SYMPOSIUM ON SOLID TUMORS
Head and Neck Cancer: Changing Epidemiology, Diagnosis, and Treatment

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Head and neck cancers account for less than 5% of all cancers and for less than 3% of all cancer deaths in the United States. The populations at risk for head and neck cancers are those who have a long-standing history of smoking and alcohol use. More recently, the incidence of oropharyngeal cancer in younger populations has been increasing and is associated with exposure to the human papillomavirus. This subset of patients appears to have a better overall prognosis and to respond better to treatment. This review is limited to head and neck cancers of squamous cell histology, which constitute more than 90% of head and neck cancers. Because treatment of head and neck cancers is complex and involves multiple modalities, a multidisciplinary approach is needed. This review focuses on the goal of organ preservation and postoperative treatment of high-risk patients with the concurrent use of chemotherapy and radiation therapy. This review also highlights recent advances in treatment using molecularly targeted therapies, specifically the role of inhibitors of the epidermal growth factor receptor in locally advanced and recurrent/metastatic squamous cell cancer of the head and neck. Studies in the English language were identified by searching the MEDLINE, EMBASE database (1980-2007) using the search terms head and neck, squamous cell, carcinoma, chemotherapy, radiation, human papillomavirus, epidermal growth factor receptor, and targeted therapy.

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EPIDEMIOLOGY

Worldwide, an estimated 644,000 new cases of head and neck cancers are diagnosed each year, with two-thirds of these cases occurring in developing countries. In the United States, head and neck cancers account for 3.2% (39,750) of all new cancers and 2.2% (12,460) of all cancer deaths.1 The incidence of head and neck cancers is 3-fold higher among men than women and more common in the African American than in the white population. The 5-year survival rate is better for white than for African

RISK FACTORS

Smoking and alcohol are by far the most common etiological factors. Heavy tobacco users have a 5-fold to 25-fold higher risk of developing head and neck cancers than non-smokers. Alcohol can further increase this risk; for example, a person who has a more than 40 pack-year history of smoking and who consumes 5 alcoholic drinks per day has a 40-fold increased risk.5 The direct effect of nicotine and polycyclic aromatic hydrocarbons in tobacco is consideredcarcinogenic.5 The mutation of tumor

TUMORIGENESIS

Tumorigenesis in the aerodigestive tract is driven by specific genetic alterations caused by continuous exposure to carcinogens. During the past decade, the molecular aspects of head and neck cancer have been a major area of investigation, and some of the important discoveries with therapeutic implication will be highlighted here.

Cyclin D1 (CCND1) is an oncogene that activates cell-cycle progression, which is amplified in 30% to 50% of patients with head and neck cancer.19 Overexpression and

ANATOMY AND CLINICAL PRESENTATION

Head and neck SCCs are commonly located in the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx.Figure 1 illustrates the various subsites of HNSCCs.28 The oral cavity includes the buccal mucosa, upper and lower alveolar ridge, retromolar trigone, floor of mouth, hard palate, and anterior two-thirds of the tongue. The oropharynx includes the base of the tongue, tonsils, soft palate, uvula, posterior pharyngeal wall, and lateral pharyngeal wall. The nasopharynx is situated behind the

DIAGNOSIS AND INVESTIGATIONS

Mucosal abnormalities detected on physical examination and malignant lymph nodes with unknown primary site should be further investigated with endoscopy (nasopharyngolaryngoscopy, esophagoscopy, and bronchoscopy, as appropriate) and biopsies of any detected abnormality. With cancer of unknown primary site, directed biopsies of the nasopharynx, hypopharynx, and the base of the tongue, as well as ipsilateral or bilateral tonsillectomy, should be performed.31, 32

Once a diagnosis has been

STAGING

After completion of the initial work-up, the extent of disease is accurately staged using the American Joint Commission on Cancer (AJCC) TMN staging system.40 The T staging for head and neck cancers differs according to the primary site; the N staging is common for all subsitesexcept the nasopharynx; and the M staging is common to all sites. Stage IV is divided into stage IVA, advanced resectable disease; stage IVB, advanced unresectable disease; and stage IVC, advanced metastatic disease.

TREATMENT OPTIONS

From 1960 to 1980, surgery and radiation therapy (RT) were considered the only effective treatment for the primary curative management of patients with head and neck cancer. In 1991, the results of the Department of Veterans Affairs Laryngeal Cancer Study was published,41 introducing the concept of organ preservation by comparing inductionchemotherapy followed by RT to surgery followed by RT in patients with resectable stage III or IV laryngeal cancer. The results revealed no significant

Oropharynx

The oropharynx includes the pharyngeal wall between the pharyngoepiglottic fold and the nasopharynx, soft palate, base of tongue, and tonsillar area. Patients with early-stage cancers (T1-T2, N0-N1) have a 5-year survival rate of 80% to 85%, whereas those with more advanced disease (T3-T4, N0; T3-4, N+; or any T, N2-N3) have a 5-year survival rate of 30% to 60%. With distant spread, this 5-year survival rate decreases further to 5% to 10%. Early-stage disease, including most favorable T2N1

TREATMENT OF SCC OF UNKNOWN PRIMARY SITE

Cancer of unknown primary site accounts for approximately 2% to 5% of all head and neck cancer diagnoses. The usual presentation is a mass in the upper or mid-cervical area. A primary tumor in the head and neck area should be suspected in middle-aged or elderly patients with a history of smoking and/or alcohol use and in younger patients without a history of excessive alcohol and/or tobacco exposure who may harbor an occult HPV-related cancer of the palatine or lingual tonsil. The latter group

TREATMENT OF ADVANCED RECURRENT AND METASTATIC DISEASE

Despite aggressive treatment of locally advanced disease, only 35% to 55% of patients remain alive and disease free 3 years after standard curative treatment. Locoregional recurrences develop in 30% to 40% of patients, distant metastases in 20% to 30%.44

Locoregional recurrences can be reclassified into resectable and unresectable recurrent disease. Patients with low-volume recurrence, particularly of cancers of the larynx and nasopharynx, can be treated with surgery using a cyberknife or

POSTOPERATIVE ADJUVANT CHEMORADIATION

Local or regional recurrence and distant metastases are frequent after surgical treatment of stage III or IV HNSCCs. The risk of failure is particularly high in patients with inadequate resection margins and extranodal spread.74, 75, 76

On the basis of the results of 2 recently completed randomized trials, guidelines have been developed for the use of chemotherapy concurrent with adjuvant RT in high-risk settings. These studies, one reported by the EORTC74 and one by the RTOG,75 had very similar

CONCLUSION

More than 90% of head and neck cancers are SCCs. Alcohol and smoking remain the major risk factors and have an additive effect. Epidemiological studies reveal that HPV virus types 16, 18, and 31 have an important role in oropharyngeal cancers; HPV-positive tumors appear to be distinct from HPV-negative cancers. Regarding the genetic aspects of head and neck cancers, the TP53 mutation, CDKN2A mutation, EGFR gene copy, and EGFR mutation have prognostic and therapeutic value in HNSCC. Clinical

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    1

    Dr Forastiere has received research funding from AstraZeneca and Amgen and is on the advisory board of Sanofi-Aventis and Amgen.

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