Carter Van Waes, Karl E. Haglund, and Barbara A. Conley
EPIDEMIOLOGY
The incidence of head and neck squamous cancer is more than 500,000 cases per year worldwide, and 40,000 to 60,000 cases per year in the United States, where it comprises approximately 3% to 5% of all new cancers and 2% of all cancer deaths. Most patients are older than 50 years, and incidence increases with age; the male-to-female ratio is 2:1 to 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. Death rates have been decreasing since at least 1975, with rates declining more rapidly in the last decade. Ninety percent of these cancers are squamous cell histology. The most common sites in the United States are the oral cavity, pharynx, larynx, and hypopharynx. Nasal cavity, buccal, 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 twofold 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. Use of smokeless tobacco, or chewing betel with or without tobacco and slaked lime (common in many parts of Asia and some parts of Africa), is associated with premalignant lesions and oral squamous cancers.
Multifocal mucosal abnormalities have been described in patients with head and neck cancer (“field cancerization”). 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.
Epstein-Barr virus (EBV) has been detected in virtually all nonkeratinizing and undifferentiated nasopharyngeal cancers but less consistently in squamous nasopharyngeal cancers. Human papillomavirus (HPV) infection is associated with up to 70% of cancers of the oropharynx and tonsil, and some larynx and squamous nasopharyngeal cancers. The incidence of HPV+ cancers seems to be increasing in several countries, and HPV positivity is more common in cancers in nonsmokers. Disorders of DNA repair (e.g., Fanconi anemia, dyskeratosis congenita) as well as organ transplantation with immunosuppression are also associated with increased risk of squamous head and neck cancer.
SCREENING
The U.S. Preventive Task Force makes no recommendations regarding regular screening for oral cancer in the general population, due to the low incidence and lack of sensitivity studies. They do recommend counseling for cessation of tobacco use and limitation of alcohol intake.
The American Cancer Society 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.
Careful examination of the head and neck is warranted in individuals with risk factors (e.g., tobacco and/or alcohol use) and suggestive symptoms. Any local/regional complaints require evaluation, especially if symptoms persist for more than 4 weeks or after treatment for presumed infection.
PREVENTION AND CHEMOPREVENTION
The most important recommendation for prevention of head and neck cancer is to encourage smoking cessation and to limit alcohol intake. As risk for HPV-associated head and neck cancer is associated with multiple sexual partners, education on safer sexual practices may also be helpful. Consideration should be given to prophylactic administration of HPV vaccines to adolescents, a treatment currently approved by the U.S. Food and Drug administration for prevention of cervical cancer (bivalent or quadrivalent vaccines) in females and genital warts in males (quadrivalent vaccine), as well as for prevention of anal precancers (quadrivalent vaccine). Data are currently being gathered on the effect of vaccination on incidence of HPV-related head and neck cancer.
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) or erythroplakia (friable reddish or speckled lesions). These lesions require biopsy and potentially excision. The risk of leukoplakias without dysplasia progressing to cancer is about 4%. However, up to 40% of severe dysplasias or erythroplasias progress to cancer.
Presently, there is no effective chemoprevention for patients at risk for head and neck squamous cancer. A recent trial with PPAR agonist pioglitazone showed regression or reduction in size of leukoplakia in ~80% of subjects. A multicenter phase II study is underway. Chemoprevention outside a clinical trial is not recommended.
ANATOMY
A simplified depiction of extracranial head and neck anatomy is presented in Figure 1.1. The major regions and subsites of the upper aerodigestive tract are divided into the nose and paranasal sinuses; nasopharynx (NP); oral cavity (OC; lips, gingiva, buccal areas, floor of mouth, hard palate, and tongue anterior to the circumvallate papillae); oropharynx (OP; soft palate, tonsils, base of tongue and lingual tonsils, and pharyngeal wall between palate and vallecula); hypopharynx (HP; pharyngeal wall and piriform sinuses, between vallecula and esophageal inlet); and larynx (epiglottis, glottis, and subglottic trachea).
FIGURE 1.1 Sagittal section of the upper aerodigestive tract. (Adapted from Oatis CA. Kinesiology: The Mechanics and Pathomechanics of Human Movement. Baltimore, MD: Lippincott Williams & Wilkins; 2004.)
Knowledge of the lymphatic drainage of the neck assists in identification of the site of a primary tumor when a palpable lymph node is the initial presentation, and in staging metastatic spread, enabling the surgeon or radiation oncologist to plan appropriate treatment of both primary and neck disease. The patterns of lymphatic drainage divide the neck into several levels (Fig. 1.2). Level I comprises the submental or submandibular nodes, which are most often involved with lesions of the oral cavity or submandibular salivary gland. Level II (upper jugular lymph nodes) extends from the skull base to the hyoid bone, and is frequently the site of metastatic presentation of naso- or oropharyngeal primaries. Level III (middle jugular lymph nodes between the hyoid bone and the lower border of the cricoid cartilage) and level IV (lower jugular lymph nodes between the cricoid cartilage and the clavicle) are most often involved by metastases from the hypopharynx, larynx, or above. Level V is the posterior triangle including cervical nodes along cranial nerve XI, frequently involved along with level II sites in cancers of the naso- and oropharynx. Level VI is the anterior compartment from the hyoid bone to the suprasternal notch bounded on each side by the medial carotid sheath, and is an important region for spread of laryngeal and thyroid carcinomas. Level VII is the area of the superior mediastinum, and portends distant metastasis.
PRESENTATION
Symptoms and signs most often include pain and/or mass effects of tumor, involving adjacent structures, nerves, or regional lymph nodes (Table 1.1). Adult patients with any of these symptoms for more than 4 weeks should be referred to an otolaryngologist. Delay in diagnosis is common due to patient delay, repeated courses of antibiotics for otitis media or sore throat, or lack of follow-up. A persistent lateralized symptom or firm cervical mass in an elderly smoker or sexually active middle-aged adult at risk for HPV is highly suggestive of squamous cell carcinoma (Fig. 1.3). For nasopharyngeal and oropharyngeal cancers, a common presenting symptom is a neck mass, often in a node in the jugulodigastric area and/or the posterior triangle. In advanced lesions, cranial nerve abnormalities may be present. Distant metastases are uncommon at presentation, but may occur with nasopharyngeal, oropharyngeal, and hypopharyngeal cancers. The most common sites of distant metastases are lung and bone; liver and CNS involvement is less common.
FIGURE 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 triangle; level VI, tracheoesophageal; level VII, superior mediastinal, is not shown. (From Robbins KT, Samant S, Ronen O. Neck dissection. In: Flint PW, Haughey BH, Lund VJ, et al., eds. Cumming’s Otolaryngology Head and Neck Surgery. 5th ed. Copyright Elsevier, 2010. Used with permission.)
DIAGNOSIS, WORKUP, AND STAGING EVALUATIONS
The history should include the following:
1.Signs and symptoms as listed in Table 1.1 and above
2.Tobacco exposure (pack-years; amount chewed; and duration of habit, current or former)
3.Alcohol exposure (number of drinks per day and duration of habit)
4.Other risk factors (chewing betel nut)
5.In nonsmokers with oropharyngeal symptoms or cervical nodes, history of HPV or oral sexual practice, particularly with multiple partners
6.In nonsmokers aged 18 to 50, history or family history of anemia, Fanconi anemia, or dyskeratosis congenita
7.Cancer history of patient and family
8.Thorough review of systems
FIGURE 1.3 Evaluation of cervical adenopathy when a primary cancer of the head and neck is suspected.
The head and neck physical examination should include the following:
1.Careful inspection of the scalp, ears, nose, and mouth
2.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
3.During examination of the nasal passages, NP, oropharynx, hypopharynx, and larynx, flexible endoscopes or mirrors as appropriate should be strongly considered for symptoms of hoarseness, sore throat, or enlarged lymph nodes not cured by a single course of antibiotics. When a neck mass with occult primary is the first presentation, the primary site can be located by clinical or flexible endoscopic examination in ~80% of cases.
4.Special attention to the examination of cranial nerves
For abnormalities identified by history, physical examination, and/or endoscopy, the following evaluations should be performed. Superficial cutaneous or oral mucosal lesions, with irregular shape, erythema, induration, ulceration, and/or friability (easy bleeding) of greater than 2-week duration warrant biopsy, as these frequently are early indicators of severe dysplasia, carcinoma in situ, or invasive malignant process. For findings or lesions involving the nose, NP, oropharynx, hypopharynx and larynx, or neck with unknown primary, computed tomography (CT) and/or magnetic resonance imaging (MRI) with contrast should first be performed to identify origin, extent, and potential vascularity of lesions. Surgical biopsy of a neck mass before endoscopy is contraindicated if a squamous cell carcinoma is suspected. 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. An open biopsy does not provide any information additional to that obtained from fine needle aspiration (FNA), and direct laryngoscopy is still necessary for staging and treatment planning. Tissue diagnosis obtained by FNA biopsy of the node has a sensitivity and specificity approaching 99%. However, a nondiagnostic FNA or negative flexible endoscopy does not rule out the presence of tumor. Positron emission tomography (PET) scans combined with CT (PET/CT) or MRI can often localize smaller or submucosal primaries of the naso- and oropharynx that present with level II or V cervical adenopathy. Intraoperative endoscopic biopsy is then done with a secure airway under anesthesia. Bilateral tonsillectomy will sometimes reveal the source of an occult cancer, especially for HPV+ cancers. Esophagoscopy and bronchoscopy may be indicated for symptoms such as dysphagia, hoarseness, cough, or to search for occult primary.
After the diagnosis of cancer is established, the patient should be staged using physical examination, endoscopic studies, and radiologic studies, which usually include CT scan and/or MRI of the primary tumor, neck, and chest. CT scan is considered the primary imaging study for evaluation of bone involvement, regional, mediastinal, and pulmonary metastasis. MRI may complement the CT scan with greater resolution of soft tissue for primary tumor staging, and evaluation of skull base and intracranial involvement. PET/CT scans 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. PET/CT scanning is indicated for staging patients with unknown primaries and for advanced head and neck cancers. A chest CT or PET/CT is indicated for all patients because of the risk of metastasis or a second lung malignancy. Body CT is not usually necessary.
Additional studies vary according to the clinical stage, symptoms, and primary site.
Specialized tests include tissue p16 immunostaining and in situ hybridization for HPV for oropharyngeal carcinoma, and tissue EBV IgA and DNA tests for nasopharyngeal carcinoma. Laboratory tests typically obtained prior to initiating therapy include complete blood counts, renal and liver function tests, serum calcium and magnesium (if platinum-based chemotherapy is to be given), baseline thyroid function tests, and pregnancy testing in females of child-bearing age. In patients with unexplained anemia, short stature, and/or micro-ophthalmia, consideration should be given to mitomycin C testing for chromosomal fragility for Fanconi anemia, as chemo- or radiotherapy is contraindicated.
Dental evaluation should be performed and any necessary extractions should be carried out 10 to 14 days prior to any planned radiation. Baseline speech, swallow, and audiometry evaluation should be performed.
STAGING CLASSIFICATION
Clinical staging is based on physical and endoscopic examinations and imaging tests. The staging systems of the American Joint Committee for Cancer (AJCC) or the Union Internationale Contre le Cancer (UICC) (tumor, node, metastasis [TNM], stages I to IV) are used. The AJCC classification has further subdivided the most advanced disease stages into stage IVA (moderately advanced), stage IVB (very advanced), and stage IVC (distant metastatic).
The staging of primary tumors is different for each site within the head and neck, although some common themes exist. The AJCC Cancer Staging Manual, which entered its seventh edition in 2009, should be consulted for details for each site and subsite. The T classification indicates the extent of the primary tumor. For primary tumors of the oral cavity, hypopharynx, and oropharynx, lesions up to 2 cm in diameter are T1, 2 to 4 cm are T2, and greater than 4 cm are classified as T3. For laryngeal carcinomas, limited involvement of one or more subsites are staged T1 and T2, respectively, while vocal cord immobility or pre-epiglottic space involvement with a larynx or hypopharynx primary indicates at least stage T3. Lesions with local invasion of adjacent cartilage, bone, or soft tissues indicate stage T4.
The N classification is uniform for all primary sites, except NP. Any clinical lymph node involvement indicates at least stage III. The presence of a single ipsilateral lymph node 3 cm or larger, multiple ipsilateral lymph nodes of any size, or contralateral lymph nodes of any size is 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 differentiation grade has not shown clear association with outcome and is not considered when staging head and neck cancers.
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 stage 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 of a palpable lymph node in the neck generally decreases the survival rate by 50% compared to the same T stage without node involvement.
Prognoses for oropharynx cancers associated with HPV, even when locally advanced, are about 30% to 50% better than similar cancers that are not associated with HPV, but this improved outlook is reduced in smokers. A subset of patients with matted lymph nodes has been reported to have poorer prognosis.
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 less commonly liver. Second primary cancers after an index head and neck cancer in smokers commonly occur in the head and neck region, the lung, or the esophagus, and may represent a significant mortality risk after curative treatment of the initial head and neck cancer. Recently, there seems to have been a decline in second primary cancer incidence in patients with an index oropharyngeal cancer. This may be due to the higher incidence of HPV-related oropharyngeal cancers, as well as the likelihood that such patients are less likely to be heavy smokers.
TREATMENT
The management of patients with squamous head and neck cancer is complex (Fig. 1.4). The choice of treatment modality depends on the stage and site of disease as well as the condition of the patient. 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 the 60% of patients with locally advanced disease (stages III, IV, and M0), curative combined-modality therapy is indicated. These therapies could include primary surgery with adjuvant radiation (with or without concomitant chemotherapy), radiation with or without concomitant systemic therapy, and neoadjuvant chemotherapy followed by radiation with or without concomitant systemic therapy. Investigational paradigms using response to one cycle of neoadjuvant chemotherapy and biomarkers in selection of patients for chemoradiation or surgery and radiation have been reported for oropharyngeal and laryngeal cancers.
FIGURE 1.4 Treatment for head and neck squamous cell carcinomas (M0).
Patients with recurrent locoregional disease or solitary lung metastasis have benefited from surgical salvage. Some patients may be best treated with radiation, or with reirradiation to a limited field. Unresectable recurrent or distant metastatic disease is usually treated with systemic therapy with palliative intent.
Patients with squamous head and neck cancer should be evaluated before treatment is initiated by a multidisciplinary team including an otolaryngologist or head and neck surgical oncologist, radiation oncologist, medical oncologist, dentist, nutritionist, speech and swallowing pathologist, and personnel involved in rehabilitation.
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 anticipates 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, prevertebral fascia and deep neck musculature, and/or the carotid artery, portends a poor outcome with surgery or other modalities. Involvement of these structures may be indicated by clinical findings such as limitation of ocular movements, tumor involving the pterygoid fossa, severe trismus, laryngeal fixation to the prevertebra, neuropathies of cranial nerves, or nodal fixation in the neck, or by CT, MRI, and PET scans.
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. Limited carcinoma in situ and T1 and T2 lesions of the larynx may be treated by microlaryngoscopic mucosal excision or cordectomy. T2 and selected T3 cancers may be approached using one of the various external supraglottic, hemilaryngectomy or extended partial laryngectomy procedures that have been developed. Newer technologies for transoral and transnasal endoscopic surgical approaches have been recently investigated for resection of T1, T2, and selected T3 carcinomas involving the oropharynx, larynx, paranasal, and skull base region. The feasibility and outcomes for transoral laser and transoral robotic surgery (TORS) coupled with neck dissection or radiation have provided an alternative approach to chemoradiation for function sparing treatment of selected T1/T2 oropharyngeal and supraglottic primaries, and multicenter trials for comparison of these treatments have been proposed. More extensive surgeries, especially those involving the function of the tongue, oral cavity, or oropharynx, may require myocutaneous or microvascular free flaps to achieve functional reconstruction of deficits affecting mucosa, innervated muscle, and/or bone. However, as will be discussed below, with the advent of primary therapy with concurrent chemoradiotherapy for advanced T3/4 cancers of the larynx, NP, oropharynx, and hypopharynx, surgery is also 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 initial surgery in patients with necks that are clinically negative when the risk of a microscopically positive lymph node is at least 30%. Therapeutic neck dissections are done for clinically obvious masses at the time of primary surgical treatment, or persistent clinical mass, radiographic, or PET abnormalities after neoadjuvant or concurrent chemoradiotherapy. 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. Due to excessive morbidity of loss of shoulder function, this surgery is now reserved primarily for very extensive disease such as N2- or N3-stage disease with extracapsular spread involving CNXI and the sternocleidomastoid muscle. The modified radical dissection preserves one or more of the nonlymphatic structures, usually CNXI without or with the sternocleidomastoid muscle. In selective neck dissections, only certain levels of lymph nodes are removed, based on the specific lymphatic drainage from the primary site, and lack of extracapsular spread. With no palpable adenopathy, and no CT or PET 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 neck examinations that are clinically negative.
Radiation Therapy
Over the past two decades, radiation therapy has evolved to a fine art that demands a keen appreciation of both tumor biology and radiation physics. The use of CT for simulation and three-dimensional techniques for treatment planning has improved accuracy in portal design based on an improved understanding of the radiographic extent of the tumor. IMRT techniques have helped to reduce normal tissue toxicity while maintaining high doses to the target volume. The advantages of these advances have been demonstrated by an improvement in locoregional control and a decrease in normal tissue toxicity. Brachytherapy offers similar advantages when performed by experienced physicians. In addition, radiation using charged particles, such as protons or carbon ions, rather than conventional photons, has theoretical advantages for sparing of sensitive normal tissues. With the number of facilities offering charged particle radiation on the rise, direct evidence supporting the theoretical advantages is now being amassed.
Advances in diagnostic imaging have contributed to improvements in radiation therapy planning. Both PET and MRI allow better tumor delineation. Current technology allows fusion of the images from various imaging techniques on each patient so that the radiation oncologist may define the tumor and critical normal structures more accurately. While the goal of IMRT is to improve treatment planning, the goal of image-guided radiation therapy (IGRT) is to improve the accuracy of treatment delivery. IGRT involves imaging patient anatomy and adapting to patient position while the patient is positioned on the treatment machine, with the goal of targeting disease more accurately, minimizing treatment delivery variation, and more effectively sparing normal tissues. 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. With this technique, gross tumor is typically administered daily doses higher than 2.1 Gy.
Altered fractionation schemes have had mixed success. These include hyperfractionation (1.2 to 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. Although altered fractionation improves outcome, this is offset by an increase in acute toxicity without increase in long-term complications. The integration of chemotherapy with altered fraction schedules is under investigation. However, preliminary results of a phase III trial (RTOG 0129) comparing standard fractionated to accelerated fractionated chemoradiation showed no difference in outcome or late toxicity between the groups. 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 glottic larynx and pharynx. However, more advanced disease (generally, stage III and IV) requires the integration of radiation therapy with other modalities.
Toxicity of Radiation
With the advances in radiation treatment planning and delivery, toxicities associated with radiation are less than they were two decades ago. Common severe acute radiation toxicity includes dermatitis, mucositis, loss of taste, xerostomia, dysphagia, and hair loss. Decreased hearing is uncommon. Dental evaluation and necessary extractions should be performed before radiation because dental extractions in a radiated mandible can lead to osteonecrosis. 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. IMRT techniques enabling the reduction of dose to the parotid glands have had more success. Similarly, permanent swallowing dysfunction can be avoided by decreasing the dose to the pharyngeal musculature. Prophylactic, pretreatment, and posttreatment evaluations by a speech therapist also help in preventing and alleviating dysphagia in these patients.
Concomitant Chemoradiation
Radiation with concomitant chemotherapy is used with the intent of organ preservation when surgery would result in the compromise of voice and swallowing functions. It is also used in patients who have stage IVB disease in attempt to cure a patient for whom surgery is not considered a good option (patient not medically fit for surgery or is disease is considered “unresectable”) or IVC disease when, although palliative, local control is desired. Studies have evaluated the use of chemotherapy administered before radiation or surgery (i.e., neoadjuvant or induction chemotherapy), instead of surgery (i.e., concomitant chemotherapy and radiation) or after surgery (i.e., adjuvant chemotherapy and radiation). The rationale for concomitant chemoradiation is based on experimental evidence of synergism between chemotherapy and radiation that is theoretically mediated by interference by chemotherapy with multiple intracellular radiation-induced stress-response pathways involved in apoptosis, proliferation, and DNA repair. The finding that certain chemotherapeutic agents (e.g., cisplatin, 5-fluorouracil [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 large randomized trials, has the advantage of not having mucositis as toxicity; although as a radiation enhancer, it does increase radiation-induced mucositis.
Radiation administered concurrently with chemotherapy or the anti-EGFR antibody cetuximab has been shown to improve survival in patients with advanced head and neck cancers (Table 1.2). Randomized clinical trials and meta-analyses show that for locally advanced head and neck squamous cell carcinoma, concomitant chemoradiation (with cisplatin) produces a small but significant survival advantage of about 8% at 5 years compared to radiation therapy alone. 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 (5 days per week) significantly improved survival rates. Administration of concurrent cisplatin with radiation is also associated with higher rates of larynx preservation in locally advanced larynx cancer, compared to radiation alone. More frequent dosing of cisplatin (e.g., weekly or daily) is postulated to increase sensitization, and is an area of active investigation. 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. Results have been presented in abstract form for patients with stage II to IV resectable cancers, comparing a taxane-based triplet neoadjuvant regimen followed by radiation and concomitant weekly carboplatin (or accelerated boost radiation with weekly Docetaxel) to concomitant accelerated boost radiation with cisplatin given every 21 days. This phase III trial showed no difference in 3-year survival, though poor accrual caused early stopping. A second phase II trial, comparing radiation given concurrent with docetaxel, 5FU and hydroxyurea, both given every other week with or without neoadjuvant taxane-based triplet chemotherapy showed better disease-free survival but similar overall survival for the neoadjuvant arm. Consequently, concomitant platinum-based chemoradiation may be considered for patients with unresectable advanced head and neck cancer with good performance status.
Concomitant chemoradiation regimens using taxanes with either 5-FU 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. Agents that inhibit 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, and increased expression has been correlated with poorer survival rates after radiation therapy. The EGFR inhibitory monoclonal antibody cetuximab has been shown to result in an enhancement of response and survival over radiation alone, although more than 50% of the trial participants had oropharyngeal primary tumors, a type previously associated with greater responsiveness to radiation. 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. Preliminary reports of RTOG 0522 showed no progression-free or overall survival benefit with the addition of cetuximab to standard cisplatin-based chemoradiation, although mature results are awaited. Recent studies suggest that additional molecular alterations, in addition to EGFR, are likely to be important for response, such as nuclear factor-kappaB (NFκB), signal transduction and transcription-3 (STAT-3), and inactivation or mutation of tumor suppressor p53, mutation or overexpression of MET, as well as epithelial-to-mesenchymal transition. Agents targeting these pathways individually, such as bortezomib, quinacrine (NF-κB, p53), and STAT decoy, have shown limited activity.
After chemoradiation in patients with N2, N3, or multiple nodes at diagnosis, elective lymph node dissection may be carried out when complete response is obtained at the primary site, especially when there is less than complete nodal response to chemoradiation. N2 or greater nodes often (about 20%) harbor tumor even if a clinically complete response is obtained in the neck with chemoradiation. 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.
Postoperative/Adjuvant Therapy
The decision to administer adjuvant radiation or chemoradiation is typically guided by pathologic findings. When surgery is the primary modality, postoperative radiation therapy or chemoradiation is generally preferred to the preoperative setting.
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 benefit in locoregional control and disease-free survival for patients receiving adjuvant concomitant cisplatin and radiation over radiation alone. The European study also identified an overall survival benefit, which the American study did not. Both the initial analysis and subsequent reanalysis of pooled data from both trials suggested that the benefits were particularly prominent and enduring in patients with positive margins or extracapsular extension of tumor. Therefore, this population is considered to be at high risk of recurrence and is typically recommended to receive postoperative concurrent cisplatin-based chemoradiation. On the other hand, radiation alone is typically recommended for patients considered to be at intermediate risk of recurrence, with risk factors such as pathologic T3–4/N0 disease, multiple positive nodes (without extracapsular extension), perineural or lymphovascular invasion, or oropharyngeal cancers with cervical nodal level IV or V involvement. Studies are ongoing to evaluate the addition of cetuximab to postoperative radiation in patients with intermediate risk factors.
Induction/Neoadjuvant Chemotherapy Followed by Radiation
The advantages of induction (neoadjuvant) 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. Induction chemotherapy has also been used experimentally as a predictive indicator of benefit for chemoradiation—responders are given definitive chemoradiation and nonresponders are treated with definitive surgery followed by radiation. In stage III and IV larynx and hypopharynx cancer, chemotherapy followed by radiotherapy compared to laryngectomy followed by radiotherapy showed no decrement in overall survival, and larynx preservation was achieved in two-thirds of surviving patients who received chemoradiation. Surgical salvage was eventually necessary for about one-third of the patients with larynx cancer treated with chemoradiation, 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 result in better local control and organ preservation, but not survival, compared to neoadjuvant chemotherapy followed by radiation or radiation alone.
Recently, several investigators have studied combinations of a taxane, a platinum, and 5-FU as induction chemotherapy prior to radiation or to concomitant chemoradiation. A phase III study in stage 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 cisplatin, 5-FU, and taxane chemotherapy compared to cisplatin and 5-FU for up to four courses prior to radiation alone. A second study used cisplatin and 5-FU 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. A third phase III trial randomized unresectable or organ preservation patients to induction therapy with cisplatin and 5-FU 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.
Induction therapy with a taxane, platinum agent, and 5-FU combination has shown response rates up to 70% in chemotherapy naïve patients with unresectable head and neck squamous cancers. Presently, induction chemotherapy with a taxane, cisplatin, and 5-FU combination, with adequate supportive care for hematologic toxicity, followed by radiation therapy can be considered as a reasonable treatment strategy, particularly in patients with unresectable cancers, advanced nodal disease (N2c/N3), and good performance status. Preliminary (abstract) reports (noted above) on trials that randomized advanced-stage resectable patients to concomitant chemoradiation treatment with or without induction chemotherapy have not yet shown a survival advantage, though seem to show a disease-free survival advantage to the neoadjuvant arm.
Reirradiation
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, so that the volume of reirradiated tissue can be minimized. Highly conformal radiation methods such as IMRT are employed to minimize dose to surrounding tissues. The total spinal cord and brain stem doses are typically of primary concern. The interval between the courses of radiation is also important for minimizing toxicities, and most trials have used 6 months as the minimum interval. In the setting of recurrence, multidisciplinary management remains important, since reirradiation has been evaluated with favorable results when delivered as a solitary modality or when delivered postoperatively or with concurrent chemotherapy. Radiation doses in the range of 60 Gy are typically delivered. Short-term local control rates of 15% to 65% are observed, and median survival times of 8 to 28 months are reported.
Supportive Care
Acute Toxicities of Treatment
Patients treated with concomitant chemoradiation therapy require frequent clinical assessment and prompt institution of supportive care to avoid severe or fatal consequences during the acute phase of treatment (during chemoradiation and 1 to 2 months following chemoradiation).
Nutrition Careful assessment of the need for a percutaneous enteral feeding device should be done. These devices have been shown to be beneficial for patients who are thin, or have lost significant weight. They are not necessary for all patients, but if not placed, such patients must be assessed every 1 to 2 weeks for toxicity and weight loss. A good rule of thumb is to place these devices if the patient loses 10% of their normal weight prior to treatment or in the initial 4 weeks of concomitant chemoradiation.
Hydration Combined chemoradiation leads to increased fluid loss, especially with severe mucositis, and/or with loss of normal taste or appetite secondary to chemoradiation. Patients should be assessed every 1 to 2 weeks for skin turgor, orthostatic blood pressure changes, lightheadedness on standing, or increased creatinine (especially with platinum combinations). If any of these symptoms or signs is present, saline hydration should be given intravenously.
Mucositis A significant number of patients receiving chemoradiation therapy will develop severe mucositis that impairs nutrition and causes severe pain. If a patient cannot swallow, or loses 10% of body weight, then assistance to nutrition, such as percutaneous enteral feeding, is indicated. Candida infection of the affected mucosal surfaces is fairly common. At the first sign of candidiasis, antifungal therapy should be instituted, topically and/or orally. A preparation containing an antifungal, anesthetic, and calcium carbonate suspension is useful. Narcotic pain control should be aggressive and patients should be taught to track pain severity and self-administer their narcotics before the peak of pain occurs. It is useful to use a transdermal administration route, using careful dose calculation based on total use of short acting narcotic, plus a short-acting (liquid) narcotic to control pain.
Hypomagnesemia This is common with high-dose platinum agents and is managed with oral or intravenous replacement.
Hypothyroidism Up to 50% of patients may have increased thyroid stimulating hormone levels (TSH) after radiation therapy. Prior to and following acute treatment and every 3 months during follow-up, TSH should be monitored and appropriate replacement therapy instituted.
Rash Cetuximab may cause an acneiform rash in the upper torso and face which may become infected if not treated. Patients should be started prophylactically on moisturizers as topical therapy. Steroid-containing topical creams and doxycycline are also helpful for a more severe rash (confluent in more than one body area). The rash often improves after the first few weeks, and may not be present in the radiation fields.
Allergic Reactions Severe and life-threatening allergic reactions have occurred with cisplatin, carboplatin, and antiepidermal growth factor receptor (EGFR) antibodies. Infusion of these agents should only be done when appropriate emergency equipment and trained personnel are available.
Late Toxicities of Treatment
A significant minority of patients will have swallowing difficulties for several years or permanently, with attendant risk of aspiration and pneumonia. Swallowing therapy and potentially continued enteral nutrition with a percutaneous tube may be necessary for these patients.
Xerostomia Risk of dry mouth due to incidental radiation to the salivary glands is present but has been lessened by more accurate treatment planning and delivery with intensity-modulated radiation therapy (IMRT) methods. Initial management typically includes saliva substitutes, oral mucosal lubricants, and frequent sips of water. Systemic cholinergic agonists can be considered for xerostomia that persists for more than 1 year after treatment completion. There is growing evidence supporting a role for acupuncture or acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in palliation of xerostomia as well.
Dental Caries An increased risk of developing dental caries accompanies any change in salivary flow or composition. For this reason, any patient who has had head and neck radiation should have regular, frequent dental evaluations. Long-term, daily use of fluoride trays is often recommended. Meticulous oral hygiene can reduce the likelihood of other late effects, such as osteoradionecrosis (ORN).
Osteoradionecrosis Bone exposure following radiation may lead to progressive ORN, which occurs in 5 to 7% of patients treated with radiation. To prevent ORN, extractions should be performed in patients with poor dentition and allowed adequate time for healing prior to therapy (at least 2 weeks). If ORN develops, patients with dead sequestra (necrotic bone) should be referred to an oral maxillofacial surgeon for sequestrectomy. Culture may provide sensitivities for IV antibiotic therapy. Sequestrectomy coupled with long-term pentoxifylline has been reported to result in healing in most patients within 1 year. Hyperbaric oxygen has been used for many years, but was not found to be of benefit in a randomized clinical trial.
Mobility Impairment Both surgery and radiation can cause fibrosis of soft tissues of the neck, impacting cosmesis and/or neck mobility. Treatment often includes physical therapy for neck stretching and strengthening and massage. The combination of tocopherol (1,000 International Units per day) and pentoxifylline (400 mg BID) improves symptoms of fibrosis, can result in some degree of regression of fibrosis, and is well tolerated. Greater regression is generally achieved with earlier initiation of therapy.
Palliative Chemotherapy
Chemotherapy is effective as palliative treatment for recurrent or metastatic squamous head and neck cancer, or in unresectable cancers in patients who cannot undergo combined modality treatment. 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. Whenever possible, patients should be encouraged to enroll in clinical trials that evaluate new agents or new combination regimens.
The choice of single-agent or combination chemotherapy depends largely on whether chemotherapy is used as part of a curative regimen, or for palliation, as well as the patient’s overall health and performance status. Combination chemotherapy yields higher response rates but has increased toxicity when compared with single agents. Common chemotherapy agents used for head and neck cancer include cisplatin, carboplatin, docetaxel, paclitaxel, 5-FU, methotrexate, and the anti-EGFR antibody cetuximab (Table 1.3). Cisplatin is considered to be standard chemotherapy for head and neck cancer either alone or in combination with 5-FU or a taxane and/or cetuximab. Carboplatin (AUC 5) may be slightly less active than cisplatin for head and neck squamous cancer, but is preferred in patients at high risk for cisplatin toxicity, e.g., patients with renal dysfunction, neuropathy, or hearing loss. Small studies have also evaluated pemetrexed, gemcitabine, ifosfamide, irinotecan, vinorelbine, and others, showing response rates of 10 to 25% and median survival of 4 to 7 months in nonrandomized clinical trials. Prior to the use of taxane combinations, meta-analyses and randomized trials demonstrated improved response for cisplatin compared with methotrexate, and improved response for cisplatin and 5-FU combination compared with single drugs, although improvement in survival with combinations versus single agents is less clear. In the metastatic setting, the combination of cisplatin and infusional 5-FU produces a 70% response rate and a 27% complete remission rate in chemotherapy-naive patients, but the response rate is 30% to 35% with less than 10% complete responses in patients who have relapsed after radiation therapy. An older randomized trial of cisplatin and 5-FU versus carboplatin (fixed dose of 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).
Both docetaxel and paclitaxel have shown antitumor activity. Paclitaxel doses of 75 mg/m2 every 3 to 4 weeks are usually tolerable in combination with a platin and/or 5-FU. Docetaxel is usually administered at doses of 60 to 100 mg/m2 every 3 to 4 weeks. Weekly schedules are being evaluated. Taxane combinations, including paclitaxel or docetaxel, cisplatin or carboplatin, with 5-FU, show promising response rates and can be given with modest toxicity if growth factors are used.
The EGFR inhibitor cetuximab is approved by the FDA for use combined with platinum-containing chemotherapy or as a single agent after progression on a platinum regimen for recurrent or metastatic disease. Cetuximab is also approved for use with radiation therapy for treatment of locally advanced squamous head and neck cancer, where there is a survival advantage compared to radiation alone (see above).
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. Imaging studies should be done approximately 10 to 12 weeks after completion of radiation therapy (if given) and then every 3 to 6 months for the first 3 years, or for any symptoms or signs suggesting recurrence or second primary cancer. The TSH level should be obtained 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 (121,122).
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 or CT is recommended. Some recurrences, as well as second primaries, can be treated with curative intent.
SITE-SPECIFIC TREATMENT OF 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 either surgery or radiation therapy as single-modality therapy. Treatment of the neck by sentinel node or supraomohyoid selective neck dissection or radiation is indicated for invasive cancers due to the significant risk of nodal metastasis. For resectable locally advanced disease (stages III and IV, and M0), surgery for the primary tumor and appropriate neck dissection is indicated (see Fig. 1.4). Postoperative radiotherapy or chemoradiotherapy is indicated for close margins, perineural or lymphatic invasion, nodal disease stage N2 or greater, or with extracapsular spread. 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 unresectable locally advanced and metastatic disease is included in sections on chemo- and radiotherapy.
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. In the last 10 years, it has become apparent that there are at least two different subtypes of oropharynx cancer. Oropharynx cancer associated with HPV infection has increased in incidence by over 200%, while the incidence non-HPV-related oropharynx cancer has decreased. Currently half or more oropharynx cancers are HPV–. Patients tend to be slightly younger than those with HPV– oropharynx cancer, and tend to have less tobacco exposure. Most of these tumors are due to high risk HPV, particularly types 16 and 18. Patients with oropharynx cancer should have their tumors assessed for HPV subtypes, and for the presence of p16 immunostaining. Oncogenes expressed by the virus (E6 and E7) interfere with the function of p53 and Rb, and drive proliferation. The absence of a functional Rb leads to p16 overexpression. The prognosis for HPV– oropharynx cancer is 30% to 50% better compared with HPV– oropharynx cancer. Currently, treatment of both HPV– and HPV– oropharynx cancers are similar. Treatment may include primary surgery with postoperative radiation or chemoradiation as necessary (multiple positive lymph nodes, extracapsular spread). TORS may be an option for some tumors, and may provide a functional surgical result. Primary chemoradiation therapy is frequently used for stage III or IV disease as a result of superior organ preservation and swallowing when compared to nonfunction sparing surgical resection and reconstruction of the tongue base, reserving surgery for management of regional node metastases or for salvage of persistent disease. The adoption of IMRT has resulted in improved functional outcomes as well. Older randomized trials, which did not assess for HPV status, show that concurrent chemoradiation significantly improves locoregional control and survival compared with radiotherapy alone. 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.
Because of the much improved prognosis of HPV– oropharynx cancers, clinical trials are assessing the efficacy of less intense treatments. RTOG 1016 (NCT01302834) compares IMRT with cisplatin versus IMRT with cetuximab in locally advanced stage III/IV oropharynx cancer that is positive for p16 expression. Several phase II trials are also evaluating TORS and reduced radiation dose for HPV– oropharynx cancers. The Eastern Cooperative Oncology Group has completed accrual to a phase II trial of paclitaxel, cisplatin, and cetuximab followed by cetuximab in combination with low-dose or standard-dose intensity-modulated radiotherapy in HPV– stage III or IV resectable oropharynx cancer (NCT01084083) and 2-year progression-free survival (PFS) results are awaited.
Non-HPV-associated cancers usually present at a locally advanced stage, and are treated with chemoradiation or induction chemotherapy followed by chemoradiation, with surgery reserved for residual disease or recurrence. In selected advanced patients, surgery could also be used as the primary modality, followed by radiation or chemoradiation as indicated. If available, clinical trials are recommended for this group, as well.
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, differentiated nonkeratinizing squamous cell carcinoma; and type III, undifferentiated nonkeratinizing carcinoma. 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% to 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.
Staging for nasopharyngeal carcinoma differs from that of other head and neck sites, particularly with regard to nodal staging. For full details, see the AJCC Cancer Staging Manual. Stage I is node-negative disease confined to the NP. In stage II disease, the tumor extends to the parapharyngeal region with or without unilateral lymph node(s) measuring 6 cm or less. The disease is considered locally advanced disease (stages III and IV) when the tumor extends beyond the parapharyngeal region to involve other structures (bone, orbit, cranial nerves, intracranial extension) or when bilateral or any supraclavicular lymph nodes are involved.
The prognoses for different stages of nasopharyngeal carcinoma are shown in Table 1.6.
General treatment guidelines are shown in Figure 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, 80% to 90%; T3–T4, 70% to 80%), and remains the standard of care for stage I cancer. However, for stage II disease, a recent randomized trial showed that concurrent weekly cisplatin (30 to 40 mg/m2) added to radiation confers an overall survival benefit over radiation alone. Thus, consideration of chemoradiation is advisable in stage II disease.
FIGURE 1.5 Treatment of nasopharyngeal carcinoma (M0).
In a randomized trial in the United States in the 1990s, concurrent cisplatin (cisplatin 100 mg/m2 every 21 to 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). On the basis of this study, concurrent chemoradiation followed by adjuvant chemotherapy is still considered standard treatment for locally advanced nonmetastatic (stage III and IV) nasopharyngeal cancer in the United States. Other drugs, such as taxanes, appear to have activity but have not been evaluated extensively.
Larynx
Risk factors include a history of tobacco and/or alcohol intake. HPV is detected in subset of laryngeal cancers. 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 glottic cancers not requiring laryngectomy (T1–T2 N0) are usually treated with microendoscopic surgery or radiation. Transoral robotic or laser surgery has been used for T1–2 and selected T3 supraglottic cancers. Locally advanced resectable tumors (T3–T4 or T2 N–) may be treated with surgery, with addition of adjuvant radiation if locoregional risk factors are present (i.e., close or positive margins, T3/4 tumor involving pre-epiglottic space, laryngeal-cricoid cartilage or hyoid bone, lymphatic or vascular or perineural involvement, multiple positive nodes, extracapsular invasion, subglottic extension, or prior tracheostomy). For supraglottic cancers with high risk of neck metastasis or other sites with lymph node involvement, neck dissection, and/or neck radiation is indicated. An alternative is the use of combined radiation and chemotherapy. In 1991, the Veterans Administration Laryngeal Study Group trial established 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 III trial conducted in the United States 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. 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. Patients who received any chemotherapy had a lower metastatic rate at 2 years than did patients who received radiation alone. Patients with high-volume T4 disease (with destruction of larynx or massive extension of supraglottic laryngeal cancer to the base of tongue), who were not likely to obtain functional laryngeal and swallowing preservation without aspiration with chemoradiation, have traditionally been treated with surgery followed by radiation therapy rather than by organ preservation therapy. Recently, however, an investigational hybrid paradigm using one cycle of neoadjuvant cisplatin has been used to “chemoselect” patients with >50% tumor reduction for concurrent chemoradiation with significant organ preservation rates, even in patients with T4 disease. Those patients with <50% tumor reduction after cisplatin or incomplete response after chemoradiation undergo total laryngectomy.
Speech rehabilitation is critically important for patients with advanced laryngeal cancer who are undergoing total laryngectomy. Phonation options include tracheoesophageal puncture at the time of total laryngectomy, esophageal speech, or a mechanical electrolarynx. 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 under Palliative Chemotherapy in this chapter.
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. Transoral robotic and laser surgery has been shown to be feasible in selected cases. 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 usually involves total laryngectomy and/or partial or total pharyngectomy and neck dissection. Even with this radical surgery and the consequent functional impairment, the survival prognosis is poor.
Combined-modality treatment with chemoradiation allows organ function preservation with chances of survival being equivalent to that after surgery (Table 1.6). Recently, the European Organisation for the Research and Treatment of Cancer (EORTC) reported on a larynx/hypopharynx preservation study. Two hundred and two patients were randomized to either total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation, or to chemotherapy with up to three cycles of induction chemotherapy (cisplatin 100 mg/m2 on day 1 – 5-FU 1,000 mg/m2 on days 1 to 5) followed by irradiation for complete responders or conventional treatment for incomplete responders. At a median follow-up of 10.5 years on 194 eligible patients, the 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year survival with a functional larynx (SFL) rate was 8.7%. This strategy did not compromise disease control or survival, which remained poor and allowed more than half of the survivors to retain their larynx.
Patients who are prone to high surgical or medical risks can be treated with chemoradiation or radiation. The management of metastatic disease is discussed under “Palliative Chemotherapy” in this chapter.
Nasal Cavity and Paranasal Sinuses
Carcinomas of the nasal cavity and sinuses are rare entities, and include squamous cancers, melanomas, esthesioneuroblastoma, and sinonasal undifferentiated carcinoma (SNUC). Non-Hodgkin’s lymphomas, plasmacytomas, sarcomas, adenoid cystic carcinoma, and other histologies may also present in the nasal cavity and 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.
Carcinomas of the nasal cavity and paranasal sinuses are usually detected in patients in advanced stages because of the relatively silent tumor location. Symptoms may include facial swelling, nasals stuffiness, pain, or epistaxis. Such patients should be evaluated by a multidisciplinary team experienced in tumors of the nasal cavities and sinuses. If feasible, surgery is the preferred primary management, but reports of good outcomes with the use surgery followed by adjuvant radiation with or without chemotherapy have been published. Hypopituitarism may be a complication of radiation treatment. Local recurrence is common for epithelial tumors, while distant metastases are less common for these tumors.
Cancer of Unknown Primary Site (of the Head and Neck)
The workup of a patient with a neck mass is shown in Figure 1.3. Nasopharyngeal, oropharyngeal, and hypopharyngeal origins are most common. PET/CT together with biopsies reveals the origin of most of these cancers. 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 usually indicates a head and neck primary tumor. Unknown primary tumors of the head and neck are usually treated with neck dissection and radiation or concurrent chemoradiotherapy as for NP or OP cancers. The prognosis is roughly equivalent to cancers with the same N (nodal) status. For patients treated by surgery and/or concurrent chemoradiotherapy, 5-year survivals of 75% to 87% have been reported.
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, 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 1.7.
The 2005 WHO classification recognizes 24 histologic subtypes of salivary gland cancers. The most common type of malignant salivary gland cancer arising from the major salivary gland is mucoepidermoid carcinoma, followed by squamous carcinoma, acinic cell, adenoid cystic, and adenocarcinoma not otherwise specified. In the minor salivary glands, mucoepidermoid cell cancer is again the most common, followed by adenoid cystic carcinoma and adenocarcinoma not otherwise specified. Salivary duct carcinoma represents a subtype of adenocarcinoma that resembles ductal carcinoma of the breast histologically, but generally has an aggressive natural history. The clinical characteristics and prognosis of specific malignant salivary gland tumors are shown in Table 1.8.
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. Lung and bone are the most frequent sites for 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, but the effect on survival is unknown.
Molecular characterization of salivary gland tumors has revealed some characteristic molecular alterations. In 50% to 70% of mucoepidermoid cancers, a translocation t(11;19)(q21;p13) creates a fusion protein product of MEC translocated 1 (MECT) with mastermind-like gene family (MAML2) that interrupts NOTCH signaling. The presence of this fusion correlates with low-grade histology and improved prognosis. In about half of adenoid cystic carcinomas, t(6;9)(q22-23;p23-24) results in a fusion of MYB and NFIB, and portends a worse prognosis, as does del(1p32-p36). A new subtype of salivary gland cancer, mammary analog secretory carcinoma, is characterized by t(12;15)(p13;q25), fusing the ETV6 and NTRK3 genes. Other molecular characteristics of salivary tumors have been evaluated. EGFR has been found to be expressed or overexpressed in mucoepidermoid and salivary duct cancers, but activating mutations and high-level amplifications appear to be rare. Expression of HER2 with amplification appears to occur in about 30% of salivary duct cancers, and the majority of these cancers appear to express androgen receptors. PTEN abnormalities and activating mutations of PIK3CA have also been described in salivary gland cancers. Thus far, trials of targeted agents have not developed a clear signal of which salivary tumors may respond to a particular targeted therapy, even when the target is present. Targeted therapies, particularly inhibitors of EGFR, VEGF or its receptors, and Her-2/neu, have been tested in phase 2 clinical trials. Larger trials or trials incorporating molecular eligibility criteria are needed to confirm the activity of these new agents against salivary gland cancers either alone, or in combination. Exploratory studies of assigning treatments based on molecular abnormalities of a particular patient’s tumor have shown intriguing results (response or prolonged time to progression). Patients with good performance status should be encouraged to enter clinical trials.
OTHER HEAD AND NECK TUMORS
Sarcoma
Soft tissue sarcomas of the head and neck account for only about 2% of all head and neck malignancies in adults. Of head and neck sarcomas, approximately 70% are seen in adults and 30% 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 NP, 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. Distant spread is typically to the lungs, but can less commonly involve other sites. In contrast to soft tissue sarcomas in other locations, in the head and neck region, local disease tends to have a greater impact on survival than does distant metastatic disease. This is likely because of the region’s tight anatomical constraints, which limit the ability to achieve the wide resection margins typically required for local control of soft tissue sarcomas. Regional nodal disease is possible with some histologic types of sarcoma, but is much less common than with squamous cell carcinoma. Sarcomas may also 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.
Initial evaluation and workup is similar to that for a squamous cell carcinoma at the same site with some key differences. MRI is likely to be more useful in defining the extent of disease for treatment planning. In addition, if sarcoma is suspected, biopsy should be performed carefully with meticulous hemostasis, since the risk of seeding the biopsy tract or any biopsy-related ecchymosis is higher with soft tissue sarcomas.
Treatment depends on stage, age of the patient, tumor type, location, and size. Rhabdomyosarcomas should be treated under the current cooperative group trial. For bone and other soft tissue sarcomas, en bloc resection with wide (>1 cm) margins is the goal, but may not be possible because of the proximity of vital structures. Elective neck radiation is not necessary because the incidence of occult positive lymph nodes is low. Given the infiltrative nature of soft tissue sarcomas, there should be a low threshold for including adjuvant radiation and/or brachytherapy to improve local control, even in low-grade sarcomas. Postoperative chemotherapy is generally advised for most osteosarcomas, and may provide a local control benefit for soft tissue sarcomas as well. Such patients should be referred to clinical trials when possible. Overall survival rate approaches 60% for patients with sarcomas of the head and neck.
Melanoma
Most cutaneous head and neck melanomas occur on the face, scalp or neck. Superficial spreading melanoma is most common, followed by nodular melanoma. The principles of staging and treatment of cutaneous melanoma of the head and neck are similar to those for cutaneous melanomas elsewhere on the body. Elective neck dissection may be considered, and superficial parotidectomy may be needed due to nodes in the parotid. Sentinel lymph node dissection requires expertise due to the complexity of lymph drainage in the head/neck region, and the possibility of sentinel nodes in the parotid gland, with risk of facial nerve injury on dissection.
Mucosal melanomas represent less than 1% of all melanomas. The peak age of diagnosis is 60 to 80 years. In SEER data from 1987 to 2009, 452 mucosal melanomas of the head and neck were reported. The majority occurred in the nasal cavity, paranasal sinuses and middle ear (73%), while fewer occurred in the oral cavity, oropharynx, NP, or salivary gland (27%). Sinonasal lesions may present with epistaxis and nasal obstruction, while oral cavity lesions are usually flat and pigmented. Because of the rarity of these tumors, most literature reports consist of small numbers of cases treated over several decades. Primary treatment is usually surgery, and adjuvant radiation therapy may improve local control, without effect on survival. Local recurrence and metastases are common. Five-year survival is about 25% for these diseases. The National Comprehensive Cancer Network (NCCN) has recently published guidelines for diagnosis, workup, treatment, and follow-up of mucosal melanomas.
Molecular profiling has demonstrated mutations in NRAS and KIT, amplification of RREB1, and loss of MYB, P16INK4a, and PTEN. Fewer patients with mucosal melanoma appear to have BRAF mutations, compared with patients with cutaneous melanoma. There have been reports of responses of mucosal melanomas to ipilumumab, as well as to targeted agents when the target is present (imatinib, c-kit), and studies employing treatment guided by molecular profiling are being performed.
Targeted Therapies and Future Directions
EGFR is overexpressed in most head and neck squamous cancers, and therapies targeting this receptor and its downstream pathways have been the subject of most extensive investigation. Increased expression of EGFR correlates with poorer prognosis in this cancer. EGFR targeted therapy with the humanized antibody cetuximab in combination with radiotherapy has been approved by the U.S. Food and Drug Administration for treatment of head and neck cancer. However, the small improvement in response of radiation with cetuximab over radiotherapy alone, and the activity of EGFR targeted therapies alone (approximately 10% response rate) suggest that EGFR is a sole driver of a relatively small subset of head and neck squamous cancers. Several mechanisms of resistance to EGFR-targeted agents have been described in head and neck squamous cancers and other tumors. Amplification or mutation of PI3K catalytic subunit in ~30% and activation of PI3K-mTOR in >70% of head and neck squamous cancers has been reported. Preclinical and clinical activity of mTOR inhibitors has been observed, and several mTOR inhibitors are under clinical investigation at National Institutes of Health (NIH) and elsewhere. Activation of the NF-κB pathway is important in head and neck squamous cancer cell survival and reported in over 70% of these cancers. While proteasome inhibitors target NF-κB, they demonstrated limited activity alone or in combination with chemotherapies or reirradiation. They were also found to antagonize the clinical therapeutic effects of cetuximab or radiotherapy, by inhibiting degradation of EGFR. STAT3 is another important cell survival pathway, for which oligonucleotide decoys have demonstrated activity in pilot studies, and for which identification of small molecule inhibitors remains an important objective. Other targets under investigation include PI3K-mTOR, MET, IGF-1R, and heat shock protein 90 inhibitors. IMRT has reduced toxicities of chemoradiation such as xerostomia and dysphagia, and other treatments that ameliorate these side effects are also under study. For supportive care, a recent pilot NIH gene therapy study demonstrated the feasibility of using adenoviral transfer of the aquaporin gene to temporarily restore salivary flow. A follow-up trial with adeno-associated virus is in the planning stages. Molecular characterization of tumors is a promising field made possible by high capacity sequencing that will likely lead to individualized treatment and prevention approaches. The NIH Cancer Genome Atlas report for genetic and pathway alterations in head and neck cancer is forthcoming.
ACKNOWLEDGMENTS
The authors would like to acknowledge Janaki Moni MD, Dexter Estrada, MD, Arlene Forastiere, MD, and David Gius, MD.
REVIEW QUESTIONS
1.A 47-year-old man presents with a neck mass and sore throat. He has a 2-year history of smoking 1 pack per day in college, but has not smoked since, and drinks one to two glasses of wine per week. He has been married for 15 years. He works as a financial consultant. Examination shows a 2 cm level II node on the left neck, and fiberoptic examination shows a mass in the left tonsil. Biopsy shows squamous carcinoma and staining for p16 is positive. PET/CT shows a 2.5 cm mass in the left tonsil, as well as 1 cm and 2 cm nodes in the left neck at level II, and a 1 cm node in the left neck at level III. He is staged as T2 N2b M0 stage IVA.
Recommendations for treatment could include the following:
A.Surgery followed by radiation therapy
B.Definitive concurrent cisplatin and radiation
C.Treatment on a clinical trial for HPV– head and neck cancer
D.Chemotherapy with cisplatin, fluorouracil, and paclitaxel
E.A, B, or C
2.A 21-year-old woman presents with a sore tongue. Examination shows a 2.5 cm raised, tender mass on the lateral left oral tongue. She is a nonsmoker. Her family history includes a brother who died of leukemia as a child. She is married and has a 19-month-old daughter. She works part time in the county library. Biopsy of the tongue lesion showed squamous cell carcinoma. PET/CT shows only the 2.5 cm tongue mass; there is no lymph node positivity on the scan.
Which of the following is TRUE?
A.Second primary head and neck tumors are a significant cause of morbidity and mortality. She should be followed up carefully for additional primary tumors
B.She should receive radiation and concomitant cetuximab for organ preservation
C.Consideration should be given to the possibility of an inherited abnormality in DNA repair
D.She should receive local excision only and close follow-up
E.A and C
3.A 58-year-old man who emigrated from southern China 10 years ago is evaluated for a 3-month history of an enlarging neck mass. Neck examination reveals two firm lymph nodes: a 4 cm left level III node and a 2 cm left supraclavicular lymph node. Fiberoptic endoscopy reveals a mass in the left NP. Biopsy revealed WHO type III nasopharyngeal carcinoma. Contrast-enhanced CT shows a 4.5 cm left level III lymph node, a 2.4 cm left supraclavicular node, as well as a mass localized to the NP with parapharyngeal extension. These were the only regions to show FDG uptake on PET/CT.
Which of the following is TRUE?
A.Surgical resection of the primary tumor with left neck dissection followed as needed by chemoradiation is the treatment of choice
B.This represents one of a minority of head and neck cancers in which a strong association with EBV has not been established
C.The recommended treatment is concurrent cisplatin chemotherapy and radiation followed by adjuvant cisplatin and 5-FU chemotherapy
D.With this stage and grade of disease, 5-year overall survival is typically about 20%
E.Both C and D
4.A 62-year-old woman presented with a 2 cm oropharyngeal squamous cell carcinoma (base of tongue) with spread to a 6 cm lymph node spanning left levels II and III. She began treatment with concurrent cisplatin and radiation. She developed oral candidiasis in her fourth week of treatment. She also experienced mucositis and throat pain with attendant anorexia and weight loss that required percutaneous feeding tube placement and narcotic pain medications. She is being seen for her end-of-treatment visit today and her weight has stabilized. She continues to use narcotics regularly for throat pain and mucositis.
Which of the following is TRUE?
A.Prophylactic anticandida treatment should be initiated for all such patients beginning concurrent chemoradiation.
B.Her percutaneous feeding tube should be scheduled for removal within the 1 to 2 months following treatment completion.
C.Any necessary dental extractions should be carried out as soon as acute toxicities of treatment subside after treatment is complete.
D.Should she have persistent xerostomia after treatment, cholinergic agonists may be considered.
E.After definitive chemoradiation, neck dissection for this patient is ill advised.
5.A 68-year-old man with an 80-pack-year smoking history and a history of alcohol intake consisting of 12 beers on most weekends presents with a stage IVA squamous carcinoma of the glottic larynx (T3 N2cM0). His weight is 68 kg and height is 66″. His performance status is good, and he has no other medical problems except mild emphysema. He lives with his wife of 42 years and is retired from a machining company where he worked for 35 years. His past history includes military service in Vietnam, with exposure to Agent Orange. Which is the best treatment choice for this patient?
A.Cisplatin with concurrent radiation
B.Radiation as definitive treatment
C.Surgery followed by postoperative concurrent cisplatin and radiation if nodal extracapsular extension of disease or positive margins on pathological examination.
D.Cetuximab and concurrent cisplatin-based chemotherapy and radiation.
E.A or C.
Suggested Readings
1.Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998;16:1310-1317.
2.Bernier J, Cooper JS, Pajak TF. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck. 2005;27:843-850.
3.Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578.
4.Chaturvedi, AK. Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol. 2012;6:S16-S24. doi:10.1007/s12105-012-0377-0.
5.Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst. 2011;103(23):1761.
6.Chung CH, Schwartz DL. Impact of HPV related head and neck cancer in clinical trials: opportunity to translate scientific insight into personalized care. Otolaryngol Clin N Am. 2012;45:795-806.
7.Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198.
8.Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti, A, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
9.Freudlsperger C, Burnett JR, Friedman JA, Kannabiran VR, Chen Z, Van Waes C. EGFR-PI3K-AKT-mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy. Expert Opin Ther Targets. 2011;15(1):63-74.
10.Fury MG, Pfister DG. Current recommendations for systemic therapy of recurrent and/or metastatic head and neck squamous cell cancer. J Natl Compr Canc Netw. 2011;9:681-689.
11.Langendijk JA, Bourhis J. Reirradiation in squamous cell head and neck cancer: recent developments and future directions. Curr Opin Oncol. 2007;19:202-209.
12.Laurie SA, Ho AL, Fury MG, Sherman E, Pfister DG. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol. 2011;12(8):815-824.
13.Lee AWM, Lin JC, Ng WT. Current management of nasopharyngeal cancer. Semin Radiat Oncol. 2012;22:233-244.
14.Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol. 2012;23(10):2708-2714.
15.Morris LGT, Sikora AG, Patel SG, Hayes RB, Ganly I. Second primary cancers after an index head and neck cancer: Subsite specific trends in the era of human papillomavirus-associated oropharygeal cancer. J Clin Oncol. 2011;29(6):739-746.
16.Pfister D, Ang KK, Brizel DM, Burtness B et al. Mucosal melanoma of the head and neck. JNCCN. 2012;10(3):320-338.
17.Pignon JP, le Maître A, Bourhis J, MACH-NC Collaborative Group. Meta-analyses of chemotherapy in head and neck cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S112-S114.
18.Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705-1715.
19.Savage SA, Dokal I, Armanios M, et al. Dyskeratosis congenita: the first NIH clinical research workshop. Pediatr Blood Cancer. 2009;53(3):520-523.
20.Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963-968.
21.The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;324:1685-1690.
22.Van Waes C. Head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2005;131:640-641.
23.Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357:1695-1704.
24.Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008;26(19):3138-3146.
25.Yoo J, Henderson S, Walker-Dilks C. Evidence-based Guideline Recommendations on the Use of Positron Emission Tomography Imaging in Head and Neck Cancer. Clin Oncol (R Coll Radiol). 2013 Apr;25(4):e33-66. doi: 10.1016/ j.clon.2012.08.007. Epub 2012 Sep 26.