Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

9. Hypopharynx and Larynx

David P. Horowitz • Micah Berman • Tony J. C. Wang • K. S. Clifford Chao

Hypopharynx and Larynx Cancer – Highlights

Key Recent Clinical Studies

Forastiere et al. (JCO 2012) reported the long-term results of RTOG 91-11; with 10.8 years median follow-up, concomitant cisplatin and radiotherapy had a significantly higher rate of locoregional control and larynx preservation than observed with induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation. Both chemotherapy groups showed improved laryngectomy-free survival as compared to radiation alone. (PMID 23182993)

Prades et al. (Acta Otolaryngol 2010) reported their phase III trial comparing induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation to concurrent cisplatin and radiation in patients with T3M0 pyriform sinus cancer. At 2 years, laryngeal preservation was significantly higher in the concurrent chemoradiotherapy arm. (PMID 19449227)

New Target Delineation Contours

FIGURE 9-9. CTV1, CTV2, and CTV3 delineation in a patient with clinically T3N3M0 squamous cell carcinoma of the right pyriform sinus who received definitive IMRT with concurrent chemotherapy. Multiple ipsilateral lymph nodes were delineated, including bulky level II nodes.

1. ANATOMY

1.1. Hypopharynx

• The hypopharynx or laryngopharynx is the most inferior portion of the pharynx. It extends from the level of the hyoid bone, the base of the vallecula, and pharyngoepiglottic folds, to the esophageal inlet and cricopharyngeus at the plane of the lower border of the cricoid cartilage (Fig. 9-1). It communicates with the oropharynx via the esophageal inlet.

• The larynx indents the anterior wall of the hypopharynx to form a horseshoe-shaped hollow cavity. This creates a central aerodigestive passageway and two lateral fossae (i.e., the pyriform sinuses) (Fig. 9-2). In this way, the hypopharynx is lateral to and behind the larynx.

• The hypopharyngeal walls are composed of four layers of tissue: mucosa, fibrous fascia, a muscular layer, and areolar coat. The epithelium of the pharyngeal mucous membrane is squamous and continuous with the nasopharyngeal epithelial membrane. There is no visible transitional zone between these two regions. However, whereas the hypopharynx is lined exclusively with stratified squamous cells, the nasopharynx is lined with a mixture of pseudostratified ciliated columnar cells and stratified squamous cells. These differences have importance in the type and differentiation of malignancies occurring in various parts of the pharynx.

• Beneath the mucous membrane of the posterior and lateral pharyngeal walls is a thin muscular layer. This muscular layer of the hypopharynx is composed of two paired constrictor muscles: the middle and the inferior constrictors. These muscles attach anteriorly to the hyoid bone and thyroid cartilage and fuse posteriorly with each other.

• The inferior constrictor muscle has two specialized divisions. The first is the cricopharyngeus muscle, which is composed of the lowermost fibers and the sphincteric guardian of the esophagus. The second part forms the cricothyroid muscle, which is the tensor of the vocal folds. This muscle inserts into the thyroid cartilage. The external branch of the superior laryngeal nerve innervates the cricothyroid muscle.

• Between the constrictor muscles and the prevertebral fascia that covers the longitudinal spinous muscles is a thin layer of loose areolar tissue called the retropharyngeal space. This is a potential space that may act as a potential route of spread for both infection and malignancy.

• The areolar layer contains the vessels, nerves, and lymphatics that lie laterally to the pharyngeal walls in a potential parapharyngeal space of loose connective tissue surrounded by the deep cervical and visceral fascia.

• Clinically, the hypopharynx is separated from the other parts of the pharynx by anatomic landmarks (Fig. 9-1). Its superior border is defined at the level of the hyoid bone, and includes the lateral and posterior pharyngeal walls and the pharyngoepiglottic folds. It extends inferiorly through the pyriform fossae, through the postcricoid region and ends at the level of inferior aspect of the cricoid.

• The hypopharynx is also subdivided into three clinical regions: the pyriform sinuses laterally, the posterolateral pharyngeal walls, and the postcricoid region. The posterior border of the larynx forms the postcricoid region, extending from the arytenoid down to the level of the inferior aspect of the cricoid. The pyriform sinuses lie lateral to the larynx. The medial wall is formed by the aryepiglottic fold and the lateral laryngeal wall (cricothyroid muscle). The anterior and lateral walls are formed by the thyroid cartilage and thyrohyoid membrane.

• The posterior and lateral hypopharyngeal walls are continuous with those of the oropharynx without a clear anatomic separation. The lateral border of the epiglottis, the lateral surface of the aryepiglottic folds, and lateral laryngeal wall compose the medial wall of the hypopharynx. The medial wall of the pyriform sinus is often considered a marginal zone.

• The anterior border of the hypopharynx is the postcricoid region, which extends from the interarytenoid area and cricothyroid muscle. The inferior border is at the inferior edge of the pharyngeal aponeurosis and its cricopharyngeal ligament. The postcricoid region abuts the dorsal surface of the cricoid lamina.

• The posterior wall is open and communicates with the hypopharyngeal lumen. The posterior and lateral walls merge with the cricopharyngeus caudally, which in turn merges with the cervical esophagus.

• The pyriform sinus apex is variable and extends beyond the level of the vocal cords, and occasionally below the cricoid cartilage. Tumors that extend to the pyriform sinus apex or postcricoid area, therefore, are not amenable to voice conservational surgical procedures.

• The arterial supply of the hypopharynx is mainly from divisions of the external carotid system: the ascending pharyngeal arteries, superior thyroid arteries, and branches from the lingual artery. A venous plexus drains the pharynx and communicates with the internal jugular vein via the superior and inferior thyroid veins.

• The lymphatics generally travel cephalad through the thyrohyoid membrane toward the upper deep cervical lymph nodes and then enter the jugulodigastric lymph nodes and the upper and middle jugular chain.

• There is also free communication with the spinal accessory lymph nodes and retropharyngeal lymph nodes; in this group, the highest nodes (Rouviere) are at the skull base. This close proximity of the lymphatics to the mucosa partly explains the high incidence of early metastases.

FIGURE 9-1. Hypopharynx and larynx in sagittal section. (From Anatomical Chart Company copyright © 2008, Lippincott Williams & Wilkins. All rights reserved.)

FIGURE 9-2. Internal pharynx, posterior view. (From Agur AMR, Dailey AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:791.)

• The lowest portions of the hypopharynx (the postcricoid region, pyriform apex, and inferior hypopharynx) can drain into a lymphatic chain that follows the recurrent laryngeal nerve to the paratracheal, paraesophageal, and supraclavicular nodes.

• The motor neural supply of the hypopharyngeal muscles is primarily from the pharyngeal plexus of nerves, which are motor-neural fibers from the glossopharyngeal (IX) and vagus (X) nerves. It also receives partial innervation from the spinal accessory nerve (XI) and the sympathetic plexus.

• The inferior hypopharynx is innervated by branches from the recurrent laryngeal nerve (X). Efferent pain fibers traveling with the internal branch of the superior laryngeal nerve through the auricular branch of the vagus (nerve of Arnold) to the ipsilateral ear cause a usually ill-defined, dull pain in the superior–posterior wall of the external auditory canal or the posterior skin of the pinna.

1.2. Larynx

• The larynx is divided into the supraglottic (epiglottis, false vocal cords, ventricles, aryepiglottic folds, arytenoids), glottic (true vocal cords, anterior commissure), and subglottic (located below the vocal cords) regions1 (Fig. 9-3).

FIGURE 9-3. Coronal section of larynx showing the compartments of the larynx, the vestibule, middle compartment with left and right ventricles, and the intraglottic cavity. (From Moore KL, Dalley AF II. Clinically Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins 1999.)

• The lateral line of demarcation between the glottis and supraglottic larynx clinically is the apex of the ventricle. The demarcation between the glottis and subglottis is ill-defined, but the subglottis is considered to begin 5 mm below the free margin of the vocal cord and to end at the inferior border of the cricoid cartilage and the beginning of the trachea (Fig. 9-4).

• The supraglottic larynx is composed of the epiglottis, false vocal cords, ventricles, and laryngeal surface of the aryepiglottic folds and arytenoids.

• The epiglottis is fibroelastic cartilage that extends from above the hyoid bone at its superior margin to an attachment at the thyroid cartilage inferiorly via the petiole and thyroepiglottic ligament. The laryngeal portion of the epiglottis is fenestrated, which provides little resistance to tumor invasion. The epiglottis attaches anteriorly to the hyoid bone via the hyoepiglottic ligament. The free edge of the epiglottis, the hyoepiglottic ligament, and the aryepiglottic folds form the superior margin of the supraglottic larynx.

• The epiglottis and arytenoids are joined together on either side, anteriorly to posteriorly, by the quadrangular membrane. The superior free aspect of this membrane forms the aryepiglottic fold, and the lower free aspect forms the false vocal cord.

• The ventricle is the space between the false vocal cords and the true vocal cords, which can be difficult to accurately assess on flexible laryngoscopy.

• The glottic larynx is composed of the true vocal cords and anterior commissure. The vocal cords extend from the bilateral arytenoids anteriorly and converge anteriorly at the anterior commissure, which attaches to the thyroid cartilage.

FIGURE 9-4. Larynx, posterior view. (From Anatomical Chart Company copyright © 2008, Lippincott Williams & Wilkins. All rights reserved.)

• Histologically, nearly the entire larynx is covered with ciliated pseudostratified columnar epithelium. The superior portion of the supraglottic larynx, including the suprahyoid part of the epiglottis and parts of the aryepiglottic folds, is lined by stratified squamous epithelium.

• The cartilage of the larynx—the thyroid, cricoid, and arytenoid cartilages—ossify to varying degrees over time. Ossification of these cartilages can make them more prone to direct tumor invasion.

• The recurrent laryngeal nerve, which is a branch of the vagus nerve, innervates the intrinsic muscles of the larynx. A branch of the superior laryngeal nerve supplies the cricothyroid muscle, an extrinsic muscle responsible for tensing the vocal cords (Fig. 9-5). Isolated damage to this nerve causes a bowing of the true vocal cord, which continues to be mobile, but the voice may become hoarse.

• The supraglottic structures have a rich capillary lymphatic plexus. The trunks pass through the pre-epiglottic space and thyrohyoid membrane and terminate mainly in the subdigastric lymph nodes; a few drain to the middle internal jugular chain lymph nodes.

• There is essentially no lymphatic supply to the true vocal cords. Lymphatic spread from glottic cancer occurs only if tumor extends to the supraglottic or subglottic areas.

• The subglottic area has relatively few capillary lymphatics. The lymphatic trunks pass anteriorly through the cricothyroid membrane to the pretracheal (Delphian) lymph nodes in the region of the thyroid isthmus. The subglottic area also drains posteriorly through the cricotracheal membrane, with some trunks going to the paratracheal lymph nodes and others continuing to the inferior jugular chain.

FIGURE 9-5. External view of the larynx. (From Anatomical Chart Company copyright © 2008, Lippincott Williams & Wilkins. All rights reserved.)

2. NATURAL HISTORY

2.1. Hypopharynx

• In the United States, hypopharyngeal tumors occur with the following decremental frequency: pyriform sinus (65% to 70%), postcricoid (20%), and hypopharyngeal wall (10% to 15%).2

• Medial wall pyriform sinus tumors, the most common group, may spread along the mucosal surface to involve the aryepiglottic folds (the most common pattern). They sometimes invade medially and deeply into the false vocal folds and larynx via the paraglottic space (Fig. 9-6). Involvement of the paraglottic space allows a lesion to behave as a transglottic carcinoma.3

• Cancers of the lateral wall and apex of the pyriform sinus commonly invade the thyroid cartilage and, less frequently, the cricoid cartilage.

• Once they penetrate the constrictor muscle, tumors can spread along the muscle and fascial planes to the base of the skull (the origin and suspension of the constrictor muscles) and along the neurovascular planes following the vagus, glossopharyngeal, and sympathetic nerves.

• Postcricoid area tumors commonly invade the cricoid cartilage, interarytenoid space, and posterior cricohyoid muscle to produce hoarseness4 Because of the tendency for early esophageal spread, some have suggested that these epiesophageal tumors are not hypopharyngeal in origin.5

• The abundant lymphatics of the hypopharynx, coupled with extensive primary disease at presentation, account for the high incidence of metastases to the regional lymph nodes (Table 9-1).

• The mid-cervical lymph nodes are most commonly involved. The incidence of metastases varies according to the site and origin in the hypopharynx (Tables 9-2 and 9-3).6

• The contralateral subdigastric nodes are the most common site harboring metastatic disease.

• Occult disease occurs irrespective of T stage in pyriform fossa tumors, with an incidence of 60% for T1 and T2, and 84% for T3 and T4 disease.2

FIGURE 9-6. Axial CT sections of a T4N1 squamous cell carcinoma of the pyriform sinus (arrows).

• In 3,419 patients, the most common metastatic site was in level II (69%), and survival decreased as the level of metastases went from level II (39% survival) to the supraclavicular region (level IV, 21% survival).7

• Pathologically confirmed node metastases decreased survival by 26% to 28% (N0 vs N+), and size of nodal disease decreased survival by an additional 12% to 18% (N1 vs N2 and N3).8,9 There is a decremental survival rate with progressive nodal disease (N0, 57%; N1, 28%; N2, 6%; N3, 0%) and a higher neck recurrence rate with progressively larger neck metastases (N0, 20%; N1, 37%; N2, 48%; N3, 83%).10

• Approximately 5% to 15% of presenting cases require an emergency tracheotomy.

• On rare occasions, direct tumor involvement or lymph node extension to the hypoglossal nerve may produce ipsilateral tongue paralysis.

2.2. Larynx

• Cancer of the larynx represents about 2% of the total cancer risk and is the most common head-and-neck cancer (skin excluded).

• The ratio of glottic to supraglottic carcinoma is approximately 3:1.

• Cancer of the larynx is strongly related to cigarette smoking. The risk of tobacco-related cancers of the upper alimentary and respiratory tracts declines among ex-smokers after 5 years and approaches the risk of nonsmokers after 10 years of abstention.11

2.2.1. Supraglottic Larynx

• Destructive suprahyoid epiglottic lesions tend to invade the vallecula and pre-epiglottic space, lateral pharyngeal walls, and the remainder of the supraglottic larynx.

• Infrahyoid epiglottic lesions grow circumferentially to involve the false cords, aryepiglottic folds, medial wall of the pyriform sinus, and the pharyngoepiglottic fold. Invasion of the anterior commissure and cords and anterior subglottic extension usually occur only in advanced lesions.

• Extension of false cord tumors to the lower portion of the infrahyoid epiglottis and invasion of the pre-epiglottic space are common.

• It may be difficult to decide whether aryepiglottic fold/arytenoid lesions started on the medial wall of the pyriform sinus or on the aryepiglottic fold. Advanced lesions invade the thyroid, epiglottic, and cricoid cartilages and eventually invade the pyriform sinus and postcricoid area.

• Disease spreads mainly to the subdigastric nodes.

• The incidence of clinically positive nodes is 55% at the time of diagnosis; 16% are bilateral.12

• Table 9-4 summarizes the clinically detected nodal metastases (%) on admission by T stage for supraglottic laryngeal carcinoma.

• Elective neck dissection reveals pathologically positive nodes in 26% of cases. Observation of initially node-negative necks eventually identifies the appearance of positive nodes in 33% of cases13,14 (Table 9-5).

• Table 9-3 summarizes the incidence and distribution of metastatic disease in clinically negative (N−) and positive (N+) neck nodes for supraglottic laryngeal carcinoma patients.

• The risk of late-appearing contralateral lymph node metastasis is 26% if the ipsilateral neck is pathologically positive (Table 9-6).15

2.2.2. Glottic Larynx

• At diagnosis, about two-thirds of tumors are confined to the true vocal cords, usually one cord. The anterior portion of the cord is the most common site.

• Subglottic extension may occur by simple mucosal surface growth, but it more commonly occurs by submucosal penetration beneath the conus elasticus. One centimeter of subglottic extension anteriorly or 4 to 5 mm of extension posteriorly brings the border of the tumor to the upper margin of the cricoid, exceeding the anatomic limits for conventional hemilaryngectomy.

• Advanced glottic lesions eventually penetrate through the thyroid cartilage or via the cricothyroid space to enter the neck, where they may invade the thyroid gland.

• In carcinoma of the vocal cord, the incidence of clinically positive lymph nodes at diagnosis approaches 0% for T1 lesions and 1.7% for T2 lesions. The incidence of neck metastases increases to 20% to 30% for T3 and T4 lesions.16

3. DIAGNOSIS AND STAGING SYSTEM

3.1. Signs and Symptoms

3.1.1. Hypopharynx

• Early pharyngeal tumors generally produce a mild, nonspecific sore throat or vague discomfort on swallowing, which persists for longer than 2 weeks.

• A major neurological finding is referred pain to the ipsilateral ear, which is referred along the internal branch of the superior laryngeal nerve (sensory division to the larynx and hypopharynx) via the vagus nerve (X) to the auricular branch of the vagus nerve (Arnold nerve).

• Dysphagia is produced by bulky tumors, deep constrictor muscle invasion, or prevertebral space invasion of the overlying strap muscles. This finding may be associated with salivary drooling, stiff neck, and a “hot potato” voice. The last finding is especially due to laryngeal or base of tongue invasion.

• Advanced disease causes significant weight loss.

• Hoarseness by invasion of larynx, blood streaked saliva, airway obstruction, halitosis, and nasal voice are other signs and symptoms that can be seen in hypopharyngeal cancers.

3.1.2. Larynx

• Hoarseness is the initial symptom of carcinomas arising on the true vocal cords. Advanced lesions of vocal cords may cause sore throat, referred ear pain through the vagus nerve (CN X) to the auricular nerve of Arnold, pain localized to thyroid cartilage, and airway obstruction.

• Hoarseness is not a prominent sign for supraglottic lesions. Mild odynophagia is the most frequent initial symptom. Early epiglottic lesions may not present with any signs or symptoms. A mass in the neck may be the first sign of supraglottic lesions. Weight loss, halitosis, dysphagia, and aspiration are late symptoms.

3.2. Physical Examination

3.2.1. Hypopharynx

• The initial history collection and physical examination should include indirect laryngoscopy and a flexible endoscopic examination under topical anesthesia. Posterior pharyngeal wall lesions may be missed during indirect laryngoscopy. The pyriform sinus may be better visualized upon phonation or during the Valsalva maneuver.

• Medial pharyngeal wall tumors can directly invade into the larynx, so assessment of vocal cord mobility is especially important.

3.2.2. Larynx

• Rigid and flexible fiberoptic endoscopes are routinely used with laryngeal mirrors for examination.

• Determination of the mobility of the vocal cords may require multiple examinations.

• Ulceration of the infrahyoid epiglottis or fullness of the vallecula is an indirect sign of pre-epiglottic space invasion. Palpation of firm fullness above the thyroid notch with widening of the space between the hyoid and thyroid cartilages also may be a sign of pre-epiglottic space invasion.

• Tumor may penetrate the thyroid ala and be felt as a subcutaneous mass, suggesting thyroid cartilage invasion.

3.3. Imaging

3.3.1. Hypopharynx

• Radiologic evaluation includes chest X-ray and computed tomography (CT) scan with contrast of the head and neck region, which are helpful in delineating cartilage and bone invasion by tumor, as well as extralaryngeal and paraglottic tumor invasion.

• In most cases, delineating the inferior border of the lesion and involvement of the esophageal inlet requires a barium swallow, including a video to evaluate the hypopharynx and cervical esophagus.

• Magnetic resonance imaging (MRI) can clearly distinguish the pharyngeal muscles from the mucosa and the lymphoid tissue lining the inner wall of the hypopharynx.

• The thickness of the posterior and lateral pharyngeal walls seen on MRI is usually less than 3 mm. If it reaches its upper limits, it can be a sign of pathologic change.

• The pharyngeal constrictor muscles are relatively easy to distinguish from the mucosal lymphoid tissue on T2-weighted MRI.

• The penetration points of pharyngeal vessels are easily visible on CT and MRI. They are extremely important places, since they may provide early perineural and perivascular spread routes of tumor to the extrapharyngeal soft tissues.

• The constrictor muscle fascia is normally not visible as a separate layer either on CT or MRI, but inflammatory or other invasive changes may cause the fascia to become pathologically visible.

• A small amount of fat is normally seen just lateral to the lateral pharyngeal wall in the deep neck in all patients. Similarly, prevertebral muscles are visible in all patients on axial CT or MRI; however, the prevertebral fascia is not normally visible. The potential retropharyngeal space is located between the constrictor fascia and prevertebral fascia.

• The space lateral to the pharynx is referred to as the parapharyngeal space above the level of the hyoid bone.

• The retropharyngeal lymph nodes are located between the posterolateral corners of the pharynx and the carotid artery from the tip of the clivus to the C3 (hyoid) level.

• The degree of distention of the pyriform sinus seen on MRI or CT varies from side to side in any given individual and, more widely between patients, depending on their anatomy and the study technique. Any thickness on the surface of the pyriform sinus usually represents some type of pathology.

• Imaging can particularly show the deep anatomical relationships of the pyriform sinus apex. The mucosa of the pyriform sinus apex is always seen as a thin line that merges medially with the mucosa in the postcricoid region.

• The postcricoid region is easily visible as the zone posterior to the cricoid cartilage where the constrictor muscle thickens to create the cricopharyngeus muscle. The lumen is not usually distended with air. Since the pharyngeal lumen is typically collapsed, the mucosa on enhanced CT or MRI is normally visible as parallel lines 1 mm or less in thickness lying along the inner borders of the cricopharyngeus muscle.

3.3.2. Larynx

• The neck should be slightly hyperextended, and the plane of section for laryngeal studies must be parallel to the true vocal cords with a slice thickness of no more than 3 to 4 mm. Occasionally, 1.5- to 2-mm slice thickness can be used for the false vocal cord, true vocal cord, and subglottic region, where a 2- to 3-mm tumor extension might make a difference in treatment approach.

• T1 lesions of the true vocal cord usually require no imaging. Any tumor that is suspicious for deep invasion should be primarily studied with CT. MRI can be better for detection of cartilage invasion. The variation in ossification of the cartilages makes interpretation difficult. In any case, however, both CT and MRI have limited capability in identifying subtle cartilage invasion.

• CT can distinguish extralaryngeal extension of the primary tumor from a lymph node mass and can define extension to the thyroid gland and other adjacent structures.

• CT is the preferred baseline examination for the detection of recurrence in the neck or postirradiation larynx.

3.4. Staging

• The American Joint Committee on Cancer (AJCC) issued new TNM guidelines for cancer of the hypopharynx and the larynx in 2010 (Edge et al).115 The new guidelines divide T4 lesions into two subgroups, T4a and T4b, for moderately advanced and very advanced disease, respectively. Readers should consult the new AJCC manual for details.

4. PROGNOSTIC FACTORS

4.1. Hypopharynx

• Age: Survival progressively declines with increasing age.

• Gender: Women have a significantly higher survival rate, 3 to 20 years, after therapy.

• Surgical Margin: Pathologic findings in pyriform sinus tumors that adversely affect survival are positive surgical margins or tumor persistence in the irradiation field after initial definitive therapy.

• Location: Tumor location influences cure rates. A decremental rate of survival for hypopharyngeal carcinomas is associated with tumor sites in the following order: pyriform sinus, pharyngeal walls, and postcricoid region.17Aryepiglottic fold and medial wall pyriform sinus tumors are usually smaller and more localized, which leads to higher cure rates than observed for postcricoid and pharyngeal wall tumors. The poorest results are seen with pyriform apex, postcricoid, and two- or three-wall tumors.

• Neck Metastasis: In pyriform sinus and aryepiglottic fold tumors, lymph node metastases reduce the cure rate by 28% and 26%, respectively. The presence of extracapsular tumor spread in the cervical lymph nodes and soft tissues of the neck is of paramount importance in survival.18,19 The presence of neck metastases also influences survival.

• The Size and Number of Neck Node Metastases: The size or number of metastases influences survival (higher for N1 than for N2 and N3) by an additional 12% to 18%.9

• T Stage: T stage influences survival. Most patients present with large tumors (82% are T3 or T4 pyriform sinus cancers).20 In pyriform sinus tumors, there is a significant decrease in cure rates for T3 and T4 disease (T1 and T2 exceed T3 and T4 by 28%).20

4.2. Larynx

• T Stage: T stage is the most important prognostic factor determining local control.

• N Stage: N stage is an important prognostic factor for predicting distant metastasis and survival.

• Gender: Female patients generally have better survival rates than seen in males.

• HPV Status: High-risk HPV is commonly found in laryngeal squamous cell carcinoma and benign laryngeal lesions.21 Analysis of a cohort of 79 patients with laryngeal cancer showed no association of HPV status with survival.22

• Subglottic extension is associated with decreased local control.23

5. GENERAL MANAGEMENT

5.1. Hypopharynx

• The best treatment for hypopharyngeal carcinoma is the one that achieves the highest locoregional control rate with least functional damage.

• The functions that need to be preserved include respiration, deglutition, and phonation, if possible, with the least risk to the host and without the use of permanent prosthetic devices.

• Most T1N0 and selected T2N0 lesions can be treated equally well with curative irradiation or conservation surgery. Invasion of the larynx by a pyriform fossa tumor with vocal cord fixation predicts a poor outcome to curative irradiation.

• Larger lesions and neck metastases require combined surgical resection and adjuvant radiation therapy.

• Treatment outcomes for hypopharyngeal cancer are summarized in Tables 9-79-8, and 9-9.

5.1.1. Surgical Management

• Contraindications for larynx conservation surgery include the following: transglottic extension, cartilage invasion, vocal fold paralysis, pyriform apex invasion, postcricoid invasion, and extension beyond the laryngeal framework.

• In all cases, at a minimum, an ipsilateral neck dissection is performed (functional, modified, or radical resection), which is almost always followed by postoperative irradiation.

• Tumors of the aryepiglottic fold are resected with an extended subtotal supraglottic laryngectomy and neck dissection if they fulfill the resection criteria of no extension beyond the larynx, transglottic extension, or vocal cord paralysis.

• Extension into the base of the tongue, epiglottis, and vallecula can be handled by extension of the operative field superiorly to resect these lesions and portions of the base of the tongue.

• Small lesions are amenable to partial laryngopharyngectomy and neck dissection if they are confined to the medial and anterior pyriform fossa walls or aryepiglottic folds, do not extend to the pyriform apex or beyond the larynx, show no postcricoid invasion or vocal cord paralysis or contralateral arytenoid involvement, and occur in patients who do not have pulmonary and cardiac disabilities.

• In patients who do not meet the criteria for conservative surgery, either a total laryngopharyngectomy or a total laryngectomy and partial pharyngectomy with reconstruction with neck dissection are performed.

5.1.2. Irradiation Alone

• Irradiation alone controls a substantial proportion of small surface lesions in the pyriform sinus. In one study of 25 T1 and T2 lesions of the pyriform sinus, 16 (64%) were controlled with irradiation alone (65 to 70 Gy in 7 to 8 weeks).42

• Nakajima et al. reported on 103 patients with T1–2 hypopharyngeal carcinoma treated with definitive radiation. Ninety-one patients had pyriform sinus tumors (83.5% medial wall); 12 patients had posterior wall tumors. T1 tumors were treated with conventional fractionation, and T2 tumors, with accelerated fractionation or concurrent chemoradiotherapy (14% of patients). Three-year locoregional control after RT was 87% for T1 tumors and 83% for T2 tumors. Eighteen patients experienced local recurrence (3 with T1 and 15 with T2); accounting for salvage surgery, final local control rate was 89%. Three patients without local recurrence underwent laryngectomy, giving a laryngeal preservation rate of 82%.32

5.1.3. Surgery and Irradiation

• Higher doses of adjuvant irradiation (60 to 66 Gy) are better delivered postoperatively than preoperatively because preoperative irradiation (usually 45 to 50 Gy in 4.5 to 5 weeks) retards healing of pharyngeal and cutaneous suture lines and may cause more complications than caused by postoperative irradiation.43

• In pyriform sinus tumors, combined therapy had higher cure rates (71%) than observed with surgery (53%) or irradiation (27%). In aryepiglottic fold tumors, combined therapy (68%) had better disease-free results than achieved with surgery (61%) or irradiation (34%) at 5 years.19

• In another study, patients with locally advanced hypopharyngeal cancer were treated with radical resection and reconstruction with an ileocolic free flap followed by chemoradiotherapy. IMRT and 2D radiotherapy were compared, with IMRT providing reduced toxicity, better restoration of phonation, and improved swallowing.44

5.1.4. Chemotherapy

• The European Organization for Research and Treatment of Cancer reported results of combined-modality therapy for head-and-neck cancer: 202 patients with operable, locally advanced squamous cell cancer of the pyriform sinus or the hypopharyngeal aspect of the aryepiglottic fold were randomly assigned to receive treatment with standard surgery and postoperative irradiation or induction chemotherapy (cisplatin and 5-fluorouracil).45

• Patients achieving a clinically complete response (CR) at the primary site after two or three cycles of chemotherapy received organ-sparing treatment with definitive irradiation (70 Gy), while those with less than a CR were treated surgically.

• At a median follow-up of 51 months (range, 3 to 106 months), the estimated survival outcomes for patients randomly assigned to receive induction chemotherapy or surgery were 3-year overall survival of 57% versus 43%, 3-year disease-free survival of 43% versus 31%, and median survival of 44 versus 25 months.

• These differences reflected a trend of improved outcome from chemotherapy and met the statistical criteria for survival equivalence of the two arms. The laryngeal preservation rate was estimated at 42%, considering only deaths from local disease as failure.

5.2. Larynx

• Table 9-10 summarizes the results of different treatment strategies used in laryngeal cancer.

• Thomas et al.46 recently presented a review of 53 studies of laryngeal cancer treated with various conservation surgical methods from 1983 through 2009. For the pooled 5,061 patients, 2-year local control was 89.8%, 2-year overall survival was 79.7%, and 2-year mean disease-free survival was 84.8%. Most of the patients had early-stage disease: of those reporting, there were 1,134 with stage T1, 2,079 with stage T2, 640 with stage T3, and 192 with stage T4 cancer. The authors concluded that partial laryngectomies were a safe option, with favorable outcomes in terms of morbidity and mortality. Local control was comparable to or sometimes better than that in RT.

• Zhang et al.47 reviewed SEER data to compare the outcomes of 13,808 laryngeal cancer patients treated with definitive RT or surgery. Of these, the primary lesion was glottic for 8,891 and supraglottic for 4,917. They noted that patient preference may play a considerable role in survival since many patients are willing to sacrifice survival duration in favor of preservation of speech. They concluded that the increased use of radiation therapy, with its improved speech preservation, had no adverse impact on overall survival.

5.2.1. Vocal Cord Carcinoma In Situ

• Stripping the cord, microexcision, and laser ablation may control carcinoma in situ; however, it is difficult to exclude the possibility of microinvasion in these specimens.

• Recurrence is frequent, and the cord may become thickened and the voice hoarse with repeated stripping.

• We recommend early radiation therapy because most patients with this diagnosis eventually receive this treatment, and earlier use of irradiation means a better chance of preserving a good voice.

• The rate of local control of carcinoma in situ with definitive radiation is similar to that for T1 lesions, and generally ranges from 85% to 100%.

5.2.1.1. Early Vocal Cord Carcinoma

• In most centers, irradiation is the initial treatment for T1 and T2 lesions. Surgery is reserved for salvage after radiation therapy failure.16,71,72

• The local control rate with definitive radiation therapy is about 90% for T1 lesions and 70% to 80% for T2 lesions.

• In a retrospective review of 585 patients treated at the University of Florida with definitive radiation therapy for T1 and T2 glottic larynx tumors, T2b tumors had decreased 5-year local control (74%) as compared to lower-stage tumors. Cause-specific survival and overall survival was similar for T2a and T2b tumors, however.73

• Although hemilaryngectomy or cordectomy produces comparable cure rates for selected T1 and T2 vocal cord lesions, irradiation is generally preferred.74

• Among patients with T2 tumors, there are conflicting data regarding the effect of impaired vocal cord mobility on local control with definitive radiotherapy.

• Zouhair et al. reported on 122 patients with T1N0 and T2N0 squamous cell carcinoma of the glottic larynx treated with radical radiation therapy (median dose 70 Gy). Anterior commissure extension and use of arytenoids protection were associated with decreased local control on multivariate analysis.75

• Use of IMRT in early-stage larynx cancer provides a more ideal dose distribution than those in 3D conformal plans, and allows for reduced dose to the carotid arteries.76,77 Cerebrovascular events are relatively more common in head-and-neck cancer patients treated with radiation, as opposed to surgery, and both carotid stenosis and thrombosis after radiation have been described.7882 Clinical outcomes for these techniques have not yet been reported.

5.2.1.2. Moderately Advanced Vocal Cord Cancer

• Fixed-cord lesions (T3) can be subdivided into relatively favorable or unfavorable lesions.

• Patients with favorable T3 lesions have disease confined mostly to one side of the larynx, have a good airway, and are reliable for follow-up.

• Patients with unfavorable lesions usually have extensive bilateral disease with a compromised airway and are considered to be in the advanced group.

• Patients with favorable lesions are advised of the alternatives to irradiation with surgical salvage or immediate total laryngectomy.83 They must be willing to return for follow-up examinations every 4 to 6 weeks for the 1st year, every 6 to 8 weeks for the 2nd year, every 3 months for the 3rd year, every 6 months for the 4th and 5th years, and annually thereafter.15

5.2.1.3. Advanced Vocal Cord Carcinoma

• The mainstay of treatment is total laryngectomy, with or without adjuvant irradiation.

• Indications for postoperative irradiation include close or positive margins, significant subglottic extension (≥1 cm), cartilage invasion, perineural invasion, extension of primary tumor into the soft tissues of the neck, multiple positive neck nodes, extracapsular extension, and control of subclinical disease in the opposite neck.8486

5.2.1.4. Surgical Treatment

• One entire cord and as much as one-third of the opposite cord is the maximum cordal involvement suitable for hemilaryngectomy in men.

• Women have a smaller larynx and usually only one vocal cord may be removed without compromising the airway.

• The maximum subglottic extension is 8 to 9 mm anteriorly and 5 mm posteriorly. These limits are necessary to preserve the integrity of the cricoid.

• Tumor extension to the epiglottis, false cord, or both arytenoids is a contraindication to hemilaryngectomy.

5.2.1.5. Treatment of Recurrence

• Radiation therapy failures may be salvaged by cordectomy, hemilaryngectomy, or total laryngectomy.

• Biller et al. reported a 78% salvage rate by hemilaryngectomy for 18 selected patients in whom irradiation failed; total laryngectomy was eventually required in two patients.87

• The rate of salvage by irradiation for recurrences or new tumors that appear after initial treatment by hemilaryngectomy is about 50%.

5.2.2. Supraglottic Larynx Carcinoma

5.2.2.1. Early and Moderately Advanced Supraglottic Lesions

• Treatment of the primary lesion for the early group is by external-beam irradiation or supraglottic laryngectomy, with or without adjuvant irradiation.

• For early-stage primary lesions with advanced neck disease (N2b or N3), combined treatment is frequently necessary to control disease in the neck. In these cases, the primary lesion is usually treated by irradiation alone, with surgery added to treat the involved neck site(s). If the same patient was treated with supraglottic laryngectomy, neck dissection, and postoperative irradiation, the portals would unnecessarily cover the primary site and the neck.

• If a patient has early, resectable neck disease (N1 or N2a) and surgery is elected for the primary site, postoperative irradiation is added only in case of unexpected findings (e.g., positive margins, multiple positive nodes, or extracapsular extension).

5.2.2.2. Advanced Supraglottic Lesions

• The surgical alternative for these lesions is total laryngectomy.

• Selected advanced lesions, especially those that are mainly exophytic, may be treated by radiation therapy, with total laryngectomy reserved for irradiation failures.

• Supraglottic laryngectomy is a voice-sparing surgery that can be used successfully for selected lesions involving the epiglottis, a single arytenoid, the aryepiglottic fold, or the false vocal cord.

• Extension of tumor to the true vocal cord, anterior commissure, or both arytenoids, fixation of the vocal cord, or thyroid or cricoid cartilage invasion precludes supraglottic laryngectomy.

• Supraglottic laryngectomy may be extended to include the base of the tongue if one lingual artery is preserved.

• All patients have dysphagia with a tendency to aspirate immediately after surgery, but almost all recover within a short time. Motivation and the amount of tissue removed are key factors in regaining swallowing function.

• Preoperatively, adequacy of pulmonary reserve is evaluated by blood gas determinations, function tests, chest roentgenography, and a work test involving walking the patient up two flights of stairs to determine tolerance to pulmonary stress.

• Voice quality is generally normal after supraglottic laryngectomy.

• Radiation technique and dose are similar to those for glottic tumors; however, because of richer lymphatics in the supraglottic region, regional lymphatics must be treated in tumors >T2 in size.15

• The addition of a neck dissection usually increases the risk of temporary lymphedema; however, it is preferable in terms of tumor control and complications that may arise from higher doses of irradiation required to control large neck nodes.38

5.2.2.3. Postoperative Treatment

• Irradiation is added for close or positive margins, invasion of soft tissues of the neck, significant subglottic extension (≥1 cm), thyroid cartilage invasion, multiple positive nodes, and extracapsular extension.

• The postoperative irradiation dose as a function of known residual disease is as follows: negative margins, 60 Gy in 30 fractions; microscopically positive margins, 66 Gy in 33 fractions; and gross residual disease, 70 Gy in 35 fractions.

• If there is subglottic extension, the dose to the stoma is boosted with electrons (typically 10 to 14 MeV) for an additional 10 Gy in 5 fractions.

5.2.2.4. Comparison of Surgery and Radiation Therapy

• The 659 patients with stage I (T1N0M0) glottic carcinoma treated with curative intent at Washington University, St. Louis, were subdivided into four groups84: 90 patients received low-dose irradiation (mean dose 58 Gy; range 55 to 65 Gy; daily fractionation 1.5 to 1.8 Gy)88; 104 patients received high-dose irradiation (mean dose 66.5 Gy; range 65 to 70 Gy; daily fractionation 2 to 2.25 Gy)89; 404 patients underwent conservation surgery; and 61 patients had endoscopic resection.87 T1A (85%) and TIB (15%) disease were equally distributed among the groups.

• No significant difference in the 5-year cause-specific survival rate was observed among the four therapeutic groups for T1 tumors (P = 0.68). Actuarial survival was significantly lower in the low-dose radiation therapy group as compared with the other three therapeutic groups (P = 0.04). Initial local control was poorer for the endoscopic (77%) and low-dose irradiation (78%) groups as compared with the high-dose irradiation (89%) and conservative surgery (92%) groups (P = 0.02), but significant differences were not found for ultimate local control following salvage treatment. Unaided laryngeal voice preservation was similar for high-dose radiation therapy (89%), conservative surgery (93%), and endoscopic resection (90%), but significantly poorer for low-dose irradiation (80%; P = 0.02).90

• Among 134 patients with stage II glottic carcinomas treated with curative intent and function preservation, 47patients were treated with low-dose radiation therapy (median dose, 58.5 Gy at 1.5- to 1.8-Gy daily fractions), 16 patients with high-dose irradiation (67.5 to 70 Gy) at higher daily fractionation doses (2 to 2.25 Gy), and 71 patients underwent conservation surgery. There were no statistically significant differences in local control, voice preservation, and 5-year actuarial and disease-specific cure rates between the conservation surgery and high-dose irradiation groups (P = 0.89). Patients treated with low-dose irradiation had statistically lower local control, 5-year survival, and voice preservation (= 0.014).91

5.2.2.5. Chemoradiotherapy for Laryngeal Preservation

• The Department of Veterans Affairs Laryngeal Cancer Study Group trial first established the use of chemoradiation as an alternative means of preserving the larynx in advanced laryngeal cancer by demonstrating no significant difference in survival between patients receiving induction chemotherapy followed by radiation therapy versus surgery plus adjuvant radiation.92

• A meta-analysis including patients with locally advanced laryngeal or hypopharyngeal carcinoma compared radical surgery plus radiation therapy with a neoadjuvant combination of cisplatin and 5-fluorouracil followed by irradiation in responders and radical surgery plus radiation therapy in nonresponders. There were 602 patients identified, with a median follow-up of 5.7 years. The pooled hazard ratio (1.19, 0.97 to 1.46) showed a nonsignificant trend (P = 0.1) in favor of the control group, corresponding to an absolute negative effect in the chemotherapy arm that reduced survival at 5 years by 6% (from 45% to 39%). Adjustment for nodal status (N0, N1–3) or tumor subsite (glottic or subglottic versus supraglottic versus hypopharynx) led to similar results. This meta-analysis suggests that because of the nonsignificant negative effect of chemotherapy on the organ-preservation strategy this procedure must remain investigational.93

• The RTOG and Head and Neck Intergroup conducted a multi-institutional randomized trial, RTOG 91-11, for 547 locally advanced laryngeal cancer patients who were randomly assigned to receive induction cisplatin plus fluorouracil followed by radiation, radiation with concurrent cisplatin, or radiation alone. At 2 years, the concurrent regimen preserved the larynx in significantly more number of patients (88%), which was the primary end point, as compared to the induction (75%, P = 0.05) or radiation alone (70%, P < 0.001) groups. Locoregional control was also significantly better with concurrent chemoradiation (P = 0.003), although survival rates were similar in all groups. Moreover, the concurrent group had nearly twice the rate of mucosal toxicity as compared to the other two groups. This trial demonstrates that concurrent chemoradiation with cisplatin plus radiation is the superior modality for preservation of the larynx in advanced laryngeal cancer.94

• Long-term results from RTOG 91-1195 with 10.8-year median follow-up, has shown that concomitant cisplatin and radiotherapy had a significantly higher rate of locoregional control and larynx preservation than found in induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation. Both the induction chemotherapy and the concurrent chemotherapy groups improved the rate of laryngectomy-free survival as compared to the radiation alone group.

• Prades et al.96 conducted a phase III trial comparing induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation to concurrent cisplatin and radiation in patients with T3M0 pyriform sinus cancer. The rate of laryngeal preservation at 2 years was significantly higher in the arm receiving concurrent chemoradiotherapy.

• EORTC 2495497 compared sequential versus alternate chemotherapy and radiotherapy in patients with locally advanced larynx and hypopharynx cancer. Both arms had similar rates of overall survival, progression-free survival, and larynx preservation. Both acute and late toxicities were similar between the groups.

• Table 9-11 summarizes the results of several randomized larynx preservation trials. Lefebvre98 recently published a thoughtful concise review of the existing larynx preservation clinical trials. Previously, consensus guidelines for larynx preservation have been presented by Lefebvre et al.99 and Ang et al.100

6. INTENSITY-MODULATED RADIATION THERAPY IN HYPOPHARYNGEAL AND LARYNGEAL CARCINOMA

6.1. Hypopharynx

6.1.1. Target Volume Determination

• If chemotherapy has been delivered before radiation, the targets should be outlined on the planning CT according to their prechemotherapy extent.

• Lymph node groups at risk in the hypopharynx include the following:

(a) Submandibular nodes (surgical level I): N2c cases or when level II is involved.

(b) Upper deep jugular (junctional, parapharyngeal) nodes: all cases.

(c) Subdigastric (jugulodigastric) nodes, midjugular, lower neck, and supraclavicular nodes (levels II through IV): all cases, bilaterally.

(d) Posterior cervical nodes (level V): all cases, when jugular node is involved.

(e) Retropharyngeal nodes: all cases, if there is evidence of jugular nodal metastases. Allen et al. described lateral retropharyngeal lymph node involvement seen on PET/CT in a patient with T2N1 hypopharyngeal cancer, and surgical series reported that up to 20% of patients with hypopharyngeal cancer had positive retropharyngeal lymph node involvement, even in the absence of other lymphadenopathy.103,104

• The target volume specification for definitive and postoperative IMRT is discussed in Chapter 4.

• Suggested target volume determination for hypopharynx carcinoma is summarized in Table 9-12.

6.1.2. Target Volume Delineation

• In patients receiving postoperative IMRT, clinical target volume 1 (CTV1) encompasses residual tumor and the region adjacent to it but not directly involved by the tumor, the surgical bed with soft tissue invasion by the tumor, or extracapsular extension by metastatic neck nodes. CTV2 includes primarily the prophylactically treated neck.

• In patients receiving definitive IMRT, CTV1 encompasses gross tumor (primary and enlarged nodes) and the region adjacent to it but not directly involved. CTV2 encompasses high-risk areas within the ipsilateral neck. CTV3 includes primarily the prophylactically treated neck.

• GTV, CTV1, CTV2 and CTV3 delineation in a patient with clinical T2N1M0 squamous cell carcinoma of the right pyriform sinus receiving definitive IMRT therapy with concurrent chemotherapy is shown in Figure 9-7. There was also a level III lymph node palpated in the right neck.

• GTV, CTV1, CTV2, and CTV3 delineation in a patient with clinical T2N2bM0 squamous cell carcinoma of the postcricoid region receiving definitive IMRT therapy with concurrent chemotherapy is shown in Figure 9-8. Multiple ipsilateral lymph nodes in levels II and V were pathologically enlarged.

• GTV, CTV1, CTV2, and CTV3 delineation in a patient with clinical T3N3M0 squamous cell carcinoma of the right pyriform sinus receiving definitive IMRT therapy with concurrent chemotherapy is shown in Figure 9-9. Multiple ipsilateral lymph nodes were delineated, including a bulky level II node.

6.1.3. Suggested Target and Normal Tissue Doses

• See Chapter 4 for suggested target and normal tissue doses.

6.2. Larynx

6.2.1. Target Volume Determination

• If chemotherapy has been delivered before radiation, the targets should be outlined on the planning CT according to their prechemotherapy extent.

• Lymph node groups at risk in the larynx include the following:

(a) Submandibular nodes (surgical level I): N2c cases, especially when level II node is involved.

(b) Upper deep jugular (junctional, parapharyngeal) nodes: all cases (at the neck side ipsilateral to the primary tumor).

(c) Subdigastric (jugulodigastric), midjugular, lower neck, and supraclavicular nodes (levels II through IV): all cases, bilaterally.

(d) Posterior cervical nodes (level V): all cases, at the neck side where there is evidence of jugular nodal metastasis.

(e) Retropharyngeal nodes: if there is evidence of metastasis.

• Suggested target volume determination for laryngeal carcinoma is summarized in Table 9-13.

6.2.2. Target Volume Delineation

• In patients receiving postoperative IMRT, CTV1 encompasses residual tumor and the region adjacent to it but not directly involved by the tumor, the surgical bed with soft tissue invasion by the tumor, or extracapsular extension by metastatic neck nodes. CTV2 includes primarily the prophylactically treated neck.

• In patients receiving definitive IMRT, CTV1 encompasses gross tumor (primary and enlarged nodes) and the region adjacent to it but not directly involved. CTV2 includes high-risk regions within the ipsilateral neck. CTV3 includes primarily the prophylactically treated neck.

• CTV1 and CTV2 delineation in a patient with pathological T2N2bM0 squamous cell carcinoma of the supraglottic larynx receiving postoperative IMRT is shown in Figure 9-10. The patient presented with hoarseness and a left neck mass. A right-sided supraglottic lesion was seen in direct laryngoscopy. Physical examination revealed two lymph nodes in the right level II neck. A laryngectomy with bilateral modified neck dissections was performed, which revealed a surgical staging of T2N2cM0. Four metastatic lymph nodes were without evidence of extracapsular extension. Postoperative IMRT was given bilaterally to the neck and to the tumor bed.

• GTV, CTV1 CTV2, and CTV3 delineation in a patient with clinical T2N1M0 squamous cell carcinoma of the supraglottic larynx receiving definitive IMRT is shown in Figure 9-11. The patient presented with hoarseness, a sore throat, and otalgia. Direct laryngoscopy showed a tumor extending mainly in the epiglottic area through the pre-epiglottic space, and left pharyngeal wall and vallecula. There was also a 2.5-cm palpable lymph node in the left level III region. Biopsy taken from this lesion confirmed the diagnosis of squamous cell carcinoma. The patient was treated with concurrent chemoradiation therapy for the preservation of larynx and salivary function.

• GTV, CTV1, CTV2, and CTV3 delineation in a patient with clinical T3N2bM0 squamous cell carcinoma of the supraglottic larynx receiving definitive IMRT is shown in Figure 9-12. The patient presented with hoarseness and sore throat. Direct laryngoscopy showed a tumor in the left false vocal cord and aryepiglottic fold. There were multiple left-sided lymph nodes. Biopsy taken from these lesions confirmed the diagnosis of squamous cell carcinoma. The patient was treated with concurrent chemoradiation therapy for the preservation of voice and salivary function.

FIGURE 9-7. Clinical target volume (CTV) delineation in a patient with T2N1M0 squamous cell carcinoma of the right pyriform sinus receiving definitive IMRT. p, parotid gland.

FIGURE 9-8. Clinical target volume (CTV) delineation in a patient with T2N2bM0 squamous cell carcinoma of the postcricoid region receiving definitive IMRT. p, parotid gland.

FIGURE 9-9. Clinical target volume (CTV) delineation in a patient with T3N3M0 squamous cell carcinoma of the right pyriform sinus receiving definitive IMRT. p, parotid gland.

6.2.3. Suggested Target and Normal Tissue Doses

• See Chapter 4 for suggested target and normal tissue doses.

6.3. Intensity-Modulated Radiation Therapy Results

6.3.1. Hypopharynx

• Following the above guidelines, eight patients with hypopharyngeal carcinoma were treated with IMRT between February 1997 and December 2000 at Washington University.105 Four patients were treated postoperatively, while four patients were treated with definitive IMRT. The T stages were one T2, five T3, and two T4. The N stages were four N0, two N1, and two N2 (AJCC staging: one stage I, three stage III, and four stage IV). Median follow-up time was 21 months (range 11 to 38 months). Two locoregional failures were observed (both in the neck), which were salvaged with surgery. No patient developed distant metastasis. All patients are alive with no evidence of disease, except one who died of intercurrent disease.

• G-tube was placed in two patients during the course of IMRT. No grade 3 to 4 late complications were observed in the patients treated with IMRT. Grade I xerostomia was observed in one patient, and trismus developed in another patient as a late sequelae.

• Lee et al. reported on 11 patients with hypopharyngeal carcinoma who were treated with IMRT with concurrent platinum-based chemotherapy. The 2-year locoregional progression-free survival rate was 73%; the 2-year overall survival rate was 53%. No patient with hypopharyngeal cancer required salvage laryngectomy. One patient with a pyriform sinus tumor required salvage neck dissection. Thirty-one percent of hypopharyngeal cancer patients were PEG dependent.106

• Studer et al. reported on 65 patients with hypopharyngeal squamous cell carcinoma treated with definitive simultaneous integrated boost IMRT (86% with concurrent chemotherapy). Ninety-two percent of patients were stage III or IV. Two-year locoregional control rate was 77% ( 86% including salvage surgery). In locoregionally controlled patients at 2 years, three patients were PEG dependent, one had a tracheostomy, and one underwent salvage laryngectomy.107

• Yang et al. reported on 76 patients with hypopharyngeal carcinoma treated with definitive IMRT using a sequential technique (median dose 70.2 Gy). Seventy- three percent of patients received concurrent cisplatin- based chemotherapy. The patients then received underwent a posttreatment CT scan 5 weeks after the initiation of therapy, and the volume reduction ratio (VRR) was calculated. Patients with tumor relapse had significantly lower VRR (27%) as compared to patients without primary tumor relapse (41%). Pretreatment GTV volume and VRR were predictors of relapse-free survival.108

• Liu et al. reported on long-term results of 27 patients with stage II–IV hypopharyngeal cancer treated with concurrent chemoradiotherapy using a simultaneous integrated boost technique. The 3-year functional laryngeal preservation rate was 60%; local-regional progression-free survival was 68%, disease-free survival was 64%, and overall survival was 52%. Two patients underwent salvage surgery for local-regional failure. Sixty-three percent of patients had grade 3 or higher late laryngeal toxicity. Fifty-nine percent of patients required nasogastric feeding, and 26% of patients required tracheostomy due to stridor.109

FIGURE 9-10. Postoperative IMRT target delineation for a patient with T2N2bM0 squamous cell carcinoma of the supraglottic larynx. p, parotid gland.

FIGURE 9-11. GTV, CTV1, CTV2, and CTV3 delineation in a patient with clinical T2N1M0 squamous cell carcinoma of the supraglottic larynx receiving definitive IMRT. p, parotid.

FIGURE 9-12. Target delineation in a patient with clinical T3N2bM0 squamous cell carcinoma of the supraglottic larynx receiving definitive IMRT. p, parotid gland.

• Huang et al. reported on 33 patients with T2–4aN0–2c hypopharyngeal cancer treated with concurrent chemoradiotherapy (median dose to PTV1 = 70 Gy), with median follow-up of 19.2 months. Five-year functional larynx-preservation survival was 40%. Five-year locoregional disease-free survival for IMRT was 67%; disease-free survival for IMRT was 52%. Five-year overall survival after IMRT was 44%; this did not vary significantly with primary surgery (P = 0.788). For patients treated with IMRT, decreased overall survival was significantly associated with T4a disease, clinical thyroid cartilage or cricoid cartilage invasion, poor performance status, and incomplete treatment response.110

• Boulmay et al.111 found that altered fractionation and concurrent cisplatin were efficacious for locally advanced cancers of the hypopharynx (n = 18), larynx (n = 3), and oropharynx (n = 14). Three-year locoregional control was 85%, and overall survival was 40%.

6.3.2. Larynx

• Following the above guidelines, seven supraglottic larynx carcinoma patients were treated with IMRT between February 1997 and December 2000 at Washington University. All patients were treated with postoperative IMRT. The T stages were two T2, three T3, and two T4. The N stages were three N0, one N1, and three N2 (AJCC staging: two stage III and five stage IV). Median follow-up time was 22 months (range 14 to 26 months). One locoregional recurrence was observed. This patient subsequently developed distant metastasis and died of disease. No additional distant metastases were observed. All other patients are alive with no evidence of disease, except one, who died of intercurrent disease.

• G-tube was placed in three patients during the course of IMRT. No grade 3 to 4 complications in patients treated with IMRT were seen. Grade I xerostomia was observed in three patients and grade II xerostomia in one patient as a late sequelae.

• Lee et al. reported on 11 patients with laryngeal carcinoma who were treated with IMRT with concurrent platinum-based chemotherapy. The 2-year locoregional progression-free survival rate was 90%; the 2-year overall survival rate was 69%. Three patients required salvage laryngectomy. One patient required salvage neck dissection. Fifteen percent of larynx cancer patients were PEG dependent.106

• A subsequent paper from the MSKCC group112 reported on a larynx preservation trial with 213 patients treated either with induction chemotherapy followed by RT or concurrent chemoradiation. Median follow-up was 9 years. Patients showing complete response to chemoradiation had an impressive 85% local control rate without neck dissection.

• Studer et al. reported on 58 patients with laryngeal squamous cell carcinoma treated with definitive simultaneous integrated boost IMRT (86% with concurrent chemotherapy). Sixty-nine percent of patients were stage III or IV. Two-year locoregional control rate was 69% (82% including salvage surgery). In locoregionally controlled patients, no patient was PEG dependent, two had tracheostomy, two underwent laryngectomy for chondronecrosis, and five underwent salvage laryngectomy.107

REFERENCES

1. Clemente CD. Anatomy: A Regional Atlas of the Human Body. Philadelphia, PA: Lea & Febiger, 1975.

2. El Badawi SA, Goepfert H, Fletcher GH, Herson J, Oswald MJ. Squamous cell carcinoma of the pyriform sinus. Laryngoscope 1982;92(4):357–364.

3. Richard JM, Sancho-Garnier H, Micheau C, Saravane D, Cachin Y. Prognostic factors in cervical lymph node metastasis in upper respiratory and digestive tract carcinomas: study of 1,713 cases during a 15-year period. Laryngoscope 1987;97(1):97–101.

4. Wang CC, Schulz MD, Miller D. Combined radiation therapy and surgery for carcinoma of the supraglottis and pyriform sinus. Am J Surg 1972;124(4):551–554.

5. Marks JE, Kurnik B, Powers WE, Ogura JH. Carcinoma of the pyriform sinus. An analysis of treatment results and patterns of failure. Cancer 1978;41(3):1008–1015.

6. McGavran MH, Bauer WC, Spjut HJ, Ogura JH. Carcinoma of the pyriform sinus. The results of radical surgery. Arch Otolaryngol 1963;78:826–830.

7. Donald PJ, Hayes HR, Dhaliwal R. Combined therapy for pyriform sinus cancer using postoperative irradiation. Otolaryngol Head Neck Surg 1980;88(6):738–744.

8. Spector JG, Sessions DG, Emami B, et al. Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope 1995;105(4 Pt 1):397–406.

9. Vandenbrouck C, Eschwege F, De la Rochefordiere A, et al. Squamous cell carcinoma of the pyriform sinus: retrospective study of 351 cases treated at the Institut Gustave-Roussy. Head Neck Surg 1987;10(1):4–13.

10. Lawrence W Jr., Terz JJ, Rogers C, King RE, Wolf JS, King ER. Proceedings: Preoperative irradiation for head and neck cancer: a prospective study. Cancer 1974;33(2):318–323.

11. Wynder EL. The epidemiology of cancers of the upper alimentary and upper respiratory tracts. Laryngoscope 1978;88(1 Pt 2 Suppl 8):50–51.

12. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972;29(6):1446–1449.

13. Fletcher GH. Elective irradiation of subclinical disease in cancers of the head and neck. Cancer 1972;29(6):1450–1454.

14. Ogura JH, Biller HF, Wette R. Elective neck dissection for pharyngeal and laryngeal cancers. An evaluation. Ann Otol Rhinol Laryngol 1971;80(5):646–650.

15. Mendenhall WM, Parsons JT, Mancuso AA. Larynx. In: Brady LW, edr. Principles and Practice of Radiation Oncology, 3rd ed. Philadelphia, PA: Lippincott-Raven, 1998:1069–1093.

16. Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. T1-T2 vocal cord carcinoma: a basis for comparing the results of radiotherapy and surgery. Head Neck Surg 1988;10(6): 373–377.

17. Farrington WT, Weighill JS, Jones PH. Post-cricoid carcinoma (a ten-year retrospective study). J Laryngol Otol 1986;100(1):79–84.

18. Brugere JM, Mosseri VF, Mamelle G, et al. Nodal failures in patients with NO N+ oral squamous cell carcinoma without capsular rupture. Head Neck 1996;18(2):133–137.

19. Spector JG, Sessions DG, Emami B, Simpson J, Haughey B, Fredrickson JM. Squamous cell carcinomas of the aryepiglottic fold: therapeutic results and long-term follow-up. Laryngoscope 1995;105(7 Pt 1):734–746.

20. Emami B, Spector J. Hypopharynx. In: Brady L, edr. Principles of Practice of Radiation Oncology, 3rd ed. Philadelphia, PA: Lippincott-Raven, 1998.

21. Duray A, Descamps G, Arafa M, et al. High incidence of high-risk HPV in benign and malignant lesions of the larynx. Int J Oncol 2011;39(1):51–59.

22. Stephen JK, Chen KM, Shah V, et al. Human papillomavirus outcomes in an access-to-care laryngeal cancer cohort. Otolaryngol Head Neck Surg 2012;146(5):730–738.

23. Garden AS, Forster K, Wong PF, Morrison WH, Schechter NR, Ang KK. Results of radiotherapy for T2N0 glottic carcinoma: does the “2” stand for twice-daily treatment? Int J Radiat Oncol Biol Phys 2003;55(2):322–328.

24. Bataini P, Brugere J, Bernier J, Jaulerry CH, Picot C, Ghossein NA. Results of radical radiotherapeutic treatment of carcinoma of the pyriform sinus: experience of the Institut Curie. Int J Radiat Oncol Biol Phys 1982;8(8):1277–1286.

25. Mendenhall WM, Parsons JT, Devine JW, Cassisi NJ, Million RR. Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 1987;10(2):88–92.

26. Mendenhall WM, Parsons JT, Cassisi NJ, Million RR. Squamous-cell carcinoma of the pyriform sinus treated with radical radiation-therapy. Radiother Oncol 1987;9(3):201–208.

27. Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Radiotherapy alone or combined with neck dissection for T1-T2 carcinoma of the pyriform sinus: an alternative to conservation surgery. Int J Radiat Oncol Biol Phys 1993;27(5):1017–1027.

28. Dubois JB, Guerrier B, Diruggiero JM, Pourquier H. Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery. Radiology 1986;160(3):831–836.

29. Marks J, Sessions D. Hypopharynx. In: Brady L, ed. Principles and Practice of Radiation Oncology, 2nd ed. Philadelphia, PA: J.B. Lippincott, 1992.

30. Amdur RJ, Mendenhall WM, Stringer SP, Villaret DB, Cassisi NJ. Organ preservation with radiotherapy for T1-T2 carcinoma of the pyriform sinus. Head Neck 2001; 23(5):353–362.

31. Rabbani A, Amdur RJ, Mancuso AA, et al. Definitive radiotherapy for T1-T2 squamous cell carcinoma of pyriform sinus. Int J Radiat Oncol Biol Phys 2008;72(2):351–355.

32. Nakajima A, Nishiyama K, Morimoto M, et al. Definitive radiotherapy for T1-2 hypopharyngeal cancer: a single- institution experience. Int J Radiat Oncol Biol Phys 2012;82(2):e129–e135.

33. Kania R, Hans S, Garcia D, Brasnu D, De Mones E, Laccourreye O. Supracricoid hemilaryngopharyngectomy in patients with invasive squamous cell carcinoma of the pyriform sinus – Part II Incidence and consequences of local recurrence. Ann Otol Rhinol Laryngol2005;114(2):95–104.

34. Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, Peters LJ. Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. Int J Radiat Oncol Biol Phys 1978;4(7–8):579–585.

35. Mendenhall WM, Parsons JT, Mancuso AA, Cassisi NJ, Million RR. Squamous cell carcinoma of the pharyngeal wall treated with irradiation. Radiother Oncol 1988;11(3):205–212.

36. Chang L, Stevens KR, Moss WT, Marquez C, Pearse HD, Cohen JI. Squamous cell carcinoma of the pharyngeal walls treated with radiotherapy. Int J Radiat Oncol Biol Phys 1996;35(3):477–483.

37. Hull MC, Morris CG, Tannehill SP, et al. Definitive radiotherapy alone or combined with a planned neck dissection for squamous cell carcinoma of the pharyngeal wall. Cancer 2003;98(10):2224–2231.

38. Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Squamous cell carcinoma of the head and neck treated with irradiation: management of the neck. Semin Radiat Oncol 1992;2(3):163–170.

39. Chen SW, Yang SN, Liang JA, Lin FJ, Tsai MH. Prognostic impact of tumor volume in patients with stage III-IVA hypopharyngeal cancer without bulky lymph nodes treated with definitive concurrent chemoradiotherapy. Head Neck 2009;31(6):709–716.

40. Hirano S, Tateya I, Kitamura M, et al. Ten years single institutional experience of treatment for advanced hypopharyngeal cancer in Kyoto University. Acta Otolaryngol 2010; 130(suppl 563):56–61.

41. Wang C. Carcinoma of the Hypopharynx, 2nd ed. Chicago: Year Book Medical Publishers, 1990.

42. Sasaki TM, Baker HW, Yeager RA, McConnell DB, Vetto RM. Aggressive surgical management of pyriform sinus carcinoma. A 15 year experience. Am J Surg 1986;151(5): 590–592.

43. Cachin Y, Eschwege F. Combination of radiotherapy and surgery in the treatment of head and neck cancers. Cancer Treat Rev 1975;2(3):177–191.

44. Tai HC, Hsieh CH, Chao KSC, et al. Comparison of radiotherapy strategies for locally advanced hypopharyngeal cancer after resection and ileocolic flap reconstruction. Acta Otolaryngol 2009;129(3):311–317.

45. McDonald TJ, DeSanto LW, Weiland LH. Supraglottic larynx and its pathology as studied by whole laryngeal sections. Laryngoscope 1976;86(5):635–648.

46. Thomas L, Drinnan M, Natesh B, Mehanna H, Jones T, Paleri V. Open conservation partial laryngectomy for laryngeal cancer: a systematic review of English language literature. Cancer Treat Rev 2012;38(3):203–211.

47. Zhang H, Travis LB, Chen R, et al. Impact of radiotherapy on laryngeal cancer survival: a population-based study of 13,808 US patients. Cancer 2012;118(5):1276–1287.

48. Mittal B, Marks JE, Ogura JH. Transglottic carcinoma. Cancer 1984;53(1):151–161.

49. Yuen A, Medina JE, Goepfert H, Fletcher G. Management of stage T3 and T4 glottic carcinomas. Am J Surg 1984;148(4):467–472.

50. Lundgren JA, Gilbert RW, van Nostrand AW, Harwood AR, Keane TJ, Briant TD. T3N0M0 glottic carcinoma–a failure analysis. Clin Otolaryngol Allied Sci 1988;13(6):455–465.

51. Meredith AP, Randall CJ, Shaw HJ. Advanced laryngeal cancer: a management perspective. J Laryngol Otol 1987;101(10):1046–1054.

52. Razack MS, Maipang T, Sako K, Bakamjian V, Shedd DP. Management of advanced glottic carcinomas. Am J Surg 1989;158(4):318–320.

53. Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Stage T3 squamous cell carcinoma of the glottic larynx: a comparison of laryngectomy and irradiation. Int J Radiat Oncol Biol Phys 1992;23(4):725–732.

54. Simpson D, Robertson AG, Lamont D. A comparison of radiotherapy and surgery as primary treatment in the management of T3 N0 M0 glottic tumours. J Laryngol Otol 1993;107(10):912–915.

55. Foote RL, Olsen KD, Buskirk SJ, Stanley RJ, Suman VJ. Laryngectomy alone for T3 glottic cancer. Head Neck 1994;16(5):406–412.

56. Kligerman J, Olivatto LO, Lima RA, et al. Elective neck dissection in the treatment of T3/T4 N0 squamous cell carcinoma of the larynx. Am J Surg 1995;170(5):436–439.

57. Hao SP, Myers EN, Johnson JT. T3 glottic carcinoma revisited. Transglottic vs pure glottic carcinoma. Arch Otolaryngol Head Neck Surg 1995;121(2):166–170.

58. Bryant GP, Poulsen MG, Tripcony L, Dickie GJ. Treatment decisions in T3N0M0 glottic carcinoma. Int J Radiat Oncol Biol Phys 1995;31(2):285–293.

59. Kowalski LP, Batista MB, Santos CR, Scopel A, Salvajolli JV, Torloni H. Prognostic factors in T3,N0-1 glottic and transglottic carcinoma. A multifactorial study of 221 cases treated by surgery or radiotherapy. Arch Otolaryngol Head Neck Surg 1996;122(1):77–82.

60. Mendenhall WM, Parsons JT, Mancuso AA, Pameijer FJ, Stringer SP, Cassisi NJ. Definitive radiotherapy for T3 squamous cell carcinoma of the glottic larynx. J Clin Oncol 1997;15(6):2394–2402.

61. Nguyen TD, Malissard L, Theobald S, et al. Advanced carcinoma of the larynx: results of surgery and radiotherapy without induction chemotherapy (1980–1985): a multivariate analysis. Int J Radiat Oncol Biol Phys 1996;36(5):1013–1018.

62. Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ. T4 laryngeal carcinoma: radiotherapy alone with surgery reserved for salvage. Int J Radiat Oncol Biol Phys 1998;40(3):549–552.

63. Mancuso AA, Mukherji SK, Schmalfuss I, et al. Preradiotherapy computed tomography as a predictor of local control in supraglottic carcinoma. J Clin Oncol 1999;17(2):631–637.

64. MacKenzie RG, Franssen E, Balogh JM, Gilbert RW, Birt D, Davidson J. Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery. Int J Radiat Oncol Biol Phys 2000;47(1):65–71.

65. Smee RI, Meagher NS, Williams JR, Broadley K, Bridger GP. Role of radiotherapy in early glottic carcinoma. Head Neck 2010;32(7):850–859.

66. Hirasawa N, Itoh Y, Ishihara S, et al. Radiotherapy with or without chemotherapy for patients with T1-T2 glottic carcinoma: retrospective analysis. Head Neck Oncol 2010;2:20.

67. Okubo M, Nishimura Y, Shibata T, et al. Definitive radiation therapy for moderately advanced laryngeal cancer: effects of accelerated hyperfractionation. Jpn J Clin Oncol 2010;40(10):944–948.

68. Al-Mamgani A, Tans L, van Rooij P, Levendag PC. A single-institutional experience of 15 years of treating T3 laryngeal cancer with primary radiotherapy, with or without chemotherapy. Int J Radiat Oncol Biol Phys 2012;83(3):1000–1006.

69. Janssens GO, Rademakers SE, Terhaard CH, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol 2012;30(15):1777–1783.

70. Onimaru R, Hasegawa M, Yasuda K, et al. Radiotherapy for glottic T1N0 carcinoma with slight hypofractionation and standard overall treatment time: importance of overall treatment time. Jpn J Clin Oncol 2011;41(1):103–109.

71. Fein DA, Mendenhall WM, Parsons JT, Million RR. T1-T2 squamous cell carcinoma of the glottic larynx treated with radiotherapy: a multivariate analysis of variables potentially influencing local control. Int J Radiat Oncol Biol Phys 1993;25(4):605–611.

72. Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ. Management of Tis, T1, and T2 squamous cell carcinoma of the glottic larynx. Am J Otolaryngol 1994;15(4):250–257.

73. Chera BS, Amdur RJ, Morris CG, Kirwan JM, Mendenhall WM. T1N0 to T2N0 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(2):461–466.

74. O’Sullivan B, Mackillop W, Gilbert R, t al. Controversies in the management of laryngeal cancer: results of an international survey of patterns of care. Radiother Oncol 1994;31(1):23–32.

75. Zouhair A, Azria D, Coucke P, et al. Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension. Strahlenther Onkol 2004;180(2):84–90.

76. Gomez D, Cahlon O, Mechalakos J, Lee N. An investigation of intensity-modulated radiation therapy versus conventional two-dimensional and 3D-conformal radiation therapy for early stage larynx cancer. Radiat Oncol 2010;5:74.

77. Tongiani R, Piazzolla S, Paolicchi A. Metyrapone modulation of tyrosine aminotransferase induction by dexamethasone in cultured hepatocytes. Biochem Biophys Res Commun 1990;166(2):801–806.

78. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 2002;20(1):282–288.

79. Haynes JC, Machtay M, Weber RS, Weinstein GS, Chalian AA, Rosenthal DI. Relative risk of stroke in head and neck carcinoma patients treated with external cervical irradiation. Laryngoscope 2002;112(10):1883–1887.

80. Bilora F, Pietrogrande F, Petrobelli F, Polato G, Pomerri F, Muzzio PC. Is radiation a risk factor for atherosclerosis? An echo-color Doppler study on Hodgkin and non-Hodgkin patients. Tumori 2006;92(4):295–298.

81. Cheng SW, Ting AC, Ho P, Wu LL. Accelerated progression of carotid stenosis in patients with previous external neck irradiation. J Vasc Surg 2004;39(2):409–415.

82. Call GK, Bray PF, Smoker WR, Buys SS, Hayes JK. Carotid thrombosis following neck irradiation. Int J Radiat Oncol Biol Phys 1990;18(3):635–640.

83. Parsons JT, Mendenhall WM, Mancuso AA, Cassisi NJ, Stringer SP, Million RR. Twice-a-day radiotherapy for T3 squamous cell carcinoma of the glottic larynx. Head Neck 1989;11(2):123–128.

84. Amdur RJ, Parsons JT, Mendenhall WM, Million RR, Stringer SP, Cassisi NJ. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int J Radiat Oncol Biol Phys 1989;16(1):25–36.

85. Huang DT, Johnson CR, Schmidt-Ullrich R, Grimes M. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys 1992;23(4):737–742.

86. Mendenhall WM, Parsons JT, Buatti JM, Stringer SP, Million RR, Cassisi NJ. Advances in radiotherapy for head and neck cancer. Semin Surg Oncol 1995;11(3):256–264.

87. Biller HF, Barnhill FR Jr., Ogura JH, Perez CA. Hemilaryngectomy following radiation failure for carcinoma of the vocal cords. Laryngoscope 1970;80(2):249–253.

88. Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ. American Committee on Cancer Manual for Staging of Cancer, 4th ed. Philadelphia, PA JB Lippincott, 1992.

89. Archer CR, Yeager VL, Herbold DR. Improved diagnostic accuracy in laryngeal cancer using a new classification based on computed tomography. Cancer 1984;53(1):44–57.

90. Spector JG, Sessions DG, Chao KSC, et al. Stage I (T1 N0 M0) squamous cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation. Head Neck 1999;21(8):707–717.

91. Spector JG, Sessions DG, Chao KSC, Hanson JM, Simpson JR, Perez CA. Management of stage II (T2N0M0) glottic carcinoma by radiotherapy and conservation surgery. Head Neck 1999;21(2):116–123.

92. 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(24):1685–1690.

93. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet2000;355(9208):949–955.

94. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091–2098.

95. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31(7):845–852.

96. Prades JM, Lallemant B, Garrel R, et al. Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus carcinoma. Acta Otolaryngol 2010;130(1):150–155.

97. Lefebvre JL, Rolland F, Tesselaar M, et al. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst 2009;101(3):142–152.

98. Lefebvre JL. Larynx preservation. Curr Opin Oncol 2012;24(3):218–222.

99. Lefebvre JL, Ang KK. Larynx preservation clinical trial design: key issues and recommendations—a consensus panel summary. Int J Radiat Oncol Biol Phys 2009;73(5):1293–1303.

100. Ang KK. Larynx preservation clinical trial design: summary of key recommendations of a consensus panel. Oncologist 2010;15:25–29.

101. Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol 1998;34(3):224–228.

102. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst1996;88(13):890–899.

103. Allen AM, Haddad RI, Tishler RB. Retropharyngeal nodes in hypopharynx cancer on positron emission tomography. J Clin Oncol 2007;25(5):599–601.

104. Amatsu M, Mohri M, Kinishi M. Significance of retropharyngeal node dissection at radical surgery for carcinoma of the hypopharynx and cervical esophagus. Laryngoscope 2001;111(6):1099–1103.

105. Chao KSC, Wippold FJ, Ozyigit G, Tran BN, Dempsey JF. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53(5):1174–1184.

106. Lee NY, O’Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69(2):459–468.

107. Studer G, Peponi E, Kloeck S, Dossenbach T, Huber G, Glanzmann C. Surviving hypopharynx-larynx carcinoma in the era of IMRT. Int J Radiat Oncol Biol Phys 2010;77(5):1391–1396.

108. Yang S-N, Liao C-Y, Chen S-W, et al. Clinical implicaions of the tumor volume reduction rate in head-and-neck cancer during definitive intensity-modulated radiotherapy for organ preservation. Int J Radiat Oncol Biol Phys 2011;79(4):1096–1103.

109. Liu WS, Hsin CH, Chou YH, et al. Long-term results of intensity-modulated radiotherapy concomitant with chemotherapy for hypopharyngeal carcinoma aimed at laryngeal preservation. BMC Cancer 2010;10:102.

110. Huang WY, Jen YM, Chen CM, et al. Intensity modulated radiotherapy with concurrent chemotherapy for larynx preservation of advanced resectable hypopharyngeal cancer. Radiat Oncol 2010;5:37.

111. Boulmay BC, Chera BS, Morris CG, et al. Definitive altered fractionation radiotherapy and concomitant weekly cisplatin for locally advanced head and neck cancer. Am J Clin Oncol 2009;32(5):488–491.

112. Rengan R, Pfister DG, Lee NY, et al. Long-term neck control rates after complete response to chemoradiation in patients with advanced head and neck cancer. Am J Clin Oncol 2008;31(5):465–469.

113. Yamazaki H, Nishiyama K, Tanaka E, et al. Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys 2006;64(1):77–82.

114. Short S, Krawitz H, Macann A, et al. TN/TN glottic carcinoma: a comparison of two fractionation schedules. Australas Radiol 2006;50(2):152–157.

115. Edge SB, Byrd DR, Compton CC, et al. (eds.) AJCC Cancer Staging Manual, 7th ed. New York: Springer Verlag, 2010.