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Chapter 43
Hypopharynx Cancer
Hiral K. Shah
Deepak Khuntia
Henry T. Hoffman
Paul M. Harari
There is a strong association between tobacco use and the development of hypopharynx cancer (13,59,68). Due to the rich lymphatic network in this anatomic region, patients commonly present with regional nodal metastases. Many hypopharynx cancer patients also carry significant medical comorbidities and social issues that present additional challenges to the successful delivery of aggressive cancer therapy. As for all complex tumors of the head and neck region, multidisciplinary evaluation and management is critical and should involve a head and neck surgeon, radiation oncologist, medical oncologist, nurse, nutritionist, speech/swallow therapist, and social worker. Although a selected cohort of early stage tumors may be amenable to organ preservation surgery, more radical surgery such as laryngopharyngectomy is often required for patients who undergo a primary operative approach for hypopharynx cancer. This ablative procedure can induce significant cosmetic and functional changes, and postsurgical rehabilitation efforts guided by knowledgeable professionals are very important to assist in patient adaptation. Increasingly, hypopharynx cancer patients are being considered for nonoperative treatment approaches using definitive radiation or chemoradiation as a means of obtaining tumor control with preservation of organ function. Regardless of the specific treatment approach, all patients require active rehabilitation therapy in an effort to maximize their ultimate speech and swallow function. Despite stepwise advances in the diagnosis and treatment of hypopharynx cancer, the overall outcome for these patients is relatively poor compared with other head and neck cancer sites. As with most tumors of the head and neck region, there is significant interest in combining molecular targeted therapies with traditional cytotoxic therapy in an effort to further improve outcome.
Anatomy
The hypopharynx, sometimes referred to as the laryngopharynx, is contiguous superiorly with the oropharynx and inferiorly with the cervical esophagus (Fig. 43.1). As general landmarks, the superior border of the hypopharynx is demarcated by the hyoid bone and the inferior border by the cricoid cartilage. With regard to cancer diagnosis and staging, there are three primary anatomic subsites within the hypopharynx: the bilateral pyriform sinuses, the postcricoid region, and the posterior pharyngeal wall.
The pyriform sinuses are essentially inverted pyramids with the medial, lateral, and anterior walls narrowing inferiorly to form the apices. Posteriorly, the pyriform sinuses are open and contiguous with the pharyngeal walls. Superiorly, the sinuses are surrounded by the thyrohyoid membrane through which passes the internal branch of the superior laryngeal nerve. Tumor involvement of the sensory branches of this nerve can result in referred otalgia. The postcricoid region is comprised of the mucosa overlying the cricoid cartilage, with the arytenoid and esophageal mucosa forming the superior and inferior borders, respectively. The posterior pharyngeal wall is predominantly comprised of squamous mucosa covering the middle and inferior pharyngeal constrictor muscles and is separated from the prevertebral fascia by the retropharyngeal space. Typically, the mucosa lining the pharyngeal wall is <1 cm in thickness and provides a minimal barrier to direct tumor infiltration. The posterior pharyngeal wall is contiguous with the lateral wall of the pyriform sinus (Fig. 43.2A,B). Sensory innervation of the hypopharynx is provided by the internal branch of the superior laryngeal nerve as well as fibers deriving from the glossopharyngeal nerve. The recurrent laryngeal nerve and the pharyngeal plexus provide the primary motor supply. The arterial supply of the hypopharynx is derived primarily from branches of the external carotid artery: superior thyroid arteries, ascending pharyngeal arteries, and lingual arteries. There is a rich network of lymphatics within the hypopharynx that drain directly through the thyrohyoid membrane and into the jugulodigastric lymph nodes, most commonly involving the subdigastric node. Additionally, there may be direct drainage into the spinal accessory nodes. Tumors involving the posterior pharyngeal wall can also drain into the retropharyngeal nodes, including the most cephalad retropharyngeal nodes of Rouviere. Epidemiology and Etiology Hypopharynx cancers are relatively uncommon. Approximately 2,500 to 3,000 cases are diagnosed annually in the United States. The pyriform sinus is the most common subsite of origin comprising 65% to 75% of hypopharynx cases (15). Although it is sometimes difficult to definitively assign tumor origin to a single subsite, approximately 10% to 20% of hypopharynx tumors arise from the posterior pharyngeal wall and 5% to 15% originate from the postcricoid region (5). Due to the rich lymphatic drainage of the hypopharynx, at least 50% of patients will manifest clinically positive cervical lymph nodes at the time of diagnosis (43). Jugular chain nodes, levels II through IV, as well as retropharyngeal nodes, are all at high risk to harbor regional metastases in patients with hypopharynx cancer. In parallel to cancers of the nasopharynx, retropharyngeal nodes may be the first site of nodal spread. Postcricoid tumors may also spread directly to pre- and paratracheal nodal basins. Due to the high propensity for advanced primary disease as well as regional nodal involvement, the majority of hypopharynx cancer patients present with stage III and IV disease. In a retrospective study from Washington University, 87% of patients with cancers of the pyriform sinus and 82% of patients with posterior pharyngeal wall tumors presented with stage III or IV disease (65). Over 90% of patients with hypopharynx cancer report past cigarette use (40). Alcohol appears to potentiate the carcinogenic effects of tobacco but in isolation is not clearly associated with an increased risk of developing hypopharynx cancer. The index hypopharynx cancer often occurs within a field of diseased mucosa characterized by high-grade dysplasia. This “field cancerization” reflects widespread mucosal exposure to carcinogens and is responsible for the high rate of synchronous and metachronous primary tumors identified in patients with P.959 hypopharynx cancer. Successful counseling with particular emphasis on smoking cessation can enhance treatment tolerance and diminish the risk of developing subsequent cancers of the upper aerodigestive tract. Patients with occupational exposure to coal dust, steel dust, iron compounds, and fumes have also shown an increased risk for developing hypopharynx cancer (6,60). Overall, the incidence of hypopharynx cancer has shown some gradual decline in the United States. From 1975 to 2001 the incidence decreased by approximately 35%, perhaps as a result of smoking cessation efforts (21). Human papilloma virus (HPV) infection is well established as a risk factor for the development of squamous-cell carcinoma of the gynecologic tract, particularly in the uterine cervix. The relationship between HPV and head and neck cancer is only recently becoming better appreciated, particularly for cancers of the nasopharynx and oropharynx. Studies have demonstrated that approximately 20% to 25% of patients with hypopharynx cancer test positive for HPV DNA (42,50). Currently, the clinical implications of the presence of HPV in hypopharynx cancer are yet to be defined. There is a recognized increased risk of developing cancers of the postcricoid region for patients with Plummer Vinson syndrome, characterized by iron-deficiency anemia, hypopharyngeal webs, weight loss, and dysphagia (75). Favorable changes in the epidemiology of hypopharynx cancer have resulted from changes in nutrition. The addition of iron to flour has made Plummer Vinson syndrome quite rare in the upper midwestern United States and Scandinavian countries where it was formerly more common. An associated decrease in hypopharynx cancer involving the postcricoid region has followed. Prognostic Factors Several prognostic factors have been identified for patients with hypopharynx cancer. Age, particularly >70 years, has been identified as an unfavorable predictor of outcome (24). This may simply reflect the diminished likelihood of elderly patients to successfully tolerate the aggressive therapy approaches required for locoregionally advanced cancers of the head and neck. Women have been found to achieve somewhat improved outcomes compared to men, although this may in part be a manifestation of earlier stage disease at diagnosis (63,64). In addition, tumor location has an impact on outcome with
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cancers of the pyriform sinus generally faring better than those arising in the postcricoid or posterior pharyngeal wall regions (63,64). As a whole, hypopharynx cancer patients fare poorly in comparison with patients harboring tumors from other head and neck sites. To a lesser extent, tobacco, alcohol, and dietary factors (carotenoids, vitamin C, vitamin E, and flavonoids) may also have an impact on outcome (23).

Biologic factors have been investigated for their potential role in hypopharynx cancer. The presence of p53 gene mutations have been associated with bulkier tumors and younger patients along with higher expression of the epidermal growth factor receptor (EGFR). However, p53 has not shown correlation with multiple primary tumors, tumor grade, or DNA ploidy (15,28). Further, definitive data in hypopharynx cancer does not exist correlating a prognostic significance of EGFR expression with overall outcome (29).
Staging
The most commonly used system for staging hypopharynx cancer is the American Joint Committee on Cancer (AJCC) 2002 edition of their staging manual, which is based on a combination of clinical and radiographic data (Table 43.1) (30). The nodal and group staging is similar to other sites within the pharynx with the exception of nasopharynx. One must always exercise good clinical judgment when designing treatment recommendations based on AJCC staging. With specific regard to hypopharynx cancer, the AJCC staging system does not differentiate the specific tumor subsite or number of walls invaded by tumor that may have prognostic significance as well as management implications. Moreover, patient factors including age, comorbid medical conditions, and motivation for organ preservation are beyond the scope of the staging system, but nevertheless represent important factors for consideration with each individual patient.
Patterns of Spread
Local Extension
Cancers arising from the pyriform sinus may spread superiorly to involve the aryepiglottic folds and arytenoids and invade the paraglottic and pre-epiglottic space. Lateral tumor extension can involve portions of the thyroid cartilage, allowing entry into the lateral compartment of the neck. High-resolution computed tomography (CT) or magnetic resonance imaging (MRI) is often useful for optimal assessment regarding the extent of tumor invasion. For tumors arising from the medial wall, the most common site of involvement for pyriform sinus tumors, there is a likelihood of tumor involvement of intrinsic muscles of the
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larynx resulting in vocal cord fixation. Inferior tumor extension beyond the apex can involve the thyroid gland.

Cancers arising within the postcricoid region can extend circumferentially to involve the cricoid cartilage or anteriorly to involve the larynx with resultant vocal cord fixation. Tumor involvement of the recurrent laryngeal nerve can also precipitate vocal cord fixation. Primary postcricoid tumors are often quite extensive and can involve the pyriform sinus, trachea, or esophagus. As a result, these tumors generally carry a worse prognosis in comparison to tumors from other subsites of the hypopharynx (66). Nodal spread to the paratracheal nodes and inferior deep cervical nodes is not uncommon. Tumor arising from the posterior pharyngeal wall can extend to involve the oropharynx superiorly, the cervical esophagus inferiorly, and the prevertebral fascia and retropharyngeal space posteriorly.
Many cancers of the hypopharynx have a propensity for submucosal spread. It can therefore be difficult to accurately quantify the full microscopic extent of disease. This is particularly true for cancers of the posterior pharyngeal wall and postcricoid regions. Careful study through serial sectioning of surgical specimens has identified that 60% of hypopharynx cancers demonstrate subclinical spread with a range of 10 mm superiorly, 25 mm medially, 20 mm laterally, and 20 mm inferiorly (39). This extensive pattern of tumor infiltration can present considerable challenges in the effort to achieve clear surgical margins or full dosimetric coverage with radiotherapy.
Regional Disease
Lymphatics of the pyriform sinus can drain through the thyrohyoid membrane, across the pretracheal nodes, and into level II and III cervical nodes (Table 43.2). Tumors arising from the posterior pharyngeal wall can involve the retropharyngeal nodes (Rouviere's nodes) extending cephalad to the base of skull. In light of cross-draining lymphatics, there is a significant risk of bilateral cervical adenopathy associated with cancers arising in the hypopharynx (51) (Fig. 43.3).
Distant Metastases
The most common site for distant metastasis to develop in patients with cancer of the hypopharynx is the lung. Approximately one quarter of patients diagnosed with hypopharynx cancer either present with distant metastasis or develop them at some time during the course of their disease (48). For those patients not rendered free of locoregional disease following initial therapy, the incidence of distant metastases increases notably with the length of time following initial treatment (45).

Field Cancerization
Carcinogens can induce dysplastic changes throughout the mucosa of the upper aerodigestive tract, leading to an increased risk for field cancerization that enhances the likelihood of synchronous or metachronous secondary primary tumors. Approximately 7% of patients with hypopharynx cancer will manifest a secondary primary tumor at initial diagnosis and between 10% to 20% will develop a secondary primary tumor over time. In fact, this second tumor risk is a significant cause of mortality in patients who survive >2 years following initial treatment (38).
Clinical Presentation
In light of the nonspecific nature of early symptoms, the majority of patients with cancers of the hypopharynx present with advanced local and/or regional disease. Frequently, there is a delay between presentation and diagnosis as patients are often managed for presumed infectious or gastrointestinal etiology. The majority of symptoms are related to local tumor spread including dysphagia and odynophagia. There may be frank esophageal obstruction, invasion of constrictor muscles, prevertebral space invasion, or strap muscle invasion. Common
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presenting signs and symptoms include dysphagia, sore throat, hoarseness, weight loss >10 pounds, and neck mass. The majority of patients present with more than one of these signs and symptoms (70). Selected patients may first come to medical attention with complaints of unilateral ear pain (referred otalgia) due to tumor involvement of the nerve of Arnold, a branch of the superior laryngeal nerve.

A comprehensive work-up for patients with cancers of the hypopharynx should include a detailed history focusing on the duration of symptoms, amount of weight loss, the presence of otalgia, changes in voice quality, and degree of dysphagia. Factors such as previous history of an upper aerodigestive tract malignancy and smoking are important. A detailed physical examination should include direct and indirect visualization of the full laryngopharyngeal axis with particular attention to the size, location, and anatomic positioning of the primary tumor as well as the mobility status of the true vocal cords. Dentition and oral health should be assessed. If the patient presents with cervical adenopathy, the size, number, location, texture, and mobility of these nodes should be documented.
Although cervical adenopathy associated with hypopharynx cancer may be analyzed with fine needle aspiration biopsy, there is little value in this approach for most patients who will undergo a direct laryngoscopy under general anesthesia in conjunction with esophagoscopy. This panendoscopy permits not only biopsy confirmation of the primary tumor site, but also mapping of the extent of the tumor as well as survey for synchronous primary tumors (Fig. 43.4).
Staging Work-Up
In addition to panendoscopy, patients should undergo either high-resolution CT with contrast (or MRI) extending from skull base to below the clavicle to help assess the extent of the primary tumor and to quantitatively and qualitatively assess cervical adenopathy (53) (Fig. 43.5 and 43.6). Patients with cancer of the hypopharynx should also undergo formal swallow evaluation to assess their functional swallow capacity before the initiation of therapy. This analysis may be done as a “bedside” study of swallowing capacity, a fiberoptic endoscopic swallowing evaluation (FEES), or through the more definitive fluoroscopic barium swallow study. This modified barium swallow study is called a cookie swallow, videopharyngogram, or oropharyngeal motility study (OPMS). Either a chest x-ray or CT is recommended to assess the presence of pulmonary metastasis.
F-18-deoxyglucose or fluorodeoxyglucose/positron emission tomography (18FDG-PET) imaging is increasingly used to help assess the extent of the primary tumor and regional adenopathy as well as the presence of distant metastasis. FDG-PET is becoming an increasingly valuable adjunct to CT and/or MRI in the radiation treatment planning process, particularly for patients treated with conformal IMRT or tomotherapy techniques. Di Martino et al. (22) compared CT, PET, color-coded duplex sonography, palpation, and panendoscopy in assessment of
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tumor and nodal status. The results of this study are summarized in Table 43.3 and support the promising sensitivity and specificity of PET scanning in head and neck cancers. Schwartz et al. (59) examined standardized uptake value (SUV) of primary and nodal metastasis in head and neck cancer patients and their relationship to clinical outcome. A primary tumor SUV >9.0 was associated with a significantly lower local recurrence-free survival and disease-free survival (DFS). There was no correlation between nodal SUV and clinical outcome.

Pathological Classification
Review of the National Cancer Data Base (NCDB) Benchmark Reports identified 3,519 cases of hypopharynx cancer reported from 1,542 hospitals during 2000 and 2001. Over 93% of the cases were reported as squamous-cell carcinoma with “other specified types” representing 6.9% of cases (53). On rare occasion, lymphoma, sarcoma, adenocarcinoma, or adenoid cystic carcinoma may present in the hypopharynx, but each histology makes up <0.5% of overall hypopharynx cancer diagnoses (21). Pretreatment Evaluation Many patients with hypopharynx cancer present with concurrent medical and social comorbidities that require consideration before initiating cancer-directed therapy. Commonly, there is a progressive history of dysphagia and odynophagia with associated weight loss. Whether these patients are treated with surgical or nonsurgical approaches, a gastrostomy tube may need to be considered as a temporary measure. It is important to optimize or at least stabilize the patient's nutritional status prior to initiating definitive therapy. It is valuable for hypopharynx cancer patients to undergo evaluation by a speech and swallow therapist to evaluate the degree of dysfunction prior to therapy. Patients may be able to use adaptive techniques to improve the effectiveness and safety of their oral intake. Additionally, close follow-up with the same speech and swallow therapist is highly desirable during and after therapy to maximize the patient's long-term functional capabilities. Since many hypopharynx patients have an active history of alcohol and tobacco use, it is important to counsel accordingly and encourage all patients to take advantage of methods and programs to facilitate smoking and alcohol cessation. All patients should undergo comprehensive dental evaluation and cleaning as well as basic education regarding oral hygiene. For patients treated with conventional radiation therapy techniques there is a significant likelihood of long-term xerostomia that can promote dental decay. If existing dentition is in poor condition, dental extractions should be considered prior to therapy, particularly for teeth that will reside within the high-dose radiation region. Typically 10 to 14 days are required following dental extractions to allow for healing prior to the initiation of radiation therapy. Custom fluoride carrier trays should be fabricated and discussed for long-term use in an effort to diminish the rate of dental decay for patients with chronic xerostomia. Finally, many patients with hypopharynx cancer will have social issues including lack of family support, financial limitations, transportation issues, poor nutrition, and hygiene habits that may hamper their ability to successfully receive adequate care. Often, the involvement of a case manager or social worker is of central importance to assist patients who require support both during as well as following cancer therapy. Management T1–2 Tumors Surgery Contemporary indications for primary surgical management of patients with early cancers of the hypopharynx include those with a history of previous head and neck radiation, those in whom organ conservation approaches are deemed possible (a relatively small proportion of cases), and those who refuse radiation. Even for hypopharynx cancer patients who will receive nonoperative treatment approaches, it remains critical for the head and neck surgeon to remain actively involved. The role of the surgeon in these cases may include endoscopic biopsy with detailed assessment of tumor extent, methods to secure the airway (tracheotomy or laser debulking), and methods to ensure adequate nutrition (gastrostomy). P.964 Patients with hypopharynx cancer also require careful evaluation regarding regional nodal metastases. For N0–1 patients treated with primary radiation or chemoradiation approaches, adjuvant neck dissection is generally unnecessary. However, for patients presenting with N2–3 neck disease, careful evaluation of tumor response in the neck is important to help gauge the potential value of adjuvant neck dissection following radiation or chemoradiation. Although an increasing number of reports suggest that detailed imaging of the neck 8 to 12 weeks postradiation with FDG-PET can serve as a valuable guide to help select those patients warranting adjuvant neck dissection, many institutions mandate adjuvant neck dissection for all patients presenting with N2–3 neck disease in an effort to maximize regional disease control. Both approaches are readily defendable at present (10,56,67,68,74). If neck dissection is performed, this provides an opportunity for the surgeon to reassess the primary tumor site under anesthesia with directed biopsy if suspicious for residual disease. If residual disease at the primary site is highly suspected or confirmed by biopsy several months following completion of radiation or chemoradiation, this will prompt consideration regarding the feasibility and advisability of salvage surgery options. A selected cohort of T1 and T2 hypopharynx cancers may lend themselves to surgical excision. These favorable subsites include the upper pyriform sinus and the posterior pharyngeal wall. The standard supraglottic laryngectomy encompasses the aryepiglottic fold and may be extended to include part of the arytenoids, base of tongue, and upper pyriform sinus. Small cancers isolated to the posterior pharyngeal wall may be removed by endoscopic laser resection or removal using an open approach. Dysphagia requiring no food by mouth status is common from the open approach, especially if reconstruction of the posterior wall is effected with an adynamic and insensate free flap. Relative contraindications to organ conservation surgery for hypopharynx cancers include transglottic tumor extension, cartilage invasion, vocal fold paralysis, postcricoid invasion, deep pyriform sinus invasion, and extension beyond the larynx. Innovations with free flap reconstruction have permitted retention of speech and swallowing and breathing functions of the larynx despite extensive resection by way of a hemilaryngopharyngectomy. The temporoparietal flap and radial forearm free flap coupled with rigid cartilaginous support have been employed to retain function in patients with hypopharynx cancers without extension to the postcricoid region or apex of the pyriform sinus (58,71). Radiation Curative radiation therapy (RT) is generally the preferred treatment option for patients with T1–2 hypopharynx tumors. This approach affords good potential for organ preservation without compromise in clinical outcome. A classical course of radiation therapy for hypopharynx cancer lasts 6 to 7 weeks, with treatment delivered 5 days per week. Conventional treatment involves a shrinking field technique that initiates with opposed lateral fields encompassing the primary tumor and upper neck lymphatics with a matched anterior field to complete treatment of the lower neck. One of the most common worldwide fractionation regimens involves the delivery of 2 Gy daily fractions to 70 Gy over 7 weeks. Altered fractionation techniques including hyperfractionation (e.g., 1.1 to 1.4 Gy twice daily) and accelerated fractionation (e.g., six fraction per week or concomitant boost regimens) have demonstrated improved locoregional control rates for head and neck cancer patients (31,54,61). A recent meta-analysis examined 15 trials that compared conventional fractionation to altered fractionation, either hyperfractionation or accelerated fractionation. The study demonstrated a small but statistically significant survival benefit of 3.4% at 5 years with altered fractionation. The benefit was higher with hyperfractionation compared to accelerated fractionation and was more pronounced for patients younger than age 50 (9). Due to the high likelihood of subclinical nodal metastases, even in the clinically N0 neck, patients traditionally receive comprehensive radiation to encompass nodal regions from skull base to clavicle. Due to the varying thickness of the head and neck, custom compensators or wedges should be used for the lateral fields to obtain a more homogeneous dose distribution. Shrinking field techniques to spare direct spinal cord dose after ~45 Gy, as well as final mucosal field reductions after 54 to 60 Gy are often appropriate with posterior neck boosting with electrons to complete the nodal dosing without excessive dose to the spinal cord. Over the past 10 to 15 years, the use of three-dimensional CT-based planning has become routine in the management of head and neck cancer patients (Fig. 43.7). CT-based planning allows precise delineation of target volume and visualization of dose distributions (Fig. 43.8). Early T-stage hypopharynx patients with N0–1 neck disease can be considered for treatment with radiation alone or concurrent radiation plus chemotherapy. In this setting, gross disease should receive 70 Gy and the contralateral neck (N0) should receive 50 to 54 Gy. With T1-N0 lesions, patients may achieve 5-year disease-specific survival (DSS) on the order of 90%, while T2-N0 lesions may achieve DSS of >70% (52). (Tables 43.4 and 43.5).
Patients with advanced N2–3 neck disease are often considered for postradiotherapy or postchemoradiotherapy neck dissection in an effort to maximize the likelihood of neck control (47). Several recent studies, including one from the University of Iowa, have assessed the value of a postradiation FDG-PET to help select those patients who might benefit most from subsequent neck dissection. For complete clinical responders, the Iowa study concluded that FDG-PET in this setting has a very high negative predictive value. The authors suggest that FDG-PET may be a valuable tool to help determine which patients should undergo adjuvant neck dissection versus observation following the completion of head and neck radiation or chemoradiotherapy (79).

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Squamous-cell carcinomas of the head and neck are rapidly proliferating tumors. There has been significant interest over the past several decades in the use of intensified radiation fractionation schedules to counter rapid tumor cell repopulation as a means of improving outcome in head and neck cancer patients treated with radiation alone. The Radiation Therapy Oncology Group (RTOG 9003) altered fractionation in a randomized trial comparing conventional fractionation to hyperfractionation, split-course, and concomitant boost techniques and demonstrated a significant improvement in DFS for the hyperfractionation and concomitant boost arms (31) (Table 43.6). Hypopharynx patients were included within the study cohort for this randomized trial. These altered fractionation regimens were associated with higher incidence of grade 3 or worse acute mucosal toxicity but no significant difference in overall chronic toxicity at 2 years following completion of treatment.
In the past several years, there has been significant interest in the use of intensity-modulated radiation therapy (IMRT) in head and neck cancer as a means of diminishing normal tissue toxicities, particularly xerostomia resulting from irradiation of major salivary glands. Excellent candidates for IMRT include patients with unilateral T1–3 primary lesions with ≤N2b neck disease. In light of the high-dose gradients that can accompany highly conformal plans, a critical component of successful IMRT delivery is the use of an accurate and reproducible localization system. At several centers, the use of an optically guided localization system is used to enhance treatment precision for patients undergoing IMRT for head and neck cancer (41) (Fig. 43.9). The cephalad margin of the N0 contralateral neck may often be limited to the C1–2 interspace in an effort to further improve parotid gland sparing (24,25).

T3–4 Resectable
Surgery
Favorable T3 hypopharynx cancers that present in the upper aspect of the pyriform sinus and permit full extirpation by either an extended supraglottic laryngectomy or extended vertical partial laryngopharyngectomy with free flap reconstruction are possible but infrequent. Many T3 and T4 hypopharynx cancers that are treated surgically will require total laryngectomy with efforts to preserve a posterior strip of the hypopharynx spanning the oropharynx to the esophagus. This preserved posterior wall of the hypopharynx may be tubed and closed on itself in selected cases. In the past it was common practice to accept primary reconstruction of this segment as adequate for swallowing with closure over a nasogastric tube. More recently primary closure has been discouraged for cases with less than a 3 to 3.5 cm width of posterior pharyngeal wall mucosa to tube on itself. Most commonly superior swallowing results when the anterior and lateral walls of the remaining hypopharynx are reconstructed with either pedicled or free flap reconstruction.
For more bulky tumors of the hypopharynx, total laryngopharyngectomy is required and refers to removal of the larynx and the entire hypopharynx. This procedure creates a gap between the oropharynx and esophagus that can be reconstructed with a tubed fasciocutaneous flap such as the radial forearm free flap or lateral thigh flap, a free jejunum, or a tubed pedicled myocutaneous flap. The myocutaneous flaps are technically difficult to tube due to the bulk of the fat and muscle underlying the skin paddle.
Laryngopharyngectomy with esophagectomy may be performed if the hypopharynx cancer extends inferior to the
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cricopharyngeus to ensure the inferior margin. In this case, reconstruction with a gastric pull-up or colon interposition are options used to restore the conduit for food and saliva extending from the oropharynx to the stomach.

Postoperative Radiation Therapy
In light of the deeply infiltrative nature of advanced hypopharynx cancers that are treated with initial surgical resection, the vast majority of patients are recommended to undergo adjuvant radiation therapy in an effort to enhance locoregional control rates. Classical indications for postoperative radiation include T4 primary tumors, close or positive microscopic margins, cartilage/bony invasion, >1 metastatic lymph node, or the presence of extracapsular extension (ECE). Conventional therapy involves the use of shrinking field techniques, as described previously, to deliver 54 to 63 Gy to all areas at risk and a boost to 60 to 66 Gy to regions of ECE and/or positive margins. The entire cervical nodal chain from the skull base to the clavicle bilaterally should be included. IMRT techniques may be considered in an attempt to reduce radiation dose to normal tissue structures such as the contralateral parotid gland and thereby preserve better salivary function.
Recently, the role of concurrent chemotherapy along with postoperative radiation has been evaluated in prospective randomized trials by the RTOG and European Organization for Research and Treatment of Cancer (EORTC). Eligibility criteria in the RTOG trial included patients with two or more positive nodes, ECE, or microscopically positive margins. All patients received 60 Gy alone or with concurrent cisplatin 100 mg/m2 every 3 weeks. This trial demonstrated an improvement in locoregional control and DFS for patients who received concurrent chemoradiotherapy. However, no significant benefit in absolute survival was confirmed (Table 43.7) (20). The EORTC conducted a similar trial that included patients with stage III (except T3 N0 larynx), stage IV, and patients with stage I or II with positive margins, lymphovascular invasion, and perineural invasion. All patients received 66 Gy alone or with cisplatin at 100 mg/m2 every 3 weeks. This trial demonstrated a significant improvement in progression-free survival and overall survival with the addition of chemotherapy (6) (Table 43.8).

Although the studies above identify that the addition of cisplatin chemotherapy to postoperative radiation can improve tumor control outcome for specific categories of high-risk patients, it is clear that this modest benefit comes at the expense of additional toxicity. Careful clinical judgment regarding the selection of patients most likely to tolerate and thereby benefit from this approach is warranted. In the definitive treatment setting, there is mounting evidence that patients >70 years of age derive little to no benefit from the addition of systemic chemotherapy to radiation in head and neck cancer (9,55). This is quite likely to be true in the postoperative head and neck cancer treatment setting as well. The inadvertent introduction of treatment breaks during the adjuvant radiation course can easily compromise the potential benefits of the combined modality therapy in this setting.
There is considerable interest in the use of molecular targeted therapies in the treatment of head and neck cancer patients. The most mature clinical data set in head and neck cancer involves the use of EGFR inhibitors such as cetuximab (monoclonal antibody against the EGFR). An international phase III trial comparing high-dose radiation alone versus radiation plus cetuximab in advanced head and neck cancer patients confirmed a locoregional control improvement (10% at 3 years) and overall survival advantage (10% at 3 years) with the addition of cetuximab (7). A relatively small subset of patients with hypopharynx cancer were enrolled in this study of 424 patients, and this subset did not demonstrate a clear advantage with use of the EGFR inhibitor treatment. Ongoing trials to examine the potential value of adding cetuximab to concurrent chemoradiation approaches in advanced head and neck cancer are in progress in both the definitive and high-risk postoperative settings.
Definitive Radiation Therapy
There are several reasons why hypopharynx cancer patients who are technically resectable may not undergo primary surgery. These include age (e.g., patients >70 or 80 years old), the presence of significant medical comorbidities and/or patient unwillingness to accept total laryngectomy. Curative-intent radiation or chemoradiation is often pursued in these settings. Conventional radiation therapy commonly involves a shrinking three-field technique to deliver ~70 Gy in 2 Gy daily fractions to areas of gross disease and 50 to 60 Gy to areas of microscopic disease. If patients are scheduled to undergo postradiotherapy neck dissection, then gross nodal disease can be limited to 60 to 63 Gy. If patients are not candidates for postradiotherapy neck dissection, then gross nodal disease should be carried to 70 Gy. Altered fractionation regimens such as hyperfractionation or accelerated fractionation should be considered for patients being treated with radiation alone, as this approach has been demonstrated to improve the likelihood of locoregional tumor control (31).
In patients with adequate performance status, concurrent chemoradiation strategies using platinum-based chemotherapy should be considered. The most comprehensive meta-analysis to examine the benefit of chemotherapy in advanced head and neck cancer confirms a small but significant survival advantage for the use of chemotherapy, with the best gains observed with the use of concurrent platinum-based regimens (8%) (9,55).
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However, this meta-analysis also confirms a steadily decreasing benefit for the use of chemotherapy with advancing patient age, such that no advantage is observed for patients >70 years of age. This same loss of statistical benefit for patients >70 years of age is also observed for the outcome gains derived from altered fractionation over conventional fractionation. Therefore, once daily radiation regimens (conventional technique or IMRT) may be quite reasonable for hypopharynx patients >70 years of age (or selected patients with modest performance status) rather than intensified fractionation regimens or the use of concurrent chemotherapy.

Recently, there has been renewed interest in the concept of induction chemotherapy approaches for patients with locoregionally advanced head and neck cancer, particularly with the introduction of taxane-containing regimens that offer promise to improve tumor response rates. Two randomized trials have been reported that compare induction 5-fluorouacil (5-FU) and cisplatin versus 5-FU, cisplatin, plus a taxane (37,73). Preliminary reports suggest a significant improvement in overall response rate with the addition of a taxane. In an effort to simultaneously enhance locoregional disease control and reduce distant metastases, several phase III trials are in progress that compare this sequential approach (triple agent induction chemotherapy followed by concurrent chemoradiation) versus concurrent chemoradiation (current standard of care) for patients with locoregionally advanced head and neck cancer (1). These aggressive approaches certainly appear worthy of controlled clinical investigation for head and neck subsites such as the hypopharynx, where the overall outcomes are poor and both locoregional control and distant metastases present a formidable challenge. Nevertheless, maturation of these trials is important before the ad hoc adoption of such complex, costly, and toxic treatment strategies. Careful assessment of tumor control, survival, and long-term functional outcome dovetailed with quality of life evaluation will be important to help place these regimens in the best perspective for advanced head and neck cancer patients.

Management of hypopharynx cancer has gradually evolved over the past decades to reflect the steady advancement of nonsurgical therapy. Data from the NCDB Benchmark reports addressing 3,519 cases diagnosed in 2000 to 2001 reveals the combination of radiation and chemotherapy to be the most common initial treatment overall (32.5%) for all stages of hypopharynx cancer (Fig. 43.10). Radiation as a single modality therapy was the most common initial treatment for stage I hypopharynx cancer (34%) followed by surgery alone (19.4%) as next most common (Fig. 43.11A). Chemoradiation was the most common treatment for stage II (34.4%), stage III (37%), and stage IV (35.7%) disease (Figs. 43.11B–D) (53).
Unresectable, Nonmetastatic Disease
The management of patients with unresectable locoregional disease without distant metastases is dependent on patient performance status. A patient with a good performance status may be offered definitive radiotherapy or concurrent chemotherapy as discussed above. In a randomized Intergroup trial of unresectable head and neck cancers, the addition of high-dose cisplatin to radiation was found to improve survival versus radiation alone, although at the expense of increased toxicity (2) (Table 43.9). However, patients with poor performance status who are not considered candidates for aggressive radiation or chemoradiation approaches should be managed with palliative intent. This may include short-course radiation regimens such as 4 to 5 Gy of five fractions over 1 to 2 weeks with a repeat of the same 3 weeks hence if favorable initial tolerance and response is achieved. Systemic chemotherapy alone can be considered, although for poor performance status patients, best supportive care with medical therapy and airway control may also be appropriate.
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Metastatic Disease
As many as one quarter of hypopharynx cancer patients will develop metastatic disease at some point in their clinical course. In this setting, treatment is palliative and should be delivered to maximize or help maintain quality of life. If patients are having difficulty with local pain, bleeding, or swallowing, palliative short-course radiation therapy can be delivered as described above. Surgery may also provide a reasonable palliative option for selected patients who have incurable disease but significant symptoms related to their localized disease. If aspiration of secretions (despite no food by mouth status and enteral feedings) persists, laryngopharyngectomy may afford a reasonable option to discuss with the patient and family members. Similarly, complete stenosis of the pharynx or upper esophagus due to tumor (or following treatment) may leave a patient with constant need for suctioning his or her own secretions. In selected patients, laryngopharyngectomy with gastric pull-up may be a reasonable palliative option. Finally, G-tube placement can be considered for patients who do not wish to pursue palliative radiation therapy or surgery. Many patients in this setting will benefit from narcotic analgesics for pain management.
Patients with adequate or good performance status should be considered for palliative chemotherapy. Several agents have shown response for recurrent and metastatic (head and neck) cancer including cisplatin, carboplatin, 5-FU, methotrexate, docetaxel, or combination regimens based on platinum or taxane and the more recent introduction of molecular targeted therapies including the EGFR inhibitors (17,19). A randomized trial has been reported comparing the efficacy of cisplatin
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alone compared with two multiagent regimens: (a) cisplatin and 5-FU and (b) cisplatin, 5-FU, bleomycin, and vincristine. Although the combination regimens demonstrated higher tumor response rates, this did not translate into a significant difference in median survival between the three arms. The combination arms were more toxic (16). In the 1990s there was significant interest in incorporating taxanes into regimens for recurrent and metastatic head and neck cancer. A randomized trial comparing cisplatin and 5-FU to cisplatin and paclitaxel demonstrated similar response rates, median survival, and 1-year survival. The cisplatin and 5-FU arm was more toxic to administer (33). There has also been significant interest in incorporating targeted therapies such as the EGFR inhibitors for head and neck cancer patients with metastatic or recurrent disease. These agents generally elicit modest response rates when given as single agents. For example, cetuximab, gefitinib, and erlotinib have generated response rates of 13%, 11%, and 4%, respectively as single agents in head and neck cancer (18,62,72). There is interest in combining traditional cytotoxic chemotherapy agents with targeted agents to improve overall outcomes. A trial comparing cisplatin alone or in combination with cetuximab demonstrated improved response rates with cetuximab, but no significant improvement in progression-free survival or overall survival (13).
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Complications
Surgery
The complications from surgery generally fall within the confines of bleeding, infection, reaction to the anesthesia, and damage to structures around or in the field of surgery. The damage to the laryngopharynx that occurs in the course of removing those tissues involved by cancer necessarily interferes with key laryngeal functions: breathing, swallowing, and speaking.
If an effort is made to preserve laryngeal function, some compromise may be required. A long-term tracheotomy, no food by mouth status with the use of gastrostomy feedings, and/or significant dysphonia are not uncommon for patients with hypopharynx cancer treated with conservation laryngeal surgery. These same complications may attend the more comprehensive laryngopharyngectomy as well. Stenosis of the neopharynx, difficulty with alaryngeal speech, and stomal stenosis may compromise the same functions ordinarily ascribed to the larynx. For all open surgical approaches, the risk of a salivary fistula is greatest for those patients previously treated with radiation. Although salivary fistulas are rare with endoscopic approaches, they have occurred in cases requiring aggressive laser resection.
Radiation Therapy
During a course of head and neck radiation therapy, there are predictable side effects that are experienced by the majority of patients: mucositis, fatigue, loss of taste acuity, radiation dermatitis, and xerostomia. Typically patients will begin to experience mucositis during the 3rd week of radiotherapy. This initially manifests as mucosal blanching within the treatment field, but can progress to patchy or confluent mucositis. Initially patients can be treated with an over-the-counter pain reliever, but once patients develop grade II or III mucositis, they will commonly require narcotic analgesics for adequate pain control. The combination of dysphagia and mucositis can result in significant nutritional compromise, necessitating intravenous hydration and parenteral nutritional supplementation. Nausea associated with treatment can also further complicate the nutritional status. These acute toxicities can become particularly pronounced in the setting of intensified radiation fractionation schedules and/or combined chemoradiotherapy. Patients may require prophylactic antiemetics. In patients receiving concurrent radiotherapy and platinum-based chemotherapy, there is clear potential for myelosuppression; therefore, blood counts should be monitored regularly. Signs or symptoms of infection should be addressed promptly. Finally, xerostomia can become problematic during the course of radiation. Ultimately, patients can be reassured that the majority of these side effects, with the exception of xerostomia, are temporary and will resolve several weeks to months following completion of therapy.
As noted, one of the acute side effects of radiotherapy that can become permanent is xerostomia. Chemical and physical modifiers of the radiation response have been utilized to reduce long-term xerostomia. The free-radical scavenger amifostine has the potential to reduce radiation effects on normal tissues if administered just prior to each radiation fraction. A randomized phase III trial demonstrated a reduction in the severity of the acute and chronic grade 2 or higher xerostomia in patients who received amifostine during RT (11). Dose-limiting toxicities commonly include hypotension and nausea. However, more recent reviews have called into question the ultimate value of amifostine in patients with advanced head and neck cancer, and currently there is no universal standard recommendation across treatment centers for the use of this radioprotector (40,76).
IMRT or tomotherapy techniques allow the clinician to physically modify the radiation dose distribution in an effort to spare critical normal tissues. This approach has been used increasingly for (head and neck) cancer patients to reduce radiation dose to the major salivary glands. A dosimetric analysis comparing radiation dose to the parotid gland and postradiation salivary function demonstrates that limiting mean dose to the parotid gland to <26 Gy is associated with improved postradiation salivary function (25).
In some cases, hypopharynx cancer patients who complete a course of radiation therapy will be noted to have persistent laryngeal edema on subsequent follow-up visits. Although in the early posttreatment phase (in fact up to 24 months), significant or newfound edema should raise suspicion regarding the possibility of persistent or recurrent disease, the majority of patients who receive high-dose radiation across major segments of the larynx and hypopharynx will manifest some degree of edema, mucosal congestion, and eventual fibrosis (see Fig. 43.4B). Generally, this collateral damage is a tolerable chronic toxicity with modest impact on patient quality of life. However, in approximately 10% to 15% of patients, this edema is severe enough to cause significant airway and swallow function compromise requiring tracheostomy.
Outcomes
There are several institutional reports of radiation therapy alone in the management of hypopharynx cancer. It is difficult to compare directly the results between surgically treated patients and radiation treated patients because there is often a selection bias whereby some patients are selected for surgery and others referred for radiotherapy. The University of Florida has systematically reported their results with radiation alone for patients with hypopharynx cancer (Tables 43.10, 43.11 and 43.12) (3,27).
In an effort to examine the potential for organ preservation in patients with advanced cancers of the hypopharynx, the EORTC conducted a randomized trial for patients who would require total laryngectomy as a surgical approach. This trial randomly allocated patients to induction chemotherapy with cisplatin and 5-florouracil followed by definitive radiation versus primary surgical resection and postoperative radiation. With a median follow-up of 10 years, this trial demonstrated no significant difference in 5- or 10-year overall survival or progression-free survival. Of note, two thirds of living patients in the chemoradiotherapy arm were able to retain their larynx (43).
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Long-Term Follow-Up
Regardless of whether patients undergo primary surgery or radiation therapy, there is value in close posttreatment surveillance by head and neck surgeon and radiation oncologist. During the first 6 months after treatment, patients should be followed every 4 to 6 weeks with clinical examination, including fiberoptic nasopharyngoscopy. Recommended guidelines include a follow-up visit every 1 to 3 months during the first year, every 2 to 4 months for the second year, every 4 to 6 months for years 3 through 5, and every 6 to 12 months thereafter. Additionally, if the patient received comprehensive head and neck radiation, the serum thyrotropin should be measured every 6 to 12 months. Imaging evaluation of the neck most commonly with CT or MRI scan are obtained at 3 to 6 month intervals during the first 2 years or as indicated based on clinical findings. Functional imaging with 18FDG-PET can sometimes prove valuable to help differentiate posttreatment fibrosis from persistent or recurrent disease.
A study by Hermans et al. (36) examined findings on CT scan of the neck 3 to 4 months following completion of radiation therapy for patients with larynx or hypopharynx cancer to examine correlation with long-term outcome. The authors suggest that in patients achieving complete radiographic resolution of all pretreatment disease, the likelihood of subsequent local failure is very small. These patients might therefore undergo routine clinical examination with repeat imaging reserved for instances where the clinical examination becomes suspicious for recurrence. For patients who achieved <50% reduction in tumor volume or retained a mass ≥1 cm on the posttreatment imaging study, the likelihood of local failure was 100% and 30%, respectively. In these patients, repeat CT at 3 to 4 months, FDG PET, or biopsy is therefore recommended. Preliminary reports indicate that the results of the first post-RT FDG-PET scan may be a strong predictor of developing locoregional disease recurrence (78).

In the posttreatment setting of hypopharynx cancer patients, the involvement of an experienced head and neck radiologist is highly desirable for optimal interpretation of imaging results. Soft-tissue changes following ablative surgery and reconstruction or following high-dose radiation or chemoradiation with resultant edema and fibrosis can be very difficult to differentiate from tumor, particularly for the inexperienced reader.
Management of Recurrence
After completion of treatment, patients should be followed closely for signs of recurrent or persistent disease. If recurrence is suspected, this should generally be confirmed by biopsy. If biopsy is confirmatory, then the patient should undergo complete restaging to assess the extent of disease. In the setting of local or regional disease alone, patients treated with initial radiation or chemoradiation can be considered for surgical salvage therapy. Although salvage surgery following comprehensive head and neck radiation and chemotherapy presents several resection and reconstructive healing challenges for the surgeon, selected patients may still derive long-term benefit from this approach. Recurrent patients who initially received comprehensive head and neck radiation have traditionally not been considered good candidates for repeat high-dose radiation in light of normal tissue tolerances. However, with the advent of highly conformal radiation delivery techniques, selected patients may benefit from reirradiation approaches in conjunction with systemic chemotherapy (77). Many patients with recurrent disease, however, are not good candidates for aggressive surgery or radiation salvage therapy and are best served with systemic chemotherapy and/or best supportive care approaches.
In the setting of distant metastatic disease, further treatment will focus on palliative goals. If the patient is experiencing significant local symptoms in the setting of asymptomatic distant metastases, palliative surgery or radiation may still warrant
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consideration. Most patients with distant metastatic disease and adequate performance status should be considered for systemic therapy and/or best supportive care options.
Quality of Life
Assessment of parameters including functional status, organ preservation, treatment cost, and patient-assessment of quality of life play an increasingly important role in the evaluation of overall treatment efficacy. For larynx and hypopharynx cancer patients, a focus of contemporary clinical investigation has been the study of treatments designed to preserve laryngeal function for patients traditionally treated with total laryngectomy. A frequently cited but somewhat controversial study by McNeil et al. (46) employed a questionnaire administered to healthy individuals and concluded that some might forgo total laryngectomy in favor of alternative therapy even if this choice diminished their ultimate chance for cure. A more recent report by El-Deiry et al. (26) evaluated long-term quality of life in a matched pair analysis comparing the surgical and nonsurgical treatment of patients with advanced head and neck cancer involving the oropharynx, hypopharynx, and larynx. Although patients in the surgery arm demonstrated worse speech outcomes than those treated with chemoradiation, this difference did not carry over to the overall quality of life score. These investigators concluded that, although it seems reasonable that organ preservation (nonsurgical) treatment will uniformly result in a higher quality of life, the complexities of human adjustment and multitude of potential treatment effects render this assumption invalid for many patients.
There have been relatively few prospective assessments of quality of life following treatment for head and neck cancer. In a subset of locally advanced patients requiring radical surgery such as total laryngectomy and partial pharyngectomy, the functional deficits are predictable. However, for patients undergoing “organ preservation” with radiation alone or in combination with chemotherapy, it can be difficult to assess the true extent and quality of organ preservation. Regardless of the primary treatment approach, these patients often require long-term speech, swallow, and dental rehabilitation. A study from Meyer et al. (49) retrospectively assessed speech intelligibility and quality of life in survivors of head and neck cancer. A total of 64 patients were enrolled; 31 underwent RT alone, five surgery alone, and 28 received both. All patients underwent comprehensive subjective and objective testing of speech function and quality of life. They found significant subjective and objective deficits in speech and quality of life even 5 years after completion of therapy. Terrell et al. (69) reported the results of a self-administered health survey of 570 patients at a Veteran's Administration hospital that demonstrated that the single most notable event having a negative impact on Quality of life was placement of a feeding tube. This was followed by medical comorbid conditions, presence of a tracheotomy tube, chemotherapy, and neck dissection.
A prospective study on quality of life utilizing the EORTC QLQ-C30 and QLQ-head and neck 35 questionnaires was conducted in Sweden on 357 patients. This study found that quality of life issues were significantly associated with the site of origin, with stage at diagnosis being the most important predictor. Additionally, patients with hypopharynx cancer exhibited the poorest quality of life (35). A study from the University of South Carolina compared swallow related quality of life after surgery or radiotherapy for head and neck cancer using a dysphagia risk factor survey, the M.D. Anderson Dysphagia Inventory (MDADI). They found significantly better scores on the emotional and functional components of the MDADI for patients undergoing chemoradiation compared to those undergoing surgery followed by radiation (34).
Conclusion
Patients with cancers of the hypopharynx commonly present with advanced disease associated with varying degrees of compromise in speech and/or swallow function. Many hypopharynx cancer patients also carry significant medical and social comorbidities. Typically, small T1–2 lesions can be managed with either primary radiation or surgery with similar clinical outcome. For intermediate stage disease that would require laryngopharyngectomy for the surgical approach, an increasingly preferred treatment option is combined chemoradiation that has demonstrated equivalence to immediate surgery in cancer survival, however, with improved organ preservation and functional outcome. For bulky hypopharynx tumors with significant airway compromise, laryngeal distortion, and cartilage destruction, it is generally best to proceed with definitive surgery with postoperative radiation or chemoradiation. Despite an aggressive approach in the overall management of hypopharynx cancer patients, ultimate cure rates remain quite poor. There are relatively few early stage patients, and for many advanced stage patients it is difficult to achieve long-term control. Even for those patients with excellent response to therapy, there exists a continuous risk for the development of second malignancies, particularly of the upper aerodigestive track with long-term follow-up. Posttreatment patients often require aggressive speech and swallow therapy to maximize their functional outcome. There is significant interest in the incorporation of molecular targeted therapies in combination with traditional cytotoxic therapy and radiation in an effort to improve outcomes.
Acknowledgments
We acknowledge the assistance of Lindell R. Gentry, M.D., Charles W. Hodge, M.D., and Wolfgang Tome, Ph.D. in image editing and collection and Gregory Allen, M.D., Ph.D. for reference editing.

44 larynx new

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Chapter 44
Larynx
William M. Mendenhall
Russell W. Hinerman
Robert J. Amdur
Anthony A. Mancuso
Douglas B. Villaret
John W. Werning
Anatomy
The larynx is divided into the supraglottic, glottic, and subglottic regions. The supraglottic larynx consists of the epiglottis, the false vocal cords, the ventricles, and the aryepiglottic folds, including the arytenoids. The glottis includes the true vocal cords and the anterior commissure. The subglottis is located below the vocal cords (Figs. 44.1 and 44.2) (12).
The lateral line of demarcation between the glottis and supraglottic larynx is the apex of the ventricle. The demarcation between the glottis and subglottis is ill-defined, but the subglottis is considered to extend from a point 5 mm below the free margin of the vocal cord to the inferior border of the cricoid cartilage or 10 mm below the apex of the ventricle.
The vocal cords vary from 3 to 5 mm in thickness. Technically, the vocal cords terminate posteriorly with their attachment to the vocal process. The mucosa between the arytenoids is called the posterior commissure.
The shell of the larynx is formed by the hyoid bone, thyroid cartilage, and cricoid cartilage; the cricoid cartilage is the only complete ring. The more mobile interior framework is composed of the heart-shaped epiglottis and the arytenoid, corniculate, and cuneiform cartilages. The corniculate and cuneiform cartilages produce small, rounded bulges at the posterior end of each aryepiglottic fold.
The thyroid and the cricoid cartilages and a portion of the arytenoid cartilage are hyaline cartilage and may partially ossify with age, particularly in men. The epiglottis is elastic cartilage; ossification does not occur, and even focal calcification is rare (57).
The external laryngeal framework is linked together by the thyrohyoid, the cricothyroid, and the cricotracheal ligaments or membranes (Figs. 44.3 and 44.4) (12).
The epiglottis is joined superiorly to the hyoid bone by the hyoepiglottic ligament. The epiglottis is joined to the thyroid cartilage by the thyroepiglottic ligament at a point just below the thyroid notch and above the anterior commissure. The arrangement of the ligaments that connect the cricoid and arytenoid cartilages and form the vocal ligaments, which are part of the true vocal cords, is shown in Fig. 44.2B (12). The conus elasticus (cricovocal ligament) is the lower portion of the elastic membrane that connects the inferior framework. It connects the upper surface of the cricoid, the vocal process of the arytenoid, and the lower thyroid cartilage; its free border is thickened into the vocal ligament.
The vocal ligaments and muscles attach to the vocal process of the arytenoid posteriorly and the thyroid cartilage anteriorly. The intrinsic muscles of the larynx, which primarily control the movement of the cords, are presented in Figures 44.2 and 44.3 (12). The extrinsic muscles are concerned primarily with swallowing. The cricothyroid muscle produces tension and elongation of the vocal cords and is innervated by the superior laryngeal nerve (Fig. 44.4) (12).
The preepiglottic and paraglottic fat spaces are essentially one contiguous space lying between the external framework of the thyroid cartilage and hyoid bone and the inner framework of the epiglottis and intrinsic muscles. Lam and Wong (49) showed that there are thin membranous septa between the paraglottic and preepiglottic space that are capable of holding a tumor in check to a limited degree. The space is traversed by blood and lymphatic vessels and nerves. Because few capillary lymphatics arise in this area, invasion of the fat space should only be associated indirectly with lymph node metastases. The fat space is limited by the conus elasticus inferiorly, the thyroid ala, the thyrohyoid membrane, the hyoid bone anterolaterally, the hyoepiglottic ligament superiorly; and the fascia of the intrinsic muscles on the medial side. Posteriorly, it is adjacent to the anterior wall of the pyriform sinus.
The laryngeal surface of the epiglottis and the free margin of the vocal cords are squamous epithelium, and the remainder is usually pseudostratified ciliated columnar epithelium. Beneath the epithelium of the free edge of the vocal cord is the lamina propria, which can be divided into three layers. There is no true submucosal layer along the free margin of the vocal fold (40). The laryngeal arteries are branches of the superior and inferior thyroid arteries.
The intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve. The cricothyroid muscle, an intrinsic muscle responsible for tensing the vocal cords, is supplied by a branch of the superior laryngeal nerve; 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 preepiglottic space and the thyrohyoid membrane and terminate mainly in the subdigastric lymph nodes; a few drain to the middle internal jugular chain lymph nodes.
There are essentially no capillary lymphatics of the true vocal cords; as a result, lymphatic spread from glottic cancer occurs only if tumor extends to supraglottic or subglottic areas.
The subglottic area has relatively few capillary lymphatics. The lymphatic trunks pass 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.
Epidemiology and Risk Factors
Cancer of the larynx represents about 2% of the total cancer risk and is the most common head and neck cancer (skin excluded). In 2003 in the United States, there were approximately 9500 new cases of cancer of the larynx (7100 men and 2400 women) and about 3800 deaths from laryngeal cancer (43). Based on 1973–1998 U.S. data, at diagnosis, about 51% of the cases remain localized, 29% have regional spread, and 15% have distant
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metastases (93). 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 is said to approach the risk of nonsmokers after 10 years of abstention (120). The role of alcohol in provoking laryngeal cancer remains unclear (111). Some evidence exists that heavy marijuana smoking may be associated with laryngeal cancer in young patients.

Patterns of Spread
Local Spread
Although supraglottic and glottic lesions tend to remain confined to their original compartments, there is no anatomic barrier to growth from one area to the next. Glottic lesions tend to be slow-growing, but after they increase in size, they quickly extend to the supraglottic and subglottic areas. Supraglottic lesions do not often start near the vocal cords. Involvement of the cords on their external epithelial surface is a late phenomenon, but submucosal extension by way of the paraglottic space occurs earlier.
The fat space is an important avenue of submucosal tumor spread for infrahyoid epiglottis, false cord, and true vocal cord lesions. As the false cord and the true vocal cord lesions penetrate anteriorly and laterally, they quickly encounter the tough perichondrium of the thyroid cartilage and may eventually be shunted by the conus elasticus (lateral cricothyroid membrane) out of the larynx via the cricothyroid space. Thyroid cartilage invasion usually occurs in the ossified section of the cartilage, commonly in the region of the anterior commissure tendon or the junction of the anterior one-fourth and the posterior three-fourths of the thyroid lamina (5).
Fixation of the vocal cord from laryngeal cancer is usually caused by invasion or destruction of the vocal cord muscle, invasion of the cricoarytenoid muscle or joint, or, rarely, invasion of the recurrent laryngeal nerve. Perineural spread is uncommon in laryngeal malignancies.
Supraglottic Larynx
Suprahyoid Epiglottis
A lesion of the suprahyoid epiglottis may produce a huge exophytic mass with little tendency to destroy cartilage or spread
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to adjacent structures. Other lesions may infiltrate the tip and destroy cartilage. The destructive lesions tend to invade the vallecula and preepiglottic space, the lateral pharyngeal walls, and the remainder of the supraglottic larynx.

Infrahyoid Epiglottis
Lesions of the infrahyoid epiglottis tend to produce irregular tumor nodules and simultaneously invade the porous epiglottic cartilage and thyroepiglottic ligament into the preepiglottic fat space and extend toward the vallecula and base of the tongue. The thick hyoepiglottic ligament is an effective tumor barrier. However, the tumor may present in the vallecula and base of tongue without involving the suprahyoid epiglottis.

Lesions of the infrahyoid epiglottis 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. Infrahyoid epiglottic lesions that extend onto or below the vocal cords are at a high risk for thyroid cartilage invasion, even if the cords are mobile (91).
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False Cord
Early false cord carcinomas, which are usually submucosal with little exophytic component, are difficult to delineate accurately. They involve the paraglottic fat space early in their development and may spread a considerable distance beneath the mucosa without producing physical signs. These carcinomas extend to the perichondrium of the thyroid cartilage quite early, but cartilage invasion is a late phenomenon. Extension to the lower portion of the infrahyoid epiglottis and invasion of the pre-epiglottic space are common. Submucosal extension involves the true vocal cord, which may appear normal. Vocal cord invasion is often associated with thyroid cartilage invasion. Submucosal extension to the medial wall of the pyriform sinus occurs early.
Aryepiglottic Fold/Arytenoid
Early lesions of the aryepiglottic fold/arytenoid are usually exophytic. It may be difficult to decide whether the lesion started on the medial wall of the pyriform sinus or on the aryepiglottic fold. As the lesions enlarge, they extend to adjacent sites and eventually cause fixation of the larynx, which is usually a result of involvement of the cricoarytenoid muscle or joint or, rarely, invasion of the recurrent laryngeal nerve. Computed tomography (CT) may distinguish the cause of fixation. Advanced lesions invade the thyroid, epiglottic, and cricoid cartilages and eventually invade the pyriform sinus and postcricoid area.
Glottic Larynx
Most lesions of the true vocal cord begin on the free margin and upper surface of the cord. When diagnosed, about two-thirds are confined to the cords, usually one cord. The anterior portion of the cord is the most common site. Anterior commissure involvement, which is common, is said to occur when no tumor-free cord can be seen anteriorly; if the lesion crosses to the opposite cord, anterior commissure invasion is certain. Small lesions isolated to the anterior commissure account for only 1% to 2% of cases. Extension to the posterior commissure area is uncommon, occurring only in advanced lesions.
Tumors at the anterior commissure may extend anteriorly via the anterior commissure tendon (Broyles' ligament) (10) into the thyroid cartilage. Kirchner (46), using whole organ sections, showed that such extension is unusual unless the tumor extends off the vocal cord onto the base of the infrahyoid epiglottis and suggested that the tendon serves as more of a barrier than an avenue of tumor spread. Early subglottic extension is also associated with involvement of the anterior commissure, and tumor may grow through the cricothyroid membrane.

Lesions that arise on the posterior half of the vocal cord tend to extend along the submucosa toward the medial side of the vocal process and invade the cricoarytenoid joint and posterior commissure; this spread is difficult to appreciate by clinical examination.
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 subglottic extension posteriorly brings the border of the tumor to the upper margin of the cricoid, exceeding the anatomic limits for conventional hemilaryngectomy. Lesions may spread beneath the epithelium along the length of the vocal cord within Reinke's space (84).
As vocal cord lesions enlarge, they extend to the false cord, vocal process of the arytenoid, and subglottic region. Infiltrative lesions invade the vocal ligament and muscle and eventually reach the paraglottic space and the perichondrium of the thyroid cartilage. 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. Lesions involving the anterior commissure often exit the larynx via the cricothyroid space after they extend subglottically (84).
A fixed cord that is associated with a lesion having less than 1 cm of subglottic extension and no false cord involvement does not ordinarily indicate invasion of the thyroid cartilage (46). If the false cord is also involved, cartilage invasion is likely.
Subglottic Larynx
Subglottic cancers are rare. Most involve the inferior surface of the vocal cords by the time they are diagnosed, so it is difficult to know whether the tumor started on the undersurface of the vocal cord or in the true subglottic larynx. Because early diagnosis is uncommon, most lesions are bilateral or circumferential at discovery. They involve the cricoid cartilages in the early stage because there is no intervening muscle layer. Partial or complete fixation of one or both cords is common; misdiagnosis or diagnostic delay is frequent.
Lymphatic Spread
The location and stage of neck nodes detected on admission for previously untreated patients with squamous cell carcinoma of the supraglottic larynx are given in Figure 44.5 (55). The disease spreads mainly to the subdigastric nodes. The submandibular area is rarely involved, and there is only a small risk of spinal accessory lymph node involvement. The incidence of clinically positive nodes is 55% at the time of diagnosis; 16% are
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bilateral (55). Elective neck dissection shows pathologically positive nodes in 16% of cases; observation of initially node-negative necks eventually identifies the appearance of positive nodes in 33% of cases (18,81). Spread to the pyriform sinus, vallecula, and base of the tongue increases the risk of lymph node metastases. The risk of late-appearing contralateral lymph node metastasis is 37% if the ipsilateral neck is pathologically positive, but the risk is unrelated to whether the nodes in the ipsilateral neck were palpable before neck dissection.
In carcinoma of the vocal cord, the incidence of clinically positive lymph nodes at diagnosis approaches zero for T1 lesions and less than 2% for T2 lesions (66). The incidence of neck metastases increases to 20% to 30% for T3 and T4 lesions. Supraglottic spread is associated with metastasis to the jugulodigastric nodes. Anterior commissure and anterior subglottic invasion are associated with involvement of the midline pretracheal lymph node (Delphian node).
Lederman (52) reported a 10% incidence of positive lymph nodes in 73 patients with subglottic carcinoma.
Clinical Presentation
Carcinoma arising on the true vocal cords produces hoarseness at a very early stage. Sore throat, ear pain, pain localized to the thyroid cartilage, and airway obstruction are features of advanced lesions.
Hoarseness is not a prominent symptom of cancer of the supraglottic larynx until the lesion becomes quite extensive. Pain on swallowing, usually mild, is the most frequent initial symptom, often described as a sore throat. Some patients report a sensation of a “lump in the throat.” Pain is referred to the ear by way of the vagus nerve and auricular nerve of Arnold. A mass in the neck may be the first sign of a supraglottic cancer. Late symptoms include weight loss, foul breath, dysphagia, and aspiration.
Diagnostic Work-Up
Physical Examination
Flexible fiberoptic endoscopes are now used routinely as a complement to the laryngeal mirror examination. The mirror often provides the best view of the posterior pharyngeal wall. The flexible fiberoptic laryngoscope is inserted through the nose and is useful in more difficult cases.
Determination of the mobility of the vocal cords frequently requires multiple examinations because the subtle distinctions between mobile, partially fixed, and fixed cords are often challenging, apparently changing from examination to examination. A cord that appeared mobile to the surgeon before direct laryngoscopy may exhibit impaired motion or even fixation after biopsy.
Ulceration of the infrahyoid epiglottis or fullness of the vallecula is an indirect sign of preepiglottic space invasion. Palpation of diffuse, firm fullness above the thyroid notch with widening of the space between the hyoid and the thyroid cartilages signifies invasion of the preepiglottic space. The preepiglottic fat space is a low-density area on the CT scan, and changes resulting from tumor invasion are easily seen.
Postcricoid extension may be suspected when the laryngeal click disappears on physical examination. Postcricoid tumor may cause the thyroid cartilage to protrude anteriorly, producing a fullness of the neck.
Invasion of the thyroid cartilage remains a difficult clinical diagnosis. Localized pain or tenderness to palpation or a small bulge over one ala of the thyroid cartilage is suggestive.
Radiographic Studies
CT scan with contrast enhancement is the method of choice for studying the larynx (Fig. 44.6) (72). The CT scan should be performed before biopsy so that abnormalities that may be caused by the biopsy are not confused with tumor. CT is preferred to magnetic resonance imaging (MRI) because the longer scanning time for MRI results in motion artifact (73). CT slices 1 to 2-mm thick are obtained at 1– to 2-mm intervals through the larynx and at 3-mm intervals for the remainder of the study. Thinner sections (1 to 2 mm through the larynx) facilitate high-quality multiplanar reformations. The gantry is angled so that the scan slices are parallel to the plane of the true vocal cords. It is also necessary to obtain a CT scan of the entire neck to detect positive, nonpalpable lymph nodes. Positive retropharyngeal nodes may be present at diagnosis in patients with laryngeal cancer who have advanced neck disease (59). Retropharyngeal adenopathy is often not apparent on physical examination but is usually appreciated on CT scan.
Contrast enhancement helps to outline the blood vessels and thyroid gland. Tumor is often enhanced, probably because of reactive inflammatory changes. In addition to CT, MRI may be obtained to define subtle exolaryngeal spread or early cartilage destruction. The value of MRI for detecting early cartilage destruction is open to speculation. Sagittal MRI may be useful in detecting early invasion of the base of the tongue.
Vocal Cord Carcinoma
Although the CT scan does not show minimal mucosal lesions and is generally not helpful for well-defined, easily visualized T1 or early T2 vocal cord carcinomas, it is almost always obtained. CT is excellent for determining subglottic extension and is often used in selected T1 and most T2 lesions for this reason alone. CT scanning is useful in the diagnosis of moderately advanced and advanced lesions; it is excellent for demonstrating extension outside the larynx into the soft tissues of the neck and has potential for determining thyroid or cricoid cartilage invasion, which tends to occur at the edges of the cartilage rather than on the face. Early cartilage involvement is difficult to detect with axial scans, but it may be demonstrated by coronal or sagittal scanning techniques. If the low-density plane of the paraglottic space is intact, cartilage is probably not invaded by tumor.
Archer et al. (6) correlated CT findings with the incidence of cartilage or bone invasion on whole-organ sections. For 12 of 14 patients with pathologic evidence of cartilage invasion, the average diameter of the tumor in two dimensions was more than 16 mm, and the lesion was located below the top of the arytenoid. Lesions in which the maximum diameter lay above the top of the arytenoid had a low incidence of cartilage invasion (6).
Supraglottic Carcinoma
The CT scan provides an excellent means for viewing the pre-epiglottic and paraglottic fat spaces. Soft tissue extension into the neck or base of the tongue can also be seen. The CT scan is also useful for determining extension to the subglottic areas (57).
Diagnostic procedures for laryngeal cancer at the University of Florida are summarized in Table 44.1 (65). A CT scan is usually performed for all patients; MRI is obtained in a small subset of patients with questionable findings on CT. Positron emission tomography is not routinely obtained. Direct laryngoscopy and biopsy with frozen section are usually performed with the patient under general anesthesia. The ventricles, subglottic area, apex of the pyriform sinus, and postcricoid area must be carefully examined because these areas are not consistently seen by
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indirect examinations. Fiberoptic telescopes (0 and 30 degrees) are introduced through the laryngoscope for inspection of these areas. A generous biopsy specimen is taken from the obvious lesion; additional biopsy specimens may be obtained from suspicious areas and from areas grossly involved. The mucosa of the margin of the cord may be stripped to provide adequate tissue if the lesion is distributed superficially along the cord and is not obviously a carcinoma.

Staging
The 2002 American Joint Committee on Cancer (AJCC) (3) staging system for laryngeal primary cancer is listed in Table 44.2. T2 glottic cancers are stratified into those with normal (T2A) and impaired (T2B) vocal cord mobility. For lesions arising in the supraglottis, the sites of origin include false cords, aryepiglottic folds, suprahyoid epiglottis, infrahyoid epiglottis, pharyngoepiglottic folds, and arytenoids. Only in the early T-stages can one identify the specific site of origin with certainty. As the lesion enlarges, the site of origin is an educated guess
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based on the location of the greatest bulk of tumor. The major difference between the 1998 and 2002 staging systems is that a glottic cancer that invades the paraglottic space is upstaged to T3 in the latter system, even with mobile vocal cords, resulting in significant stage migration. Additionally, T4 has been stratified into T4A and T4B, based on resectability.

Pathologic Classification
Nearly all malignant tumors of the larynx arise from the surface epithelium and therefore are squamous cell carcinoma or one of its variants.
Carcinoma in situ occurs frequently on the vocal cords. Differentiating among dysplasia, carcinoma in situ, squamous cell carcinoma with microinvasion, and true invasive carcinoma is a problem that the pathologist and the clinician frequently confront.
Most vocal cord carcinomas are well or moderately well differentiated. In a few cases, an apparent carcinoma and sarcoma occur together, but most of these are actually a spindle-cell carcinoma (i.e., squamous cell carcinoma with a spindle-cell stromal reaction).
Verrucous carcinoma occurs in 1% to 2% of patients with carcinoma of the vocal cord. The histologic diagnosis is difficult and must correlate with the gross appearance of the lesion.
Small cell neuroendocrine carcinoma is rarely diagnosed in the supraglottic larynx, but it should be recognized because of its biologic potential for rapid growth, early dissemination, and responsiveness to chemotherapy.
Minor salivary gland tumors arise from the mucous glands in the supraglottic and subglottic larynx, but they are rare (31).
Even rarer are chemodectoma, carcinoid, soft tissue sarcoma, malignant lymphoma, or plasmacytoma. Benign chondromas and osteochondromas are reported, but their malignant counterparts are rare.
Prognostic Factors
The extent of the primary lesion and neck disease are the major determinants of prognosis. The likelihood of local control is determined primarily by T-stage; there are conflicting data pertaining to a possible inverse relationship between N-stage and local control. The likelihood of locoregional control is impacted primarily by the overall AJCC stage, which accounts for both T- and N-stages. AJCC stage and N-stage are the major determinants of cause-specific survival. Additionally, within each N-stage, patients with positive nodes in the low neck below the level of the thyroid notch tend to have a lower cause-specific survival rate compared with those with disease confined to the upper neck. In general, women tend to have a better prognosis than men.
Treatment Selection and Technique: Vocal Cord Carcinoma
Selection of Treatment Modality
In treating vocal cord carcinoma, the goal is cure with the best functional result and the least risk of a serious complication. Patients may be considered to be in an early group if the chance of cure with larynx preservation is high, they are in a moderately advanced group if the likelihood of local control is 60% to 70% but the chance of cure is still good, and they are in an advanced group if the chance of cure is moderate and the likelihood of laryngeal preservation is relatively low. The early group may be treated initially by radiation therapy or, in selected cases, by partial laryngectomy. The moderately advanced group may be treated with either irradiation with laryngectomy reserved for relapse or by total laryngectomy with or without adjuvant postoperative irradiation. The obvious advantage of the former strategy, which we use at the University of Florida, is that there is a fairly good chance that the larynx will be preserved. Although some patients may be rehabilitated with a tracheoesophageal puncture after laryngectomy, only about 20% of patients use this device long term and the majority use an electric larynx (62). The advanced group is treated with total laryngectomy and neck dissection with or without adjuvant radiation therapy or by radiation therapy and adjuvant chemotherapy (68). Data suggest that if patients whose tumors show a partial or complete response to two to three cycles of neoadjuvant chemotherapy are then given high-dose radiation therapy, the cure rates are comparable with those obtained with initial total laryngectomy (16). Another less expensive and less toxic method to select patients likely to be cured by radiation therapy alone is to calculate the primary tumor volume on
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pretreatment CT or MRI. Data indicate that primary tumor volume is inversely related to the probability of local control after irradiation (61,64). Recent data indicate that whereas induction chemotherapy probably does not improve the likelihood of locoregional control and survival, concomitant chemotherapy and irradiation results in an improved possibility of cure compared with irradiation alone (23,68,90). There is a subset of patients with high volume, unfavorable, advanced cancers who may be cured by chemoradiation but have a useless larynx and permanent tracheostomy and/or gastrostomy (61). These patients are best treated with a total laryngectomy, neck dissection, and postoperative irradiation.
Carcinoma in Situ
Lesions diagnosed as carcinoma in situ may sometimes be controlled by stripping the cord. However, it is difficult to exclude the possibility of microinvasion on these specimens. Recurrence is frequent, and the cord may become thickened and the voice hoarse with repeated stripping. Localized carcinoma in situ can also be excised using the CO2 laser.
Early radiation therapy for carcinoma in situ often means a better chance of preserving a good voice, especially as many patients with this diagnosis eventually receive this treatment (28).
Many patients with a diagnosis of carcinoma in situ have obvious lesions that probably contain invasive carcinoma. We have often proceeded with radiation therapy rather than put the patient through a repeated biopsy procedure.
Early Vocal Cord Carcinoma
In most centers, irradiation is the initial treatment prescribed for T1 and T2 lesions, with surgery reserved for salvage after radiation therapy failure (60,71). Although hemilaryngectomy or cordectomy produces comparable cure rates for selected T1 and T2 vocal cord lesions, irradiation is generally preferred (71,79). Supracricoid laryngectomy, as reported by Laccourreye et al. (47) is a procedure designed to remove moderate-sized cancers involving the supraglottic and glottic larynx. The larynx may be removed with preservation of the cricoid and the arytenoid with its neurovascular innervation, the defect is closed by approximating the base of the tongue to the remaining larynx. The oncologic and functional results of this procedure in selected patients are reported to be excellent. Transoral laser excision also may provide high cure rates for select patients with small, well-defined lesions limited to the midthird of one true cord (58,103). A small subset of transoral laser surgeons, notably Professor Steiner, use this technique successfully in moderately advanced cancers (71). The major advantage of irradiation compared with partial laryngectomy is better quality of the voice. Partial laryngectomy finds its major use as salvage surgery in suitable cases after irradiation failure. Even if the patient has a local recurrence after salvage partial laryngectomy, there is a third chance with total laryngectomy, which may still be successful.
Verrucous lesions have the reputation of being unresponsive to radiation therapy and, in some instances, converting into invasive, often anaplastic, metastasizing lesions. Partial laryngectomy is recommended for early verrucous carcinoma of the glottis, but irradiation is recommended if the alternative is total laryngectomy. We have observed typical verrucous lesions that have disappeared with radiation therapy and not recurred. O'Sullivan et al. (80) also have made this observation. Additionally, a variety of tumors that recur after unsuccessful treatment (with surgery, radiation therapy, and/or chemotherapy) are more likely to exhibit more aggressive behavior.
Moderately Advanced Vocal Cord Cancer
Fixed-cord lesions (T3) may be subdivided into relatively favorable or unfavorable lesions. 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 T3 lesions have disease confined mostly to one side of the larynx, have a good airway, and are reliable for follow-up. Some degree of supraglottic and subglottic extension usually exists. The extent of disease and tumor volume, in particular, are related to the likelihood of control after radiation therapy (61).
The patient with a favorable lesion is advised of the alternatives of irradiation with surgical salvage or immediate total laryngectomy. Recent data suggest that the likelihood of locoregional control is better after some altered fractionation schedules compared with conventional once-daily radiation therapy (24,68). Follow-up examinations are recommended every 4 to 6 weeks for the first year, every 6 to 8 weeks for the second year, every 3 months for the third year, every 6 months for the fourth and fifth years, and annually thereafter. The patient must understand that total laryngectomy may be recommended purely on clinical grounds without biopsy-proven recurrence and that the risk of laryngeal osteochondronecrosis is about 5%.
Evaluation of cord mobility after 50.4 Gy or at the end of radiation therapy has not been helpful in predicting local control (64). Some patients in whom the vocal cord remained fixed have had local tumor control of the disease for 2 years or longer after radiation therapy.
The major difficulty in using irradiation for the more advanced lesions is distinguishing radiation edema from local recurrence during follow-up examinations (87). Progressive laryngeal edema, persistent throat pain, or fixation of a previously mobile vocal cord frequently signifies recurrent disease in the larynx, although a few patients with these findings remain disease-free with long-term follow-up.
Extended hemilaryngectomy has been used by a few surgeons in the treatment of well-lateralized fixed-cord lesions. A permanent tracheostomy is usually required because a portion of the cricoid is resected, but a useful voice may be retained (88).
Advanced Vocal Cord Carcinoma
Advanced lesions usually show extensive subglottic and supraglottic extension, bilateral glottic involvement, and invasion of the thyroid, cricoid, or arytenoid cartilage, or frequently all three (5,6). The airway is compromised, necessitating a tracheostomy at the time of direct laryngoscopy in approximately 30% of patients. Clinically positive lymph nodes are found in about 25% to 30% of patients.
The mainstay of treatment is total laryngectomy, with or without adjuvant radiation therapy. The most frequent sites of local failure after total laryngectomy are around the tracheal stoma, in the base of tongue, and in the neck lymph nodes or soft tissues of the neck. If the neck has clinically negative findings before surgery and if postoperative irradiation is planned, neck dissection may be withheld, and radiation therapy may be used to treat both sides of the neck. However, in practice, most surgeons prefer to perform elective bilateral selective (levels II-IV) neck dissections in conjunction with a total laryngectomy for T3N0 or T4N0 laryngeal cancer, even if postoperative irradiation is planned. If the lymph nodes are clinically positive, a therapeutic neck dissection is performed at the time of laryngectomy.
The indications for postoperative radiation therapy include close or positive margins, significant subglottic extension (1 cm or more), cartilage invasion, perineural invasion,
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endothelial-lined space invasion, extension of the primary tumor into the soft tissues of the neck, multiple positive neck nodes, extracapsular extension, and control of subclinical disease in the opposite neck (2,41). Preoperative irradiation is indicated for patients who have fixed neck nodes, have had an emergency tracheotomy through tumor, or have direct extension of tumor involving the skin.
Definitive irradiation is prescribed for the patient who refuses total laryngectomy or is medically unsuitable for major surgery.
As previously stated, there is evidence that two to three cycles of neoadjuvant chemotherapy followed by radiation therapy in patients obtaining at least a partial response may provide a moderate likelihood of larynx preservation without compromising cure (16). Recent data suggest that concomitant chemotherapy and irradiation is more efficacious than irradiation alone or induction chemotherapy followed by radiation therapy (23,90). The optimal combination of concomitant chemotherapy and irradiation is unclear (68).
A randomized intergroup trial (Radiation Therapy Oncology Group 91–11) compared three treatment arms: Arm A, three cycles of induction cisplatin and fluorouracil followed by irradiation in complete and partial responders; Arm B, radiation therapy and concomitant cisplatin (100 mg/m2 on days 1, 22, and 43 of radiation therapy); and Arm C, once-daily irradiation (70 Gy in 35 fractions during 7 weeks) alone (23). Five hundred forty-seven patients were randomized and followed for a median of 3.8 years; 518 patients were evaluable. The rates of larynx preservation were: Arm A, 72%; Arm B, 84%; and Arm C, 67%. The rates of larynx presentation were significantly improved for Arm B; there was no significant difference between Arm A and Arm C. The 5-year survival rates were similar for the three treatment groups: Arm A, 55%; Arm B, 54%; and Arm C, 56%. The likelihood of developing distant metastases was lower for the two groups of patients that received adjuvant chemotherapy.
Surgical Treatment
Cordectomy is an excision of the vocal cord and may be performed by the transoral approach usually with a laser or externally by a thyrotomy. Its use is usually confined to small lesions of the middle third of the cord. After cordectomy, a pseudocord is formed, and the patient has a useful, if somewhat harsh, voice.
Vertical partial laryngectomy (i.e., hemilaryngectomy) allows removal of limited cord lesions with preservation of voice. One entire cord with as much as a third of the opposite cord with the adjacent thyroid cartilage is the maximum cordal involvement suitable for surgery in men; women have a smaller larynx, and usually only one vocal cord may be removed without compromising the airway. Partial fixation of one cord is not a contraindication to hemilaryngectomy, but only a few surgeons have attempted hemilaryngectomy for selected fixed-cord lesions. The maximum subglottic extension suitable for hemilaryngectomy is 8 to 9 mm anteriorly and 5 mm posteriorly; this limit is necessary to preserve the integrity of the cricoid. Tumor extension to the epiglottis, false cord, or both arytenoids is a contraindication to hemilaryngectomy.
Supracricoid partial laryngectomy is used for selected T2 and T3 glottic carcinomas and entails removal of both true and false cords as well as the entire thyroid cartilage. The cricoid is sutured to the epiglottis and hyoid (cricohyoidopexy).
Total laryngectomy with or without neck dissection is the operation of choice for advanced lesions and as a salvage procedure for radiation therapy failures in lesions that are not suited for conservation surgery. The entire larynx is removed, and the pharynx is reconstructed. A permanent tracheostomy is required. Speech may be reconstituted with a prosthesis or with an electrolarynx. One hundred four (63%) of 166 patients entered into the surgery and postoperative irradiation arm of the Veterans Affairs Laryngeal Cancer Study Group randomized trial were evaluable for communication status at 2 years after treatment (38). Ninety-six patients had undergone a total laryngectomy and communicated as follows: Tracheoesophageal, 27 (28%); esophageal, 5 (5%); artificial larynx, 47 (50%); nonvocal, 7 (7%); and no data, 10 (10%) (38). One hundred seventy-three patients underwent total laryngectomy and postoperative radiotherapy at the University of Florida and 69 patients were evaluable for 5 years or longer (62). Voice rehabilitation was accomplished as follows: Tracheoesophageal, 19%; artificial larynx, 57%; esophageal, 3%; nonvocal, 14%; and no data, 7%.
Radiation Therapy Technique
Irradiation for T1 or T2 vocal cord cancer is delivered by small portals covering only the primary lesion. The cervical lymph node chain is not electively treated. For T1 lesions, radiation therapy portals extend from the thyroid notch superiorly to the inferior border of the cricoid and fall off anteriorly. The posterior border depends on the posterior extension of the tumor (73). For T2 tumors, the field is extended depending on the anatomic distribution of the tumor. The field size ranges from 4 × 4 cm to 5 × 5 cm (plus an additional 1 cm of “flash” anteriorly) and is occasionally 6 × 6 cm for a large T2 lesion. Portals larger than this increase the risk of edema without improving the cure rate.
A commonly used dose-fractionation schedule at many institutions is 66 Gy for T1 lesions and 70 Gy for T2 cancers given in 2-Gy fractions. Evidence suggests that increasing the dose per fraction may improve the likelihood of local control (4,19,36,37,45,69,97,119). Ample data suggest that 1.8 Gy once daily results in significantly lower local control rates compared with 2 Gy once daily (45). Yamakazi et al. (121) recently reported a prospective trial in which patients with T1N0 squamous cell carcinoma of the glottic larynx were randomized to definitive radiotherapy at 2 Gy per fraction or 2.25 Gy per fraction. The 5-year local control rates were 77% after 2 Gy per fraction and 92% after 2.25 Gy per fraction (p = .004); there was no difference in either acute or late toxicity. Patients with T1 or T2 vocal cord cancer who are treated with once-a-day fractionation at the University of Florida are irradiated with 2.25 Gy per fraction; the dose-fractionation schemes used are shown as follows: Tis–T2 A, 63 Gy in 28 fractions; and T2B, 65.25 Gy in 29 fractions.
At the University of Florida, patients are treated in the supine position; the field borders for a patient with a T1N0 cancer are depicted in Fig. 44.7 (73). The field is checked by the physician at the treatment machine according to palpable anatomic landmarks. This allows the treatment volume to be kept at a minimum and reduces the risk of geographic miss. A three-field technique, using 4-or 6-MV x-rays, is used to deliver approximately 95% of the dose through opposed lateral wedged fields weighted to the side of the lesion; the remaining dose is delivered by an anterior field shifted 0.5 cm toward the side of the lesion (Fig. 44.8) (73). The tumor dose is usually specified at the 95% normalized isodose line.
Irradiation of T3 and T4 lesions requires larger portals, which include the jugulodigastric and middle jugular lymph nodes (Fig. 44.9) (74,85). The inferior jugular lymph nodes are included in a separate low-neck portal. Patients treated at the University of Florida are irradiated in a continuous-course twice daily at 1.2 Gy per fraction to a total dose of 74.4 Gy. The portals are reduced after 45.6 Gy in 38 fractions; the reduced portals cover only the primary lesion.
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Intensity-modulated radiation therapy (IMRT) is employed if there is a clear advantage associated with this technique. Disadvantages associated with IMRT include increased dose inhomogeneity, increased total body dose, and increased labor and expense. The most common indications for IMRT for laryngeal cancers are the occasional patients with a node-positive T3–T4 cancer in which the retropharyngeal nodes are electively irradiated and the dose to the contralateral parotid gland reduced and/or a difficult low match between the lateral fields used to treat the primary site and upper neck and the anterior low neck field in a patient with a short neck and large shoulders. In the latter instance, IMRT could be used to encompass the entire target volume and avoid the problem of field junctioning entirely. IMRT is especially useful for patients with extensive subglottic invasion where achieving an adequate inferior margin with conventional lateral portals may not be possible.

Evidence from both retrospective and randomized trials points to improved therapeutic ratios with altered fractionation schedules (68). Given that irradiation is effective treatment for head and neck primary squamous cell carcinoma, it should not be surprising that higher doses of irradiation given more intensively would be more effective at providing tumor control. Because most observers have noted no increase in late toxicity with the various regimens, it generally is concluded that these schedules yield an improved therapeutic ratio. A recently updated Radiation Therapy Oncology Group 90–03 trial (24,109) reported on 1,073 patients who were randomly selected to receive one of four fractionation schedules:
· Standard fractionation: 2 Gy per fraction, once a day, 5 days a week, to a total dose of 70 Gy in 35 fractions during 7 weeks;
· Hyperfractionation: 1.2 Gy per fraction, twice daily (≥6 hours apart), 5 days a week, to a total dose of 81.6 Gy in 68 fractions during 7 weeks;
· Accelerated fractionation with split: 1.6 Gy per fraction, twice daily (≥6 hours apart), 5 days a week, to a total dose of 67.2 Gy in 42 fractions during 6 weeks, including a 2-week rest after 38.4 Gy, or;
· Accelerated fractionation with concomitant boost: 1.8 Gy per fraction, once a day, 5 days a week to a large field, plus 1.5 Gy per fraction once a day to a boost field given 6 or more hours after treatment of the large field for the last 12 treatments days, to a total dose of 72 Gy in 42 fractions during 6 weeks.
The 5-year locoregional failure rates were standard fractionation, 59%; hyperfractionation, 51%; accelerated split course, 58%; and concomitant boost, 52%. Both the hyperfractionation and concomitant boost schedules yielded locoregional control rates that were significantly better than standard fractionation. There was a trend toward improved overall survival with hyperfractionation, but no difference in cause-specific survival. Acute toxicity was increased with all three altered fractionation schedules; there was a modest increase in late effects with the concomitant boost schedule.
The treatment technique used for postoperative irradiation after total laryngectomy is depicted in Figure 44.10 (2). The treatment technique for preoperative irradiation is essentially the same as that used for irradiation alone. Alternatively, IMRT may be employed for the indications discussed previously.
Treatment of Recurrence
Most recurrences appear within 18 months, but late recurrences may appear after 5 years. The latter are likely second primary malignancies. The risk of metastatic disease in lymph nodes increases with local recurrence (63).
Recurrence after Radiation Therapy
With careful follow-up, recurrence is sometimes detected before the patient notices a return of hoarseness. There is often minimal lymphedema for 1 to 2 months after irradiation, which usually subsides or stabilizes. An increase in edema, particularly if associated with hoarseness or pain, suggests recurrence, even if there is no obvious tumor. Fixation of a previously mobile
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vocal cord usually implies local recurrence, but we have occasionally observed a patient who has experienced a fixed cord with an otherwise normal-appearing larynx and who has not shown evidence of recurrence.
It may be difficult to diagnose recurrence if the tumor is submucosal. Generous, deep biopsies are required. If recurrence is strongly suspected, laryngectomy may rarely be advised without biopsy-confirmed evidence of recurrence. Positron emission tomography may be useful to distinguish recurrent tumor from necrosis.
Radiation therapy failures may be salvaged by cordectomy, hemilaryngectomy, supracricoid partial laryngectomy, or total laryngectomy. Biller et al. (8) reported a 78% salvage rate by hemilaryngectomy for 18 selected patients in whom irradiation failed; total laryngectomy was eventually required in 2 patients. Only two patients died of cancer. These investigators offered guidelines for using hemilaryngectomy: Contralateral vocal cord is normal, arytenoid is not involved, subglottic extension does not exceed 5 mm, and vocal cord is not fixed. In our experience, 14 patients irradiated for T1 or T2 vocal cord cancers underwent a hemilaryngectomy after local recurrence and 8 were successfully salvaged (60).
Recurrence after Surgery
The rate of salvage by irradiation for recurrences or new tumors that appear after initial treatment by hemilaryngectomy is about 50%. Lee et al. (53) reported seven successes among 12 patients; one lesion was later controlled by total laryngectomy. Total laryngectomy can be used successfully to treat hemilaryngectomy failures not suitable for radiation therapy. Irradiation rarely cures patients with recurrence in the neck or stoma after total laryngectomy.
Treatment Selection and Technique: Supraglottic Larynx Carcinoma
Selection of Treatment Modality
Patients with supraglottic laryngeal carcinoma may be considered to be in an early or favorable group suitable for radiation therapy or conservation laryngectomy or an unfavorable group often requiring total laryngectomy.
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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 (39). Transoral laser excision is effective in experienced hands for small, selected lesions (103). Total laryngectomy is rarely indicated as the initial treatment for this group of patients and is reserved for treatment failures.
Radiation therapy and supraglottic laryngectomy are highly successful modes of therapy for early lesions (39). Approximately 50% of supraglottic laryngectomies performed at the University of Florida have been followed by postoperative irradiation because of neck disease and, less often, positive margins.
The decision to use radiation therapy or supraglottic laryngectomy depends on several factors including the anatomic extent of the tumor, medical condition of the patient, philosophy of the attending physician(s), and the inclination of the patient and family. Overall, about 80% of patients are treated initially by irradiation. Approximately half of the patients seen in our clinic whose lesions are technically suitable for a supraglottic laryngectomy are not suitable for medical reasons (e.g., inadequate pulmonary status or other major medical problems); these patients are treated with radiation therapy.
Analysis of local control by anatomic site within the supraglottic larynx shows no obvious differences in local control by irradiation for similarly staged lesions. Invasion of the pre-epiglottic space is not a contraindication to supraglottic laryngectomy or irradiation. Primary tumor volume based on pretreatment CT is inversely related to local tumor control after radiation therapy (61). A large, bulky infiltrative lesion, especially one with extensive preepiglottic space invasion, is a common reason to select supraglottic laryngectomy.
The status of the neck often determines the selection of treatment of the primary lesion. Patients with clinically negative neck nodes have a high risk for occult neck disease and may be treated by radiation therapy or supraglottic laryngectomy and bilateral selective neck dissections, (levels II–IV).
If a patient has an early-stage primary lesion but advanced neck disease (N2b or N3), combined treatment is frequently necessary to control the neck disease (70). In these cases, the primary lesion is usually treated by irradiation alone, with surgery added to the treatment of the involved neck site(s). If the same patient were treated with supraglottic laryngectomy, neck dissection, and postoperative irradiation, the portals would unnecessarily cover the primary site and the neck. If the patient has early, resectable neck disease (N1 or N2a) and surgery is elected for the primary site, postoperative irradiation is added only because of unexpected findings (e.g., positive margins, multiple positive nodes, or extracapsular extension). We prefer to avoid routine high-dose preoperative or postoperative irradiation in conjunction with a supraglottic laryngectomy because the lymphedema of the remaining larynx may be considerable, although it eventually subsides. However, Lee et al. (54) from M.D. Anderson Cancer Center reported excellent results with combined supraglottic laryngectomy and postoperative irradiation for moderately advanced lesions.
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Advanced Supraglottic Lesions
Although a subset of these patients may be suitable for a supraglottic or supracricoid laryngectomy, total laryngectomy is the main surgical option. Selected advanced lesions, especially those that are mainly exophytic, may be treated by radiation therapy and concomitant chemotherapy (90) with total laryngectomy reserved for irradiation failures.
For patients whose primary lesion is to be treated by a total or partial laryngectomy and who have resectable neck disease, surgery is the initial treatment, and postoperative irradiation is added if needed. If the neck disease is unresectable, preoperative radiation therapy is used. The indications for preoperative and postoperative irradiation have been previously outlined.
Surgical Treatment
Supraglottic Laryngectomy
Supraglottic laryngectomy is 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 the tumor to the true vocal cord, the anterior commissure, or both arytenoids; fixation of the vocal cord; or thyroid or cricoid cartilage invasion precludes supraglottic laryngectomy. The supraglottic laryngectomy may be extended to include the base of the tongue if one lingual artery is preserved.
All patients have difficulty swallowing with a tendency to aspirate immediately after surgery, but almost all learn to swallow again in a short time; motivation and the amount of tissue removed are key factors in learning to swallow again. Preoperatively, adequate 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. The voice quality is generally normal after supraglottic laryngectomy.
Supracricoid Laryngectomy
This procedure is an option for lesions extending from the supraglottis into one or both vocal cords. However, vocal cord fixation is a relative contraindication. At least one arytenoid must be preserved for successful decannulation and phonation. Extension to the cricoid and thyroid cartilage destruction also preclude its use. Phonation and respiratory function are reconstituted by approximating the cricoid to the hyoid (cricohyoidopexy).
Wide-Field Total Laryngectomy
Total laryngectomy is performed as previously described.
Radiation Therapy Technique
The primary lesion and both sides of the neck are treated with opposed lateral portals; wedges are used to compensate for the contour of the neck (Fig. 44.11) (73). The lower neck nodes are irradiated through a separate anterior portal. IMRT may be employed to spare one or both parotids and to avoid a low match line in the occasional patient with a short neck and large shoulders. We currently use the concomitant boost fractionation schedule when employing IMRT.
In the case of clinically positive nodes, an electron beam portal may be used to increase the dose to the posterior cervical nodes after the fields are reduced to avoid the spinal cord at 45 Gy. CT is obtained 4 weeks after completing radiotherapy, and a neck dissection is added if the residual cancer in the nodes is thought to exceed 5%; otherwise the patient is observed and a CT is repeated in 3 months (70).

Patients experience a sore throat, loss of taste, and moderate dryness during irradiation. Edema of the arytenoids may occur and give a sensation of a lump in the throat. Tracheostomy is rarely necessary, even for bulky lesions.
Edema of the larynx may persist for several months to a year. Patients who continue to smoke heighten the side effects of dryness, dysphagia, and hoarseness.
Preoperative and Postoperative Treatment Technique
If total laryngectomy is required and the lesion is resectable, postoperative radiation therapy is preferred because there is no evidence that preoperative irradiation produces any better locoregional control or survival rates than surgery and postoperative radiation therapy. Irradiation is added for close or positive margins, invasion of soft tissues of the neck, significant subglottic extension (1 cm or more), thyroid cartilage invasion, multiple positive nodes, and extracapsular extension. The high-risk areas are usually the base of the tongue and the neck.
The dose for postoperative irradiation 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. All patients are treated with a continuous course, one fraction per day, 5 days per week. The lower neck is treated with doses to 50 Gy in 25 fractions at Dmax. If there is subglottic extension, the dose to the stoma is boosted with electrons (usually 10 to 14 MeV) for an additional 10 Gy in five fractions. The treatment technique is shown in Fig. 44.10 (2). If postoperative irradiation is added after a supraglottic laryngectomy, the dose is lowered to 55.8 Gy
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given in 1.8 Gy fractions. This dose produces acceptable rates of local control and laryngeal edema (94).

The treatment technique used for preoperative radiation therapy is essentially the same as that used for patients treated with irradiation alone, using doses of 50 to 60 Gy at 1.8 to 2 Gy per fraction. Thereafter, the dose is boosted to areas of unresectable disease (usually the neck) to total doses ranging from 65 to 70 Gy.

Treatment of Recurrence
Failures after supraglottic laryngectomy or radiation therapy can frequently be controlled by further treatment; therefore, recognition of recurrence should be vigorously pursued (39). Salvage of patients with recurrence after combined total laryngectomy and irradiation is uncommon. Stomal recurrences are occasionally controlled by radiation therapy or surgery.
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Results of Treatment
Vocal Cord Cancer
The local control and survival rates after treatment of early-stage glottic carcinoma are depicted in Tables 44.3, 44.4, 44.5 and 44.6 (71). The local control and survival rates are similar for transoral laser excision, open partial laryngectomy, and radiotherapy. Larynx preservation rates are also comparable. Voice quality depends on the amount of tissue removed with partial laryngectomy and is probably similar for patients with limited lesions treated with laser to those undergoing radiotherapy and poorer for patients undergoing open partial laryngectomy (71).
Foote et al. (22) reported on 81 patients who underwent laryngectomy for T3 cancers at the Mayo Clinic between 1970 and 1981. Seventy-five patients underwent a total laryngectomy and 6 underwent a near-total laryngectomy; 53 patients received a neck dissection. No patient underwent adjuvant irradiation or chemotherapy. The 5-year rates of locoregional control, cause-specific survival, and absolute survival were 74%, 74%, and 54%, respectively. The results of definitive radiation therapy patients with T3 glottic carcinoma are depicted in Table 44.7 (85) and are similar to the surgical outcomes reported by Foote et al. (22).
The survival and control rates of patients with T3 fixed-cord lesions treated at the University of Florida are presented in Table 44.8 (67). There was no relationship between subsequent local control and whether the vocal cord remained fixed or became mobile during irradiation. The incidence of severe complications, including those after the initial treatment and any later salvage procedures, was 15% after radiation therapy alone and 15% after surgery alone or combined with adjuvant irradiation. The vocal quality varied from fair to nearly normal.

The results of treatment of T4 vocal cord carcinoma in four surgical series and two radiotherapy series are summarized in Table 44.9 (35).
Parsons et al. (86) reviewed the literature and reported a local control rate of 62% in a series of 87 patients treated with irradiation alone for T4 glottic carcinoma.
Combined-Therapy Results
The proportion of patients suitable for a supraglottic laryngectomy is depicted in Table 44.10 (39). Depending on the referral patterns, a modest subset of patients is suitable for this operation. The extent of neck disease for patients treated with either surgery or radiotherapy is shown in Table 44.11 (39). In general, patients treated with supraglottic laryngectomy appropriately have earlier stage neck disease and would be anticipated to have a lower risk of distant failure and improved survival. The local control rates after transoral laser, radiotherapy, and supraglottic laryngectomy are summarized in Tables 44.12, 44.13 and 44.14, respectively (39). In general, the local control rates after transoral laser excision are fairly good for patients with T1–T2 tumors and tend to deteriorate for those with more advanced disease. The local control rate are excellent for patients selected for supraglottic laryngectomy. However, the incidence of severe complications tends to be higher after supraglottic laryngectomy compared with radiotherapy and transoral laser excision (Table 44.15) (39).
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Follow-Up Policy
Follow-up of patients with early lesions is planned for every 4 to 8 weeks for 2 years, every 3 months for the third year, and every 6 months for years 4 and 5, and then annually for life.
Follow-up of patients with vocal cord or supraglottic larynx lesions treated by radiation therapy or conservative surgery is almost more important than the treatment itself because early detection of recurrence usually results in salvage that may include cure with voice preservation.
If recurrence is suspected but the biopsy is negative, patients are reexamined at 2- to 4-week intervals until the matter is settled. The value of follow-up CT scans for detecting early local recurrence is investigational.
Wagenfeld et al. (112) studied 740 cases of glottic larynx cancer treated from 1965 to 1974 to determine the incidence of second respiratory tract malignancies. There was a minimum follow-up of 5 years. There were 48 second respiratory tract malignancies, although only 14 were expected. Twenty-five were in the lung, and 23 were scattered among other head and neck sites. Only 7 of the 23 second head and neck primary lesions resulted in death; these second lesions were frequently diagnosed in an early stage during routine follow-up for the glottic lesion.
Because the risk of a lethal lung primary lesion is nearly as great as that of dying of an early glottic carcinoma, it makes sense to obtain annual chest roentgenograms. Approximately 50% of patients who receive moderate-to-high dose radiotherapy to the entire thyroid gland will develop hypothyroidism within 5 years, so that thyroid functions are checked every 6 to 12 months and thyroid replacement is initiated if the thyroid-stimulating hormone level begins to rise (27).
Sequelae of Treatment
Surgical Sequelae
Neel et al. (78) reported a 26% incidence of nonfatal complications for cordectomy. Immediate postoperative complications included atelectasis and pneumonia, severe subcutaneous emphysema in the neck, bleeding from the tracheotomy site or larynx, wound complications, and airway obstruction requiring tracheotomy. Late complications included granulation tissue that had to be removed by direct laryngoscopy to exclude recurrences, extrusion of cartilage, laryngeal stenosis, and obstructing laryngeal web.
The postoperative complications and sequelae of hemilaryngectomy include chondritis, wound slough, inadequate glottic closure, and anterior commissure webs (25). The complications associated with supraglottic laryngectomy and total laryngectomy for supraglottic carcinomas include fistula (8%), carotid artery exposure or blowout (3% to 5%), infection or wound sloughing (3% to 7%), and fatal complications (3%) (25). The risk of complications increased if tumor margins were involved by tumor; there was no change in risk associated with age, sex, race, laryngeal site, stage of primary tumor, size of primary tumor, use of low-dose preoperative irradiation, or status of the positive nodes.
The incidence of complications after treatment of supraglottic carcinoma is depicted in Table 44.15 (39).
Radiation Therapy Sequelae
The acute reactions from the treatment of early vocal cord cancer using a tumor dose of 2.25 Gy per day to administer a total dose 63 Gy (60Co, five fractions per week) are relatively mild. During the first 2 to 3 weeks, the voice may improve as the tumor regresses. The voice generally becomes hoarse again because of radiation-induced changes, even though the tumor continues to regress. A mild sore throat develops beginning at the end of the second week, but medication is usually not required. The voice begins to improve approximately 3 weeks after completion of treatment, usually reaching a plateau in 2 to 3 months. Patients with extensive lesions often recover a normal voice, although not as frequently as those with small tumors.
Edema of the larynx is the most common sequela after irradiation for glottic or supraglottic lesions. The rate of clearance of the edema is related to the irradiation dose, volume of tissue irradiated, addition of a neck dissection, continued use of alcohol and tobacco, and size and extent of the original lesion. Edema may be accentuated by a radical neck dissection and may require 6 to 12 months to subside.
Soft tissue necrosis leading to chondritis occurs in fewer than 1% of patients, usually in those who continue to smoke. Soft tissue and cartilage necroses mimic recurrence, with hoarseness, pain, and edema; a laryngectomy may be recommended as a last resort for fear of recurrent cancer, even though biopsy specimens show only necrosis.
Corticosteroids such as dexamethasone (Decadron) have been used to reduce radiation-induced edema after recurrence has been ruled out by biopsy. If ulceration and pain occur, administration of an antibiotic such as tetracycline may help. Of 519 patients with T1N0 or T2N0 vocal cord cancer treated at the University of Florida, 5 (1%) experienced severe complications (60), including total laryngectomy for a suspected local recurrence (1 patient), permanent tracheostomy for edema (3 patients), and a pharyngocutaneous fistula after a salvage total laryngectomy (1 patient).
In patients irradiated for supraglottic carcinoma, sore throat persists 3 to 4 weeks after completion of treatment. There is an associated dry mouth from irradiation of the salivary and parotid glands, a loss of taste, and a sensation of a lump in the throat. It is unusual for patients to require a tracheotomy before irradiation unless severe lymphedema develops at the time of direct laryngoscopy and biopsy. However, in patients who have recovered from the direct laryngoscopy and biopsy without obstruction, a tracheotomy has rarely been required during a fractionated course of radiation therapy.
Patients treated twice a day with 1.2 Gy fractions (continuous-course technique) to total doses of 74.4 to 76.8 Gy usually have more brisk acute reactions than those treated once a day with 2-Gy fractions. Approximately 20% treated with twice-a-day irradiation require temporary gastrostomy feeding tubes because they have difficulty in swallowing (1).
Examples of acute chondritis requiring discontinuation of treatment have not been seen, although most epiglottic lesions exhibit cartilage invasion.
The epiglottis, both suprahyoid and infrahyoid portions, remains thicker than normal for long periods of time, but this is not often associated with difficulty in swallowing, respiratory obstruction, or aspiration. The patient is cautioned to eat and drink slowly until the edema resolves. The false cord and arytenoids may develop some edema.
Lesions of the suprahyoid epiglottis frequently destroy the tip of the epiglottis, and it may require some time for the exposed cartilage to heal. Successful irradiation of infrahyoid epiglottis tumors is not associated with a high rate of necrosis, even though most of these lesions penetrate the porous epiglottic cartilage.
The incidence of severe late complications in 274 patients treated with radiation therapy alone or combined with neck dissection at the University of Florida was 4% (39).
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