and Carol M. Lewis1
(1)
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chapter Overview
Head and neck cancer (HNC) survivors present with unique needs related to the long-term effects of cancer therapy on upper aerodigestive tract functions. Management of HNC varies depending on the patient’s individual stage and subsite of HNC, cancer treatment history, and psychosocial needs. In general, long-term functioning is optimized by multidisciplinary treatment planning with consideration of both acute and late adverse effects. Risk-reduction strategies such as oral care, targeted exercise, swallowing therapy, nutritional counseling, and audiologic monitoring are best implemented early in the HNC treatment trajectory. Posttreatment surveillance facilitates detection of recurrences and second primary tumors, as well as monitoring of long-term functional rehabilitation needs.
Introduction
Head and neck cancer (HNC) accounts for roughly 5% of all cancers. In 2010, 36,540 cases of oral cavity and oropharyngeal cancers and 12,720 cases of laryngeal cancer were diagnosed in the United States. Oral cavity and oropharyngeal cancers comprised 3% of all cancers in men (Jemal et al. 2010). More than 85% of cases of HNC are squamous cell carcinoma (Mehanna et al. 2010b), which will be the focus of this chapter.
The upper aerodigestive tract (UADT) is separated into different subsites; the treatment of cancer in each of these subsites requires specific anatomic and functional considerations. The nasopharynx is posterior to the nasal cavity, superior to the palate, and inferior to the skull base. The oral cavity starts at and includes the lips and ends posteriorly at the soft palate. The oropharynx includes the soft palate and posterior pharyngeal wall and is limited inferiorly by the level of the hyoid bone. The hypopharynx starts at the level of the hyoid bone and extends to the inferior aspect of the cricoid bone. The larynx encompasses the epiglottis, arytenoids, and aryepiglottic folds superiorly and extends inferiorly to 1 cm below the true vocal folds (TVFs).
The management of cancer arising in these subsites requires multidisciplinary planning. The head and neck oncology team should consist of a head and neck surgeon, medical oncologist, radiation oncologist, dentist, speech pathologist, dietitian, and social worker at the very minimum, and treatment plans should be formulated through multidisciplinary discussion.
Overview of Treatment Modalities
Chemotherapy
Eradication of systemic disease is the goal of chemotherapy, although in HNC, chemotherapy functions as an adjuvant to surgery and radiation therapy (RT) to improve local and regional control. Chemotherapy also serves a palliative role in patients with distant metastases or locoregional recurrence for whom surgery or RT are no longer reasonable options. In the latter group, approximately one-third of patients will obtain a 3- to 6-month survival benefit from chemotherapy (Brockstein and Volkes 2006).
As an adjuvant treatment, chemotherapy can be given as induction therapy prior to definitive surgery or RT or concurrently with postoperative or definitive RT. The advantages of induction therapy include the potential to decrease tumor burden, predict response to subsequent treatment, and decrease morbidity by facilitating less extensive definitive treatment. Perhaps the most well-known example of induction chemotherapy in HNC is the Department of Veterans Affairs Laryngeal Cancer Study Group, which demonstrated identical 2-year overall survival rates in patients receiving induction chemotherapy and definitive RT (with salvage surgery as indicated) and, for patients who did not respond to induction chemotherapy, in those who underwent surgery with postoperative RT. In the former group of patients, 64% had laryngeal preservation, and 39% of the patients with laryngeal preservation were disease-free with an intact larynx (Department of Veterans Affairs Laryngeal Cancer Study Group 1991).
When given concurrently with RT, chemotherapy acts to enhance the efficacy of RT. Although concurrent chemoradiation has never been compared with surgery in a randomized fashion, the reported rates of overall survival for certain cancers rival those published for surgical management (Forastiere et al. 2003). In patients undergoing surgery for disease with adverse features, such as extracapsular spread (wherein the tumor grows outside the capsule of the lymph node), concurrent postoperative chemoradiation has been shown to improve locoregional control and overall survival (Cooper et al. 2004).
Radiation Therapy
RT may take the form of external beam RT, conformal RT, or brachytherapy. External beam RT, or standard RT, is delivered with beam energy specific to the depth of the tumor. Conformal RT, or intensity-modulated radiation therapy, customizes the high-dose region to the tumor, or target volume. Conformal fields are composed of numerous smaller beams, each with a target dose and acceptable range of doses, as determined by its mark. In brachytherapy, the radioactive source is placed in close proximity to the target volume. It can be placed into the tumor itself (interstitial) or superficially, and radiation is delivered at a continuously low rate. Because the radiation is confined, there is less risk to surrounding structures, but this method is limited by the volume of the tumor and the extent of needed coverage. RT can be given as definitive, adjuvant, or palliative treatment. Definitive treatment doses are generally 66–70 Gy (over 6–7 weeks). Postoperative doses are generally 60–66 Gy.
Surgery
The role of surgery is recognized in current American Joint Cancer Committee staging for various subsites of HNC. Stage T4b represents unresectable disease; this is defined anatomically and includes encasement of the carotid, intracranial extension, or invasion of the prevertebral fascia, skull base, pterygoid plates, masticator space, or mediastinal structures. Surgical planning must account for anticipated functional effects to limit treatment morbidity.
Overview of Head and Neck Cancer
The incidence of HNC increases with age and is more common in men, with male to female ratios ranging from 2:1 to 15:1, depending on the site of HNC (Mehanna et al. 2010a). The major risk factors are alcohol and tobacco, including smokeless forms. Alcohol and tobacco account for 75% of cases of HNC, and are both independent and synergistic risk factors (Conway et al. 2009). Quitting smoking for 1–4 years reduces the risk of HNC, with further benefit at 20 years, at which point the risk is similar to that associated with never smoking. Similarly, quitting alcohol for 20 or more years confers the same benefit as never drinking (Marron et al. 2010). A genetic predisposition is suggested: HNC in a first-degree relative confers a 1.7-fold increased risk (Conway et al. 2009). This may be related to the metabolism of tobacco and alcohol (Mehanna et al. 2010a).
Another risk factor of HNC is viral infection. Eighty percent to 90% of patients with non-keratinizing nasopharyngeal cancer have been found to have abnormally elevated antibody titers to Epstein Barr virus proteins. More recently, human papilloma virus (HPV) has been associated with oropharyngeal carcinoma; patients whose tumors are HPV-positive have a significantly higher overall survival rate than those whose tumors are not (Ang et al. 2010).
Treatment and Survival
Oral Cavity
Oral cavity cancer is a surgical disease. Surgery is the mainstay of treatment for all stages and postoperative RT is recommended for histologic evidence of perineural invasion, lymphovascular invasion, positive margins, cartilage or bone invasion, or nodal disease. If there is extracapsular extension, then postoperative chemoradiation is recommended. Reconstruction may range from healing by secondary intent to free flap reconstruction, depending on the extent of resection. If the patient cannot have surgery (e.g., because of comorbid illness), definitive RT may be considered, with chemotherapy for advanced disease. The 5-year overall survival rates for patients with stages I-IV disease are 75–95%, 65–85%, 45–65%, and 10–35%, respectively.
Oropharynx
In recent decades, treatment of oropharyngeal cancer has trended towards definitive RT, largely because of similar survival outcomes between patients who undergo surgery and those who undergo definitive RT, with the expectation of superior function after nonsurgical organ preservation. Chemotherapy is given in the neoadjuvant setting for bulky or low cervical adenopathy, or for large tumors. Concurrent chemoradiation is indicated for large (T3 or T4) tumors or N2 or N3 adenopathy. The role of surgery was largely salvage until recent endoscopic and robotic advances enabled minimally invasive approaches to select early-stage tumors. The 5-year overall survival rates for patients with stages I-IV disease are 67%, 46%, 31%, and 32%, respectively (Seikaly and Rassekh 2001). Patients with HPV-positive tumors have better prognoses, with 3-year overall survival rates of 82.7% compared with 57.1% in patients with HPV-negative tumors (Ang et al. 2010).
Nasopharynx
The primary treatment for nasopharyngeal cancer is definitive RT, with concurrent chemotherapy for large primary tumors or N2/N3 cervical adenopathy. Induction chemotherapy is considered for patients with large primary tumors or bulky or low adenopathy. The role of surgery is largely salvage. For patients with stage I-IV disease, 5-year overall survival rates are approximately 70%, 60%, 60%, and 40%, respectively.
Hypopharynx/Larynx
The management of hypopharyngeal and laryngeal cancers largely depends on what treatment will best maintain function. Early-stage tumors are generally managed with single-modality treatment (definitive RT or surgery) and late-stage tumors are managed with either concurrent chemoradiation or surgery with postoperative RT. Induction chemotherapy is considered for bulky tumors or adenopathy. Five-year disease-free survival rates for patients with stage I-IV laryngeal cancer are 84–90%, 83–85%, 73–75%, and roughly 45%, respectively.
Posttreatment Surveillance
Posttreatment surveillance serves the purpose of detecting recurrences and second primary tumors. In addition, it benefits patients’ psychological and emotional well-being and addresses functional rehabilitation (Manikantan et al. 2009). Overall, HNC recurrences are reported for 33–49% of patients (Boysen et al. 1992; de Visscher and Manni 1994), with 76% and 87% of recurrences presenting within the first 2 and 3 years after treatment, respectively (Boysen et al. 1992). The rate of second primary tumors is roughly 15% (de Visscher and Manni. 1994); most arise within the UADT, more commonly in the oral cavity, oropharynx, and hypopharynx than in the larynx, although lung second primary tumors are also prevalent.
The National Comprehensive Cancer Network recommends a history and physical examination every 1–3 months for the first year, every 2–4 months for the second year, every 4–6 months for years 3–5, and every 6–12 months thereafter. At MD Anderson, we follow HNC patients every 3 months for the first year, every 4 months for the second year, and every 6 months for the third year. For patients in whom recurrence is of particular concern, closer monitoring is undertaken. Posttreatment imaging, when indicated, is obtained within 3 months of completing treatment and at indicated intervals thereafter. If the patient has been irradiated, thyroid function studies are drawn with every visit because post-RT hypothyroidism may occur any time between 4 weeks and 10 years after treatment. Chest imaging is obtained at least annually for detection of second primary tumors or distant metastases. Because the overwhelming majority of recurrences occur within the first 3 years of treatment, patients are referred to a HNC survivorship program after 3 years of uneventful surveillance.
The foundation of long-term surveillance is composed of symptom management and complete physical examination. This involves the examination of both ears, looking specifically for middle ear fluid, and a full cranial nerve examination. Direct inspection of the oral cavity (all sides of the oral tongue, floor of mouth, hard palate, and buccal, gingival, and labial surfaces), soft palate, and tonsillar fossae should be performed. The tongue base, tonsillar fossae, and any concerning findings should be palpated. If the examining physician is comfortable with indirect mirror laryngoscopy or nasopharyngoscopy, one of these should be undertaken. Cervical palpation for adenopathy or thyroid masses must be included. Worsening pain, dysphagia, or dysphonia are symptoms that warrant further investigation or referral to the treating team. Axial imaging may be helpful in cases in which the region of concern cannot be examined or in which anatomy has been so altered as to render adequate examination difficult.
Upper Aerodigestive Tract Function and Head and Neck Cancer
Normal Function
HNC has the potential to adversely affect a number of complex UADT functions, including respiration, speech, and swallowing. During normal respiration, the laryngopharynx serves as a conduit for air exchange between the upper and lower airways. Pulmonary airflow through the larynx also serves as the power source to generate vibratory sound production as the TVFs adduct during phonation. This phonatory signal resonates throughout the vocal tract and is shaped into words by the articulators in the oral cavity (i.e., the lips, tongue, and teeth). Normal deglutition is commonly described in four phases: (1) oral preparatory, (2) oral, (3) pharyngeal, and (4) esophageal. In the oral preparatory phase of swallowing, food or liquid is taken into the mouth and manipulated into a cohesive bolus that is then propelled posteriorly to the pharynx by the tongue during the oral phase of swallowing. Two primary actions occur in the pharyngeal phase of swallowing: (1) laryngeal closure to prevent tracheal aspiration, and (2) bolus propulsion to the esophagus via tongue base retraction and pharyngeal contraction.
Long-Term Effects of Treatment
Long-term effects of treatment for HNC vary depending on the primary site of disease and treatment regimen. In general, surgical resection affects function by anatomically or structurally altering the UADT. The local effects of surgical resection are related to the normal function of the resected structures and the volume of the resection. For instance, the lingual defect after glossectomy impairs articulation, bolus formation, and lingual pressures to assist with bolus propulsion during swallowing. Resection of the supraglottic larynx disrupts normal airway closure during swallowing and increases the risk of aspiration, whereas total laryngectomy results in complete loss of voice (aphonia), requiring various methods of alaryngeal voice restoration. In addition, emerging experience suggests a functional advantage of using minimally invasive approaches, such as endoscopic or robotic resection, rather than traditional open approaches that disrupt adjacent normal tissue will leave patients with better function.
Fibrosis has long been considered a primary source of late functional complications after RT. The fibrotic process is self-inducing and may spread to adjacent regions, causing chronic, often progressive symptoms. In addition, denervation of oral, pharyngeal, or laryngeal structures may occur as a result of direct neural infiltration by the tumor, chemotoxicity, iatrogenic surgical injury, or as a late effect of RT. Roughly half of survivors who present with late, refractory radiation-associated dysphagia have de novo cranial neuropathies, most commonly X and XII, years after treatment. In addition, preliminary data from the National Institutes of Health Laryngeal Study Section found at least partial denervation of suprahyoid musculature on electromyography in most (>90%) nonsurgical HNC patients with chronic dysphagia after RT or chemoradiation (Martin et al. 2010). The pathophysiology of peripheral motor neuropathy after RT is not fully understood, but devascularization and compressive injury from adjacent fibrosis is most commonly suggested.
Lymphatic insufficiency is a common consequence of surgery and RT. Blockage, damage, or removal of lymph vessels results in abnormal accumulation of interstitial fluid or lymphedema. In early stages, lymphedema is associated with a soft swelling. Lymphedema can progress in later stages to a hard, fibrotic process. This under-recognized complication of treatment for HNC is often thought to be a cosmetic issue, but the potential functional implications of chronic lymphedema are increasingly recognized (Smith and Lewin 2010).
Dysphagia
Denervation and fibrosis of the oral, laryngeal, and pharyngeal musculature may occur or persist long after the completion of treatment for HNC. These late effects ultimately impair range of motion of key swallowing structures and have been implicated as the primary mechanisms of chronic dysphagia in HNC survivors. In severe cases of chronic dysphagia, dietary restrictions and malnutrition mandate lifelong gastrostomy tube dependence. HNC survivors may also experience aspiration of food and liquids, posing a risk for potentially life-threatening aspiration pneumonia (Rosenthal et al. 2006). A variety of metrics are used to estimate the burden of dysphagia in HNC survivors, and rates depend greatly on the specific subsite of disease and treatment modality. The prevalence of aspiration in long-term HNC survivors reported in the literature ranges from 23% (stage III/IV HNC treated with chemoradiation) to 44% (all sites, stages, and treatment modalities; Campbell et al. 2004; Rütten et al. 2011), whereas rates of chronic gastrostomy dependence (>2 years after treatment) are typically lower (6–22%; Ang et al. 2005; Cheng et al. 2006). Neither aspiration nor gastrostomy rates should be considered sensitive indicators of the presence of dysphagia; many HNC survivors maintain oral intake despite significant physiologic swallowing impairment and aspiration.
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