Timothy J. Kruser, Hiral K. Shah, Henry T. Hoffman, Nitin A. Pagedar, and Paul M. Harari
There is a strong association between tobacco use and the development of hypopharynx cancer.1–3 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 (H&N) region, multidisciplinary evaluation and management are critical and should involve the H&N surgeon, radiation oncologist, medical oncologist, nurse, nutritionist, speech or 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 H&N cancer sites.4 As with most tumors of the H&N region, there is significant interest in combining molecular targeted therapies with traditional cytotoxic therapy in an effort to further improve outcomes.
ANATOMY
The hypopharynx, sometimes referred to as the laryngopharynx, is contiguous superiorly with the oropharynx and inferiorly with the cervical esophagus (Fig. 46.1). 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 predominantly comprises the 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. 46.2).
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 to the retropharyngeal nodes, including the most cephalad retropharyngeal nodes of Rouviere.
FIGURE 46.1. Posterior view of the hypopharynx shows the relationship of the pyriform sinus, pharyngeal wall, and postcricoid region within the head and neck. (From Putz R, Pabst R, Sobotta: Atlas der Anatomie des Menschen, 2001. © Elsevier GmbH, Urban & Fischer Verlag München, with permission.)
EPIDEMIOLOGY AND ETIOLOGY
Hypopharynx cancers are relatively uncommon. Approximately 1,800 cases per year were diagnosed annually in the United States from 1990 to 2004,4 and the population-adjusted annual incidence rate in the United States was 0.7 per 100,000 from 2000 to 2008, according to the National Cancer Institute’s Surveillance, Epidemiology, and End-Results (SEER) database.5 Hypopharyngeal cancers accounted for 5.2% of upper aerodigestive tract cancers during that time. Approximately three-fourths of hypopharyngeal cancers occur in men, with a mean age of 65 years. Over 90% of patients with hypopharynx cancer report past cigarette use.6 Alcohol appears to potentiate the carcinogenic effects of tobacco. Additionally, alcohol consumption at medium to high levels for a long period of time can increase the likelihood of hypopharynx cancer in nonsmoking patients.7 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 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.8,9 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.10
Human papilloma virus (HPV) infection is well established as a risk factor for the development of squamous cell carcinoma of the gynecologic tract, particularly uterine cervix. The relation between HPV and H&N cancer is now becoming much better appreciated, particularly for cancers of the oropharynx, where it may approach 60% to 70% in some series. Studies have demonstrated that approximately 20% to 25% of patients with hypopharynx cancer test positive for HPV DNA,11,12 and seropositivity for antibodies against the HPV-16 E6 and E7 antibodies has been associated with a significantly elevated risk of hypopharyngeal cancer.13 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.7Favorable 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.
FIGURE 46.2. A: Posterior view of resected larynx and hypopharynx specimen afforded by incision through the posterior pharyngeal wall, cricopharyngeus, and cervical esophagus in the posterior midline. The aryepiglottic folds (marked) and arytenoids separate the pyriform sinuses (hypopharynx) from the larynx. B: The three primary anatomic subsites (posterior pharyngeal wall, postcricoid region, and pyriform sinuses) are revealed in this posterior view of the hypopharynx with the posterior pharyngeal wall incised.
FIGURE 46.3. Five-year survival by mucosal site for head and neck cancers from 1990 to 1999 cases. (From Cooper JS, Porter K, Mallin K, et al. National Cancer Database report on cancer of the head and neck: 10-year update. Head Neck 2009;1:748–758, with permission.)
FIGURE 46.4. Observed survival for hypopharyngeal cancer in the United States is calculated for new cases identified in the NCDB in 2003 and includes all pathologic types and the selected anatomic sites: C129, C130, C131, C132, C138, C139. Staging according to sixth edition of the AJCC Cancer Staging Handbook. (From National Cancer Data Base. Commission on Cancer. American College of Surgeons. Benchmark Reports. Available at: http://cromwell.facs.org/BMarks/BMPub/Ver10/bm_reports.cfm, with permission.)
TABLE 46.1 AMERICAN JOINT COMMITTEE ON CANCER 2010 T STAGING FOR HYPOPHARYNX CANCER
PROGNOSTIC FACTORS
Several prognostic factors have been identified for patients with hypopharynx cancer. Age, particularly older than 70 years, has been identified as an unfavorable predictor of outcome.7 This may simply reflect the diminished likelihood of elderly patients to successfully tolerate the aggressive therapy approaches required for locoregionally advanced cancers of the H&N. 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.14,15 In addition, tumor location has an impact on outcome, with cancers of the pyriform sinus generally faring better than those arising in the postcricoid or posterior pharyngeal wall regions.14,15 As a whole, hypopharynx cancer patients fare poorly in comparison with patients harboring tumors from other H&N sites (Figs. 46.3 and 46.4).4,16 To a lesser extent, tobacco, alcohol, and dietary factors (carotenoids, vitamin C, vitamin E, and flavonoids) may also have an impact on outcome.17
Biologic factors have been investigated for their potential role in hypopharyngeal cancer. The presence of p53 gene mutations has 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.18,19 Further, there are conflicting data regarding the prognostic significance of EGFR expression for patients with hypopharyngeal cancer.20 Some studies suggest EGFR overexpression portends a worse prognosis for patients undergoing (chemo)radiotherapy but not for patients treated with primary surgical resection.21,22
STAGING
The most commonly used staging system for hypopharynx cancer is the American Joint Committee on Cancer’s (AJCC) 2009 seventh edition of the AJCC Cancer Staging Handbook and is based on a combination of clinical and radiographic data (Table 46.1).23 No significant changes were made between the sixth and seventh editions other than to alter the classification of extension to the esophagus (previously T4a, from the tumor-node-metastasis [TNM] classification) toT3. The nodal and group staging is similar to other sites within the pharynx with the exception of nasopharynx. Although AJCC staging is a useful tool to broadly group similar cancer types, it should not be used as a blueprint for management. 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
It is sometimes difficult to definitively assign tumor origin to a specific subsite in the hypopharynx when the tumor overlaps more than one subsite. Of the hypopharynx cancer cases recorded in the National Cancer Institute’s SEER database between 2000 and 2008, 83% of tumors with a known subsite arose in the pyriform sinus. An additional 9% arose from the posterior pharyngeal wall, and 4% originated in the postcricoid region.5
Due to the high propensity for advanced primary disease as well as regional nodal involvement, the majority of hypopharynx cancer patients present with stages 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.24
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 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.14 Nodal spread to the paratracheal nodes and inferior deep cervical nodes is not uncommon. Tumors 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.25 This extensive pattern of tumor infiltration can present considerable challenge in the effort to achieve clear surgical margins or full dosimetric coverage with radiotherapy.
Regional Disease
Due to the rich lymphatic drainage of the hypopharynx, more than 50% of patients will manifest clinically positive cervical lymph nodes at the time of diagnosis, and ultimately 65% to 80% of patients will have nodal involvement, as 30% to 40% of N0 necks harbor micrometastatic disease when electively dissected.26 Jugular chain nodes, levels II to IV, as well as retropharyngeal nodes are all at high risk of harboring regional metastases in patients with hypopharynx cancer. Postcricoid tumors may also spread directly to pre- and paratracheal nodal basins. In light of cross-draining lymphatics, there is a significant risk of bilateral cervical node metastasis (Fig. 46.5).27,28
Distant Metastases
The most common site for distant metastasis to develop in patients with cancer of the hypopharynx is the lung. Previously, approximately one-quarter of patients diagnosed with hypopharynx cancer presented with distant metastases, although this incidence in more recent reports is estimated at approximately 16%.29 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.30
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 second 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 more than 2 years following initial treatment.6
FIGURE 46.5. Nodal distribution patterns for a series of 267 patients with hypopharynx cancer as summarized by admission records at the M.D. Anderson Cancer Center. (From Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972;29:1446–1449, with permission.)
CLINICAL PRESENTATION
In light of the nonspecific nature of early symptoms, the majority of patients with cancers of the hypopharynx present with advanced local 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 pharyngeal obstruction, invasion of constrictor muscles, prevertebral space invasion, or strap muscle invasion. Common 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.31 Roughly 25% of patients will present with clinical stage III disease and 50% with clinical stage IV disease; however, reflux symptoms can be a common presentation leading to diagnosis of stage I or II hypopharyngeal tumors.6 Selected patients may first come to medical attention with complaints of unilateral ear pain (referred otalgia) due to tumor involvement of the visceral sensory nerves of the pharynx.
FIGURE 46.6. A: Outpatient clinic photograph taken through a rigid endoscope mounted with a 35-mm camera of a newly diagnosed exophytic T2 tumor arising from the right pyriform sinus with involvement of the adjacent aryepiglottic fold. There was no compromise of vocal cord mobility, and clinical staging of the primary lesion was T2. B: Photographic examination 1 year following 70-Gy radiation and concurrent cisplatin chemotherapy with complete tumor regression and excellent functional status of the laryngopharynx. Note mild to moderate mucosal edema of supraglottic structures following high-dose radiation.
FIGURE 46.7. Axial computed tomography image from the same case as in Figure 46.6, depicting the T2 hypopharynx tumor involving the right pyriform sinus.
PRETREATMENT EVALUATION AND STAGING WORKUP
A comprehensive workup 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. A previous history of another upper aerodigestive tract malignancy and a history of tobacco smoking are commonly associated. The 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 (FNA) biopsy, there is little value in this approach, because most patients will receive advanced radiographic imaging to further define the nodal involvement. On rare occasions FNA may be useful to help distinguish other coexisting causes of lymphadenopathy such as lymphoma. Most patients will undergo a direct laryngoscopy under general anesthesia in conjunction with esophagoscopy. This panendoscopy allows not only biopsy confirmation of the primary tumor site, but also mapping of the extent of the tumor as well as the ability to survey for synchronous primary tumors (Fig. 46.6A). Use of transnasal fiberoptic techniques makes it possible for a panendoscopy to be done for selected patients without anesthesia in the clinic setting.
In addition to panendoscopy, patients should undergo either high-resolution CT with contrast (or MRI) extending from the skull base to below the clavicle to help assess the extent of the primary tumor and to quantitatively and qualitatively assess cervical adenopathy (Figs. 46.7 and 46.8).27 Although a chest x-ray has traditionally been used to assess for the presence of pulmonary metastasis, 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) imaging (with accompanying CT for coregistration) is increasingly used to assess the extent of regional adenopathy and to survey for the presence of distant metastasis. FDG-PET is becoming an increasingly valuable adjunct to CT or MRI in the radiation treatment planning process, particularly for patients treated with conformal intensity modulated radiation therapy (IMRT) or tomotherapy techniques. Di Martino et al.32 compared CT, PET, color-coded duplex sonography, palpation, and panendoscopy in assessment of tumor and nodal status. The results of this study are summarized in Table 46.2 and support the promising sensitivity and specificity of PET scanning in H&N cancers. Schwartz et al.33 examined standardized uptake value (SUV) of primary and nodal metastasis in H&N 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. However, there was no correlation between nodal SUV and clinical outcome.
A recent prospective multicenter study of 233 H&N squamous cell carcinoma (SCC) patients (including 46 hypopharyngeal cancer) highlighted the potential impact of PET imaging on H&N SCC management.34 TNM staging and therapeutic decisions were first determined based on conventional workup, and then physicians were unblinded to FDG-PET data and asked to restage the patients and reanalyze their therapeutic decisions. PET and conventional workup revealed discordant TNM staging in 100 patients (43%). PET was deemed significantly more accurate than conventional staging and improved the staging in 20% of patients. Incorporation of PET data ultimately impacted management in 32 patients (13.7%) (Table 46.3), supporting the use of FDG-PET in H&N SCC staging.
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 determine the degree of dysfunction prior to therapy. This may be done as a bedside study of swallowing capacity, a fiberoptic endoscopic evaluation of swallowing, or (usually preferably) through the more definitive fluoroscopic barium swallow study. This modified barium swallow study is called a cookie swallow, video pharyngogram, or oropharyngeal motility study and is most commonly done with a speech pathologist in attendance. If objective swallowing dysfunction is present, patients may be taught 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.
Because 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.
FIGURE 46.8. Axial gadolinium-enhanced T1-weighted magnetic resonance image scan with fat-saturation depicting metastatic lateral retropharyngeal node with evidence of central necrosis and peripheral enhancement.
TABLE 46.2 COMPARISON OF VARIOUS MODALITIES FOR STAGING
TABLE 46.3 IMPACT OF FDG-PET ON STAGING, MANAGEMENT FOLLOWING CONVENTIONAL WORKUP
PATHOLOGICAL CLASSIFICATION
In SEER data from 2000 to 2008, 93.9% of hypopharynx cancers were squamous cell carcinoma, with lymphoma, sarcoma, adenocarcinoma, and adenoid cystic carcinoma each accounting for approximately 0.5% of cases.5Similarly, the National Cancer Data Base (NCDB) Benchmark Reports evaluated 17,654 cases of hypopharyngeal cancer in the United States between the years of 2000 and 2008. Over 90% of cases were SCC.16
TABLE 46.4 GENERAL TREATMENT RECOMMENDATIONS BASED ON HYPOPHARYNX TUMOR STAGE
TABLE 46.5 FIVE-YEAR ONCOLOGIC OUTCOMES FOR TRANSORAL MICROLASER SURGERY FOR T1 OR T2 HYPOPHARYNGEAL TUMORS
MANAGEMENT
For patients presenting with early-stage, resectable disease, voice-preserving surgery and definitive radiotherapy alone are viable and acceptable treatment options. The vast majority of patients, however, present with stage III or IV disease and warrant multimodality treatment. A key consideration in determining the favored approach for these patients is the likelihood and motivation to preserve laryngopharyngeal function (Table 46.4).
Primary Surgery
T1 and T2 Tumors
Contemporary indications for primary surgical management of patients with early cancers of the hypopharynx include those with a history of previous H&N radiation, those in whom organ conservation approaches are deemed possible, and those who refuse radiation. Even for hypopharynx cancer patients who will receive nonoperative treatment approaches, it remains critical for the H&N 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). The surgeon will also play a vital role in multidisciplinary oncologic follow-up after nonoperative treatment.
Selected 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, the base of the tongue, and the 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 nothing by mouth status is common from an 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 cartilage invasion, vocal fold fixation, postcricoid invasion, deep pyriform sinus invasion, and extension beyond the larynx.
Innovations with free-flap reconstruction have allowed retention of speech, 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.35
In recent years, advancements in organ preservation surgery have included the use of transoral laser microsurgery and transoral robotic surgery. For selected cases, these approaches can achieve oncologic tumor removal, while limiting normal tissue disruption, thereby potentially avoiding tracheostomy and the use of feeding tubes.36–39 This approach may involve concurrent or delayed neck dissection following transoral resection of the primary lesion (to allow for final margin assessment). The necks in some T1N0 patients may be observed with close interval follow-up CT scans. Adjuvant (chemo)radiotherapy is utilized in the majority of patients using this approach (see “Postoperative Radiotherapy” below for indications) and should generally encompass the primary tumor site as well as bilateral necks and supraclavicular fossae. Recent results have demonstrated that appropriately selected T1 or T2 lesions can achieve negative margins by transoral laser microsurgery or transoral robotic surgery.36 Oncologic outcomes appear similar to open surgical approaches using this technique and are likely accompanied by lower rates of permanent gastrostomy tube or tracheostomy placement (Table 46.5).
T3 or T4 Resectable Tumors
Favorable T3 hypopharynx cancers that present in the upper aspect of the pyriform sinus and allow full extirpation by either an extended supraglottic laryngectomy or extended vertical partial laryngopharyngectomy with free flap reconstruction are infrequent. Most 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 if closure over a nasogastric tube was possible. 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 a pedicled or free flap.
For more bulky tumors of the hypopharynx, total laryngopharyngectomy, removal of the larynx and the entire hypopharynx, is required. This procedure creates a gap between the oropharynx and esophagus that must be reconstructed with a tubed fasciocutaneous flap such as the radial forearm free flap or anterolateral 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 cricopharyngeus to ensure the inferior margin. In this case, gastric pull-up or colon interposition are reconstructive options used to restore the conduit for food and saliva extending from the oropharynx to the stomach.
TABLE 46.6 RESULTS OF RTOG POSTOP CHEMORADIATION TRIAL
TABLE 46.7 RESULTS OF EORTC POSTOPERATIVE CHEMORADIATION TRIAL
TABLE 46.8 GENERAL ANATOMIC LANDMARKS FOR FIELD DESIGN USING CONVENTIONAL HEAD AND NECK RADIOTHERAPY FOR HYPOPHARYNX CANCER
Palliative Surgery
For patients with incurable, metastatic disease at presentation, or with symptomatic local recurrence not amenable to curative salvage therapy attempts, surgery can play an important role in palliation. If aspiration of secretions (despite nothing 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 the constant need for suctioning his or her own secretions. In selected patients, laryngopharyngectomy with gastric pull-up may be a reasonable palliative option. Finally, gastric feeding tube placement can be considered for patients who do not wish to pursue palliative radiation therapy or surgery.
Postoperative Radiation Therapy
Most advanced hypopharynx cancers that are treated with initial surgical resection have unfavorable features that warrant the addition of postoperative 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 or bony invasion, more than one metastatic lymph node, or the presence of extracapsular extension (ECE). Conventional therapy involves the use of a shrinking-field technique to deliver 54 to 63 Gy to all areas at risk and a boost to 60 to 66 Gy to regions of ECE 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.
The Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC) have evaluated the role of concurrent chemotherapy along with postoperative radiation in prospective randomized trials. 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 disease-free survival for patients who received concurrent chemoradiotherapy. However, no significant benefit in absolute survival was confirmed (Table 46.6).40 The EORTC conducted a similar trial that included patients with stage III (except T3N0 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 (Table 46.7).41 A subsequently published post hoc analysis of the combined data from these trials suggested that patients with ECE and positive margins were most likely to benefit from the addition of chemotherapy, while those with two or more involved lymph nodes without ECE as their only risk factor did not appear to benefit from the addition of chemotherapy.42
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. A recently updated meta-analysis demonstrated similar modest benefit from the addition of concurrent chemotherapy in the postoperative setting as compared to the definitive setting. However, this analysis showed that patients older than 70 years of age derive little to no benefit from the addition of systemic chemotherapy to radiation in H&N cancer.43 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.
Definitive Radiation Therapy
T1 and T2 Tumors
Curative radiation therapy (RT) is generally the preferred treatment option for patients with T1 or T2 hypopharynx tumors (see Table 46.4). 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 (Table 46.8). One of the most common worldwide fractionation regimens involves the delivery of 2 Gy daily fractions to 70 Gy over 7 weeks. 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 the skull base to the clavicle. Due to the varying thicknesses of the head and neck, custom compensators or wedges should be used for the lateral fields to improve dose homogeneity. Shrinking field techniques to spare direct spinal cord dose after approximately 45 Gy, as well as final mucosal reductions after 54 to 60 Gy, are often appropriate with posterior neck boosting, with electrons to supplement posterior chain nodal dosing without excessive dose to the spinal cord.
SCC of the H&N 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 outcomes in H&N cancer patients treated with radiation alone. Altered fractionation techniques, including hyperfractionation (e.g., 1.1–1.4 Gy twice daily) and accelerated fractionation (e.g., 6 fraction per week or concomitant boost regimens), have demonstrated improved locoregional control rates for H&N cancer patients.44–46 A recent meta-analysis examined 15 trials that compared conventional fractionation to altered fractionation, either hyperfractionation or accelerated fractionation. This meta-analysis 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 50.47
Early T-stage hypopharynx patients with N0 or N1 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 T1N0 lesions, patients may achieve 5-year disease-specific survival (DSS) on the order of 90%, while T2N0 lesions may achieve DSS above 70% (Tables 46.9 and 46.10).48–52
The use of three-dimensional CT-based planning has become routine in the management of H&N cancer patients (Fig. 46.9). CT-based planning allows precise delineation of target volume and visualization of dose distributions (Fig. 46.10). In the past several years, there has been significant interest in the use of IMRT in H&N 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 to T3 primary lesions with N2b or less 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 an optically guided localization system is used to enhance treatment precision for patients undergoing IMRT for H&N cancer.53 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.54,55 A recent randomized trial of conventional radiotherapy versus IMRT in patients with T1-4N0-3 oropharyngeal and hypopharyngeal tumors at high risk for xerostomia highlighted the benefits of IMRT for parotid sparing. Patients were treated either postoperatively or definitively, and the contralateral parotid was constrained to <24 Gy to the whole gland. Grade 2 or worse xerostomia was significantly reduced at both 12 months (74% conventional vs 38% IMRT) and at 24 months (83% conventional vs 29% IMRT).56 These benefits translated to significantly better quality-of-life scores in the IMRT group and strongly support a role for IMRT in H&N SCC radiotherapy.
TABLE 46.9 LOCAL CONTROL FOR CARCINOMA OF THE POSTERIOR PHARYNGEAL WALL TREATED WITH RADIATION ALONE
TABLE 46.10 CAUSE-SPECIFIC AND OVERALL SURVIVAL FOR CARCINOMA OF THE PYRIFORM SINUS TREATED WITH RADIATION ALONE
FIGURE 46.9. Digitally reconstructed radiograph depicting a classical lateral field designed to encompass the T2 pyriform sinus cancer from Figures 46.6 and 46.7 plus bilateral cervical lymphatics from skull base to cricoid, with a matching anterior low-neck field to extend the lymphatic coverage to the level of the clavicle.
FIGURE 46.10. Beam’s eye projections of intensity-modulated radiation therapy target contours for patient with T2N2bM0 tumor of the right pyriform sinus (same case as depicted in Figs. 46.6, 46.7 and 46.9). A,B: Depict anterior and lateral projections highlighting the GTV (red, 70 Gy), high-risk CTV1 (green, 60 Gy), low-risk CTV2 (blue, 54 Gy), and bilateral parotid glands. C: Demonstrates transverse, sagittal, and coronal treatment planning images depicting head and neck intensity-modulated radiation therapy isodose distributions for the same patient. The left parotid gland received a mean dose of 22 Gy.
T3 and T4 Tumors
There are several reasons why hypopharynx cancer patients who are technically resectable may not undergo primary surgery. These include age (e.g., patients over 70 to 80 years old), the presence of significant medical comorbidities, 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 approximately 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 given the overall survival benefit observed with these approaches over standard fractionation in meta-analysis.47
In patients with adequate performance status, concurrent chemoradiation strategies using platinum-based chemotherapy should be considered. The recently updated meta-analysis to examine the benefit of chemotherapy in advanced H&N cancer confirms a significant survival advantage for the use of concomitant chemotherapy (6.5%), with the effect of single-agent platin significantly higher than other monochemotherapies.43 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 over 70 years of age. This same loss of statistical benefit for patients over 70 years of age is also observed for the outcome gains derived from altered fractionation over conventional fractionation.47 Therefore, once-daily radiation regimens without concurrent chemotherapy may be quite reasonable for hypopharynx patients over 70 years of age or for those patients with modest performance status.
Another alternative to concomitant chemotherapy or accelerated fractionation is the more recent introduction of molecular-targeted therapies in the treatment of H&N cancer patients. The most mature clinical dataset in H&N 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 H&N cancer patients confirmed a locoregional control improvement (10% at 5 years) and overall survival advantage (10% at 5 years) with the addition of cetuximab.57,58 A relatively small subset of patients with hypopharynx cancer was 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 H&N cancer are in progress in both the definitive and high-risk postoperative settings.
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 16,136 cases diagnosed in 2000 to 2008 reveal the combination of radiation and chemotherapy to be the most common initial treatment overall for stage II (32.6%), stage III (47.8%), and stage IV (43.8%) disease.16 Over 50% of stage III and stage IV cases received initial treatment with chemotherapy in some form—either alone or in combination with radiation or surgery. Radiation as a single-modality therapy was the most common initial treatment for stage I hypopharynx cancer (24.4%), followed by surgery alone (21.0%) as the next most common. It has been reported that approximately 35% to 45% of patients with advanced hypopharyngeal tumors treated with concurrent chemoradiotherapy utilizing IMRT can be expected to live 5 years, with laryngeal preservation in approximately two-thirds of survivors (Table 46.11).59,60 These survival rates from single institutions utilizing IMRT should be interpreted cautiously in light of less favorable outcomes identified through a cross-sectional analysis of patients diagnosed with hypopharyngeal cancer in the United States in 2003. Review of the NCDB data identified 5-year observed survival for the majority of hypopharyngeal cancers (stage IV) to be only 19.8% (see Fig. 46.4).16
FIGURE 46.11. The stage-specific first course of treatment for hypopharyngeal cancer in the United States from 2000 to 2008 is presented with unknown stage excluded. S, surgery; XRT, radiotherapy; Ch, chemotherapy. (From National Cancer Data Base. Commission on Cancer. American College of Surgeons. Benchmark Reports. Available at: http://cromwell.facs.org/BMarks/BMPub/Ver10/bm_reports.cfm, with permission.)
TABLE 46.11 ONCOLOGIC OUTCOMES FOR PATIENTS UNDERGOING CONCURRENT CHEMORADIOTHERAPY AND INTENSITY-MODULATED RADIATION THERAPY FOR ADVANCED HYPOPHARYNGEAL CANCERS
Induction Chemotherapy and Sequential (Chemo)radiation
Recently, there has been renewed interest in the concept of induction chemotherapy approaches for patients with locoregionally advanced H&N cancer. 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 with tumors that would require total laryngectomy as the surgical approach. This trial randomly allocated patients to induction chemotherapy with cisplatin and 5- florouracil (5-FU) 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 larynxes.60
More recently the introduction of taxane-containing regimens have been demonstrated to improve outcomes in patients receiving induction chemotherapy. Three randomized trials have been reported that compare induction 5-FU and cisplatin versus 5-FU, cisplatin, plus a taxane. The EORTC study (TAX-323) randomized patients with locoregionally advanced, unresectable disease to either induction cisplatin and fluorouracil (PF) versus induction docetaxel, cisplatin, and fluorouracil (TPF) followed by definitive radiation alone.62 Treatment with TPF improved the median overall survival from 14.5 months to 18.8 months, with a 27% reduction in the risk of death. Similar results were noted in TAX-324, which utilized similar induction chemotherapy arms (TPF vs. PF), followed by concurrent chemoradiotherapy with carboplatin.63 Five-year survival in the TPF arm was 52% versus 42% receiving PF, while no increased rates of gastric feeding tubes or tracheostomies were noted between groups. A subgroup analysis of larynx and hypopharynx patients demonstrated improved survival in these patients, as well as higher rates of laryngectomy-free survival.64
In addition to enhanced survival outcomes, a recent randomized French study demonstrated that TPF induction chemotherapy (compared to PF induction) results in superior tumor response rates (80% vs. 59%) as assessed by laryngoscopy and CT or MRI.65 Those with response to induction chemotherapy were treated with organ-preserving (chemo)radiotherapy, while nonresponders received laryngectomy and postoperative (chemo)radiation. The higher response rates in the TPF arm allowed for higher rates of laryngeal preservation (70% vs. 57% at 3 years), without a detriment in overall survival (60% at 3 years in both arms). These aggressive approaches certainly appear worthy of consideration for H&N subsites such as hypopharynx where the organ preservation is desirable and overall outcomes are poor, with both locoregional control and distant metastases presenting a formidable challenge. Patients with good performance status, no contraindications to taxanes or platins, a high tumor burden or advanced nodal disease may be optimal candidates for this approach.66 Nevertheless, these strategies are costly and toxic, and it is unknown how these outcomes compare to concurrent chemoradiation approaches. 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 best perspective for advanced H&N cancer patients.
Postradiotherapy Neck Dissection
Patients with hypopharynx cancer also require careful evaluation regarding regional nodal metastases. For N0 or N1 patients treated with primary radiation or chemoradiation approaches, adjuvant neck dissection is generally unnecessary. However, for patients presenting with N2 or N3 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. An increasing number of reports suggest that detailed imaging of the neck 12 weeks postradiation with FDG-PET can serve as a valuable guide to help select those patients warranting adjuvant neck dissection. One such study from the University of Iowa 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 H&N radiation or (chemo)radiotherapy.67 Despite these emerging data, many institutions mandate adjuvant neck dissection for all patients presenting with N2 or N3 neck disease in an effort to maximize regional disease control.68–70 Both approaches are readily defendable at present. 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.
Palliative Radiotherapy
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, concurrent chemoradiotherapy, or induction chemotherapy with sequential (chemo)radiotherapy, as discussed above. 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 × 5 fractions over 1 to 2 weeks with repeat of the same 3 weeks hence if favorable initial tolerance and response is achieved. A recent study suggests using a 3.7 Gy fraction twice daily × 2 consecutive days for 3 cycles every 2 to 3 weeks, as described in RTOG-85-02, may have similar palliative efficacy with less toxicity as compared to other palliative regimens.71 Other approaches described include 50 Gy in 16 fractions72 and 30 Gy in 5 fractions, 2 fractions per week.73 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.
Palliative Chemotherapy
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, as described above. 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. Median overall survival for patients with metastatic disease is 6 to 10 months.74 Single-agent cisplatin is usually the first regimen, as it has been shown to improve overall survival.75 Combinations of cytotoxic chemotherapies have demonstrated improved response rates over cisplatin alone, but have not improved survival and are accompanied by increased toxicity76 and therefore are uncommonly utilized. However, recent randomized studies have shown efficacy of the anti-EGFR monoclonal antibody cetuximab. In combination with cisplatin as first-line treatment, cetuximab improved overall survival from 7.4 months to 10.1 months over cisplatin alone.77 As second-line therapy in patients who have progressed through platinum-based chemotherapy, cetuximab also has demonstrable activity as either monotherapy78 or in combination with platinum-based chemotherapy.79
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, nothing by mouth status with the use of gastrostomy feedings, and 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 H&N 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 third 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 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.80 Dose-limiting toxicities commonly include hypotension and nausea. There has been concern over possible tumor-protective effects of amifostine, but a recent meta-analysis does not suggest this.81 However, data supporting the use of amifostine to reduce xerostomia has been generated in the setting of conventional radiation, and the magnitude of benefit on xerostomia of parotid-sparing IMRT appears greater than that of amifostine.55,56 Therefore, the ultimate value of amifostine in patients with advanced H&N cancer, especially in the setting of IMRT, has been called into question.82 Currently there is no universal standard recommendation across treatment centers for the use of this radioprotector.
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. 46.6B). 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.
LONG-TERM FOLLOW-UP
Regardless of whether patients undergo primary surgery or radiation therapy, there is value in close posttreatment surveillance by H&N surgeon and radiation oncologist in a multidisciplinary fashion. Follow-up care is designed initially to survey for recurrence. As duration from time of intervention to clinic visits lengthen, the focus shifts to surveillance for second primaries (i.e., lung), to address morbidity from treatment, and to provide generalized support.
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 H&N radiation, the serum thyroid-stimulating hormone level 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.83 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 or larger 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.67
In the posttreatment setting of hypopharynx cancer patients, the involvement of an experienced H&N 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 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 H&N radiation and chemotherapy presents several resection and reconstructive healing challenges for the surgeon, selected patients may still derive long-term benefit from this approach. Select patients with low-volume localized disease may be candidates for transoral laser microsurgery for recurrent disease following radiation.84 Recurrent patients who initially received comprehensive H&N radiation have traditionally not been considered good candidates for repeat high-dose radiation in light of normal tissue tolerances. However, two recent prospective RTOG studies have demonstrated that reirradiation to the H&N is feasible.85,86 With the advent of highly conformal radiation delivery techniques, selected patients may benefit from reirradiation approaches in conjunction with systemic chemotherapy.87 A retrospective study from Memorial Sloan-Kettering Cancer Center has suggested that IMRT is beneficial for local control in this setting,88 and a recent prospective trial of reirradiation utilizing IMRT suggests long-term disease control can be achieved in select patients with tolerable toxicity.89 Many patients with recurrent disease, however, are not good candidates for aggressive surgery or salvage radiation therapy and are best served with systemic chemotherapy or best supportive care approaches.
QUALITY OF LIFE
Assessment of parameters, including functional status, organ preservation, treatment cost, and patient-assessment of quality of life (QOL), 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.90 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.91 evaluated long-term QOL in a matched pair analysis comparing the surgical and nonsurgical treatment of patients with advanced H&N 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 QOL score. These investigators concluded that, although it seems reasonable that organ preservation (nonsurgical) treatment will uniformly result in a higher QOL, the complexities of human adjustment and multitude of potential treatment effects render this assumption invalid for many patients. Alternatively, a study from the Medical University of South Carolina compared swallow-related QOL after surgery or radiotherapy for H&N cancer using a dysphagia symptom 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.92
There have been relatively few prospective assessments of QOL following treatment for H&N 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.93 retrospectively assessed speech intelligibility and QOL in survivors of H&N cancer. A total of 64 patients were enrolled; 31 underwent RT alone, 5 surgery alone, and 28 received both. All patients underwent comprehensive subjective and objective testing of speech function and QOL. They found significant subjective and objective deficits in speech and QOL even 5 years after completion of therapy. Terrell et al.94 reported the results of a self-administered health survey of 570 patients at a Veterans’ Administration hospital that demonstrated that the single most notable event having a negative impact on QOL 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 QOL utilizing the EORTC QLQ-C30 and QLQ-H&N35 questionnaires was conducted in Sweden on 357 patients. This study found that QOL 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 QOL.95 Similarly, another study prospectively examining swallow function in H&N cancer patients demonstrated that worse swallowing was associated with hypopharyngeal tumor sites.96 Although the use of IMRT can have a significant impact on xerostomia and QOL measures in H&N cancer patients,97,98 the intimate approximation of hypopharyngeal tumors to pharyngeal constrictor musculature does not allow for sparing of these structures vital to long-term swallow function, likely contributing to the poorer QOL of hypopharynx patients in comparison to other H&N cancer patients.99
CONCLUSION
Patients with cancers of the hypopharynx commonly present with advanced disease associated with varying degrees of compromise in speech or swallow function. Many hypopharynx cancer patients also carry significant medical and social comorbidities. Typically, small T1 or T2 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.
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