGFR-targeted agents have been described in other tumors. In squamous cancers of the head and neck, there is a small incidence of ras mutations or the EGFR mutations described for colon and lung cancers. However, the EGFRvIII mutations, which lack the extracellular domain, seem to be present on a substantial number of squamous head and neck cancers, in conjunction with wild-type EGFR receptors. The presence of EGFRvIII mutants correlates with decreased response to EGFR inhibitors as well as to cisplatin in vitro (126). As in other cancers, angiogenesis may be a good target, and studies are underway with angiogenesis inhibitors in squamous cancers, as well as differentiated and medullary thyroid cancers. Other promising targets under investigation as single agents and in combination with chemotherapy or radiation include mTOR, Akt, c-met, STAT-3, NF-κB, and IGF-1R. Treatments that ameliorate the toxicities of chemoradiation such as xerostomia and dysphagia are also under study. Better discernment of the optimal curative treatment for an individual patient as well as individualized therapy for recurrent or metastatic disease awaits improved diagnostics. Molecular characterization of tumors is a promising field that will likely lead to individualized treatment and prevention approaches.