Carcinoma of the hypopharynx

Surg Oncol Clin N Am 13 (2004) 81–98

Carcinoma of the hypopharynx Christine G. Gourin, MD, FACS*, David J. Terris, MD, FACS Department of Otolaryngology–Head and Neck Surgery, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA

Carcinoma of the hypopharynx is uncommon, accounting for 4% of all malignancies of the head and neck reported by the National Cancer Data Base and 7% of all malignancies of the upper aerodigestive tract [1,2]. Squamous cell carcinoma (SCC) accounts for 95% of hypopharyngeal pathology. Hypopharyngeal carcinoma is associated with the highest mortality of all cancers of the head and neck. Poor survival rates are attributed to a preponderance of late presentations and to the unique behavior of tumors occurring in this location. Tumors of this region typically remain silent until the disease has reached an advanced stage and causes symptoms from airway or digestive tract obstruction or pain from neural invasion. Hypopharyngeal carcinoma is associated with a high incidence of submucosal spread, which can be difficult to detect clinically and can result in underestimating the extent of disease. Cervical metastases are present in 60% to 80% of patients and signify more advanced disease and a poorer prognosis [3–7]. More than 75% of patients who have hypopharyngeal tumors have stage III or IV disease at presentation [1]. The overall 5-year disease-specific survival rate is approximately 30% to 35% [1,2]. Recent advances in reconstructive techniques and perioperative care have allowed resection of advanced disease with single-stage reconstruction of a functional alimentary tract. In addition, improved locoregional control has been demonstrated with the use of combined-modality therapy. Overall survival rates remain poor and largely unaffected, however, because of a shift in the pattern of failure from local to distant disease and the development of second primary tumors. Therefore, treatment goals are aimed at eradicating disease and restoration of function, while causing the least morbidity and the most effective palliation of symptoms.

* Corresponding author. E-mail address: [email protected] (C.G. Gourin). 1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1055-3207(03)00122-4

82

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

Clinical behavior The hypopharynx is described as the region of the pharynx that begins at the level of the hyoid bone and extends to the inferior border of the cricoid cartilage. Within the hypopharynx are three anatomic subsites: the paired pyriform sinuses, the postcricoid area, and the posterior hypopharyngeal wall. The pyriform sinus is the most commonly involved site, representing more than 60% of all cases, and the postcricoid region is least commonly involved, accounting for fewer than 5% of cases [2]. Isolated early-stage lesions of the pharyngeal wall or pyriform sinus have the best prognosis and long-term survival but comprise fewer than 20% of hypopharyngeal carcinomas [3,7–10]. Tumor staging based on the American Joint Committee on Cancer classification system (AJCC Cancer Staging Manual, 6th edition; Springer-Verlag: New York, 2003. pp. 33–45.) shows that contiguous involvement of adjacent sites portends more advanced disease (Box 1). The proximity of the hypopharynx to the larynx and cervical esophagus mandates that the extent of disease be accurately determined before embarking on treatment. Hypopharyngeal carcinoma is unique in demonstrating a high propensity for extensive submucosal spread. The true extent of disease may be initially underestimated because of submucosal extension and the presence of skip lesions [3]. Using whole organ, serial sectioning studies, Ho et al [11] found that submucosal tumor extension was present in 60% of specimens. In one third of patients, submucosal spread was not detectable on gross examination, appearing histologically as tongues and islands of tumor infiltration beneath an intact mucosa. The limits of submucosal extension in this series were 10 mm superiorly to the oropharynx, 25 mm medially, 20 mm laterally, and 20 mm inferiorly toward the esophagus. The incidence and extent of submucosal spread were higher in patients who had undergone previous radiation therapy, with macroscopically undetectable submucosal spread present in 82% of patients [11]. These data provide useful guidelines for treatment planning. The hypopharynx is served by an extensive lymphatic network. Lymphatic drainage proceeds first to the jugular lymphatics and then to the tracheoesophageal nodes, lateral pharyngeal and retropharyngeal nodes, and the parapharyngeal space. Tumors that involve the posterior hypopharyngeal wall and the medial wall of the pyriform sinus have bilateral nodal drainage and have a high incidence of involvement of the contralateral neck. Between 60% and 75% of patients will have clinically involved neck nodes (node-positive [N+]) at presentation, and more than one third of patients without clinical evidence of nodal disease will harbor occult metastases [3–8]. In patients with N+ disease, zones II (72%–75%), III (55%–72%), and IV (21%–45%) are most often affected; zones I (1%– 10%) and V (11%–15%) are less commonly affected [12,13]. Contralateral occult metastases are present in 37% of patients with N+ disease [14]. In

Box 1. Staging of hypopharyngeal cancer Tumor stage Tis: Carcinoma in situ T1: Tumor limited to one subsite of the hypopharynx and 2 cm or less in greatest dimension T2: Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures [2 cm but not more than 4 cm in greatest diameter, without fixation of hemi-larynx T3: Tumor [4 cm in greatest diameter or with fixation of hemi-larynx T4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissue. Note: central compartment soft tissues includes prelaryngeal strap muscles and subcutaneous fat T4b: Tumor involves prevertebral fascia, encases carotid artery, or involves mediastinal structures Nodal stage N0: No regional lymph node metastases N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes or bilateral or contralateral lymph nodes, none greater than 6 cm N2a: Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3: Metastasis in a lymph node more than 6 cm in greatest dimension Distant metastasis M0: No distant metastasis M1: Distant metastasis present TNM stage Stage I: T1, N0, M0 Stage II: T2, N0, M0 Stage III: T3, N0, M0; T1 or T2 or T3, N1, M0 Stage IV: T4, N0 or N1, M0; any T, N2 or N3, M0; any T, any N, M1 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002) published by Springer-Verlag New York (For more information, visit www.cancerstaging.net). Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed written permission of Springer Verlag New York, Inc., on behalf of the AJCC.

84

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

patients who have clinically N0 tumors, 36% harbor occult nodal metastases in the ipsilateral neck, and 27% have occult disease in the contralateral neck [14]. Metastatic disease involves the retropharyngeal lymph nodes in at least 20% of patients who have hypopharyngeal cancer [15]. The true incidence of retropharyngeal nodal involvement is probably not known because dissection of this level is not routinely performed. The incidence of clinically involved retropharyngeal nodes by imaging criteria in patients with hypopharyngeal cancer is 5% [16]. Imaging studies may underestimate retropharyngeal nodal disease based on the small size (\1.5 cm) of nodes in this location and will miss occult metastases [17]. A histologic study of routinely dissected retropharyngeal nodes showed metastases in 20% of patients with hypopharyngeal carcinoma [15]. The highest incidence of retropharyngeal node metastases was seen in patients with disease involvement of the posterior wall of the hypopharynx (57%) or the cervical esophagus (50%). Retropharyngeal nodes were positive for occult metastases in 15% of patients with stage N0 disease [15]. Metastases to the thyroid gland and paratracheal lymph nodes occur in 30% of patients who have hypopharyngeal tumors [18]. A 20% incidence of occult nodal metastases to ipsilateral paratracheal lymph nodes has been reported in patients with postcricoid lesions and tumors that involve the pyriform fossa apex staged N0 [14]. Occult metastases may involve lymph nodes in the parapharyngeal space, which has been described as a site of recurrent disease in 5% of patients when untreated [8]. These data, taken together, require that both sides of the neck and the retropharyngeal, tracheoesophageal, and parapharyngeal nodes be included in treatment planning. Distant metastases are present in 6% of patients at initial presentation [2,10]. The most common sites of involvement are the lungs, bone, and liver. Between 12% and 32% of patients develop clinically apparent distant metastases during the course of treatment [3,6–8,11,19–23]. The incidence of distant metastases is increased in patients who have stage IV disease, advanced-stage neck disease (N2 or N3), involvement of retropharyngeal nodes, extracapsular spread, and lymphovascular invasion [7,8,17,19,23–25]. Most mortality in the first 2 years following diagnosis is caused by locoregional recurrence; after 2 years, distant metastatic disease is responsible for a greater proportion of treatment failures [3,8]. Locoregional recurrence may eclipse the appearance of distant metastatic disease, and with improved locoregional control, distant metastatic disease may subsequently become apparent. Disease control above the clavicles has been associated with a higher incidence of distant metastases in studies that reported results of radiation therapy, with or without surgery [7,19]. Others, however, have shown no correlation between the incidence of distant metastases and locoregional disease control [20,22,25,26]. Salvage of distant metastatic disease is possible in only 6% of patients, and more than 90% of

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

85

patients die within 2 years of detection of distant metastases [20]. The incidence of distant metastases may be significantly decreased by the addition of chemotherapy to radiation therapy according to several reports and a European Organization for Research and Treatment of Cancer (EORTC) trial specifically evaluating pyriform sinus cancer [27–30]. Most patients who have hypopharyngeal cancers present with advancedstage disease. Early-stage cancer is considered to be any T1 or T2 lesion with N0 neck disease, whereas T3 or T4 lesions, or any primary lesion associated with N+ neck disease, are considered to be advanced cancers (Table 1). A nationwide review of 2939 cases of hypopharyngeal cancer from 1980 to 1992 showed that 9% of patients had stage I disease, 11% had stage II disease, 22% had stage III disease, and most (56%) had stage IV disease at presentation [2]. The 5-year disease-specific survival rates by stage was 63% for stage I, 58% for stage II, 42% for stage III, and 22% for stage IV disease. Second primary tumors are present in 7% of patients at the time of initial diagnosis [2]. Between 10% and 17% of patients will subsequently develop a second primary tumor, which is a significant cause of mortality in patients who survive for more than 2 years after the initial diagnosis of hypopharyngeal cancer [3,7]. A history of previous head and neck cancer is present in 16% to 23% of patients, and prior treatment, such as radiation therapy, may significantly limit treatment options available to the patient [2,7]. Treatment Currently, several treatment options exist for patients who have hypopharyngeal cancer. Surgery combined with radiation therapy is the standard treatment for most patients who have hypopharyngeal carcinoma. Radiation therapy alone also may be used and seems to be most useful for small (T1 or T2) lesions. Hyperfractionated radiation therapy seems to confer some advantages over conventional radiation therapy in improved locoregional control. Finally, organ preservation therapy using chemoradiation is being increasingly studied and may result in larynx preservation in one third of patients.

Table 1 American Joint Committee on Cancer TNM staging classification

T1 T2 T3 T4

N0

N1

N2

N3

I II III IV

III III III IV

IV IV IV IV

IV IV IV IV

86

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

Surgical treatment Preoperative evaluation is critical in determining the appropriate surgical approach for treatment of hypopharyngeal carcinoma. The location and extent of disease determine the extent of resection required. Accurate staging is necessary to answer the following questions: Will excision leave a partial or circumferential hypopharyngeal defect, Will total laryngectomy be required, and What is the extent of neck dissection that is required? The predilection of hypopharyngeal carcinoma for submucosal spread must be kept in mind when planning resection of the primary tumor. Wei [18] suggested that, based on measurements of submucosal extension in whole organ studies, an adequate resection margin in patients who have not received previous radiation therapy is 15 mm superiorly, 30 mm inferiorly, and 20 mm laterally. Patients who have undergone previous radiation therapy require resection margins of 20 mm superiorly, 40 mm inferiorly, and 30 mm laterally. The deep margin in either situation should be greater than 1 mm to ensure complete removal of the tumor without leaving residual disease in the prevertebral musculature [18]. Posterior hypopharyngeal wall Posterior hypopharyngeal wall lesions may be treated with wide local excision. Endoscopic resection has been described for carefully selected small lesions that are widely accessible endoscopically [31]. The resulting defect may be left to granulate secondarily. More commonly, the hypopharynx may be approached through either a suprahyoid pharyngotomy or lateral pharyngotomy; usually a combination of both approaches is required for adequate exposure and resection, particularly for midline disease. The lesion is excised down to the prevertebral fascia, keeping in mind the extent of resection required to address the possibility of submucosal extension of disease. Prevertebral involvement dooms this approach to failure. The resulting partial posterior hypopharyngeal wall defect usually requires coverage with a split-thickness skin graft, local or regional flaps, or free-skin or visceral flaps. Split-thickness skin grafts should be used whenever possible because of their ease of harvest and minimal morbidity to the patient. The graft is sewn to the prevertebral fascia and musculature and bolstered for 5 days. Larger defects can be reconstructed using the deltopectoral skin flap or the pectoralis major myocutaneous flap. The deltopectoral flap is an axialpattern skin flap that is based on perforators of the internal mammary artery. Its use requires a staged procedure. The flap is a medially based skin paddle from the upper chest and is initially elevated and reset several weeks in advance of its use when possible, to encourage development of a blood supply to its most distal tip. Subsequently, the flap is inset into the defect and divided at yet a later stage. Before modern methods of soft tissue reconstruction, the deltopectoral flap was widely used. It has been largely

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

87

replaced by the pectoralis major myocutaneous flap. The pectoralis flap is based on the thoracoacromial artery, which provides an extremely reliable and predictable blood supply. The pectoralis flap may be harvested with or without an associated skin paddle: harvest of the overlying skin adds to the bulk of the flap, which, even when used as a muscle-only flap, is significant. The bulk of the pectoralis flap may interfere with swallowing but undergoes atrophy with time. Free flaps are a third option for reconstruction. The radial forearm and lateral thigh flaps may be harvested as free-skin flaps for use in hypopharyngeal reconstruction. These require microvascular anastomosis and result in some donor site morbidity but are thin and pliable and well suited for use in the hypopharynx. The use of any free flap requires suitable recipient vessels. The jejunal free flap may be used as a patch graft and has an advantage of providing lubrication to this area, but it requires a laparotomy for harvest with intestinal anastomosis and thus increased morbidity. Pyriform sinus Lesions of the pyriform sinus, by virtue of their proximity to the larynx, require at least a partial resection of the larynx for adequate excision. Earlystage lesions, such as T1 lesions or T2 lesions of less than 2 cm, can be treated by partial laryngopharyngectomy or extended supraglottic partial laryngectomy. Transoral CO2 laser excision of pyriform sinus tumors recently has been reported by one group to be effective, with results comparable to transcervical approaches [32]. Regardless of the approach used, aspiration is expected in the postoperative period, and candidates for partial laryngopharyngectomy must have adequate pulmonary reserve and be in otherwise good medical condition. Pulmonary function tests may provide some objective measure of pulmonary function, but far more physiologically useful is a determination of an active lifestyle and good exercise tolerance. The ability to climb two flights of stairs (the ‘‘Ogura stair test’’) is a reliable test of adequate pulmonary reserve [33]. Contraindications to partial laryngopharyngectomy are severe chronic obstructive pulmonary disease, previous pulmonary resection, an inactive or bed-ridden patient, or extension of the tumor to within 1.5 cm of the pyriform apex. Arytenoidectomy is usually required for adequate excision of the pyriform fossa. This procedure is unsafe for any tumor that is larger than 2 cm; larger tumors require total laryngectomy with partial pharyngectomy, which results in a significant partial pharyngeal defect. Similarly, partial laryngopharyngectomy is unsafe for cancer that involves the apex of the pyriform sinus. The proximity of the apex of the pyriform to the postcricoid mucosa requires total laryngectomy and cervical esophagectomy in addition to partial pharyngectomy for removal of the tumor and results in a circumferential pharyngeal defect [3]. Partial pharyngeal defects may be closed primarily if sufficient mucosa remains to give a tension-free closure over a #36 Maloney esophageal

88

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

dilator. If insufficient mucosa remains, closure may be achieved with the use of the pectoralis major myocutaneous flap, or free-skin or visceral flaps. The pectoralis major flap is the preferred method of reconstruction to patch partial pharyngeal defects because of its ease of harvest, low morbidity, and reliability. For posterior defects, the bulk of the pectoralis major flap may interfere with swallowing, but this seems to be less of a problem with lateral defects after resection of the pyriform fossa. The radial forearm, lateral thigh, and jejunal free flaps may be used to fill the defect but carry significantly higher donor site and surgical morbidity. Circumferential pharyngeal defects require more involved reconstructive efforts, with a greater potential for stricture formation and anastomotic failure. Cervical skin flaps, regional flaps, such as the deltopectoral flap and pectoralis major flap, and free-radial forearm, lateral thigh, and jejunal flaps all have been used successfully. Cervical skin-flap reconstruction is a foreign concept to most recently trained head and neck surgeons, but before the development of the deltopectoral and pectoralis major flap, medially based cervical skin flaps were used extensively to reconstruct pharyngoesophageal defects. Wookey popularized this technique in the 1940s when he developed a method of pharyngoesophageal reconstruction (the so-called ‘‘Wookey procedure’’) by elevating a laterally based skin flap to form the new posterior wall of the pharyngoesophageal defect. At a second staged procedure several months later, medially based flaps from the original flap were elevated and closed longitudinally in the midline to create a new pharyngoesophageal segment [34]. The deltopectoral flap is used in a similar fashion, by elevating and transposing the flap and, at a second staged procedure, subsequently dividing the pedicle and closing the defect. Both the Wookey procedure and the deltopectoral flap are associated with a significant incidence of flap complications and, because these are staged procedures, there are an average of three procedures before successful reconstruction is accomplished. The length of hospitalization and the time to oral alimentation is measured in week to months. Flap necrosis, fistula formation, and stenosis have been reported to occur in 90% of patients who have undergone surgical reconstruction with cervical skin flaps [35]. Because laterally based cervical skin flaps tend to have marginal circulation at the tip, partial flap loss occurs frequently. The incidence of complications has been reported to be 56% with the deltopectoral flap, likely because of better blood supply compared with cervical skin flaps [35]. Staged reconstruction of pharyngoesophageal defects has been supplanted by newer methods of reconstruction but may be useful when multiple reconstructive efforts fail. The pectoralis major myocutaneous flap allows single-stage reconstruction of circumferential defects and is widely used for this purpose today. The bulk of the pectoralis major flap makes tubing the flap difficult, similar to attempting to roll up a telephone book. Postoperative complications, including stenosis, stricture, and fistula formation, have been reported in 41% of patients [36]. In addition, the thickness of the pectoralis flap and its

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

89

adynamic properties may impair swallowing function. Functional outcome seems to be better when the pectoralis major is used to reconstruct a partial defect as opposed to a circumferential defect: patients with circumferential defects have greater difficulty swallowing after pectoralis major reconstruction [37,38]. Free-flap reconstruction of circumferential defects can be accomplished using jejunal free flaps or free-skin flaps, such as the radial forearm, lateral thigh, and scapular flaps. Jejunal free flaps have the advantage of being tubular and match the defect closely in caliber; insetting is relatively straightforward. Free-skin flaps, like the pectoralis flap, must be tubed to reconstruct a circumferential defect, with a longer suture line resulting and greater potential for anastomotic complications. The secretory properties of the jejunum have been believed to be beneficial, particularly in patients treated with radiation therapy, but in the current authors’ experience, excessive mucus production often results and interferes with tracheoesophageal voice restoration. The main disadvantage of the jejunal flap is the requirement for laparotomy, with three enteric anastomoses resulting from harvest. Abdominal complications related to laparotomy occur in 6% of patients, and fistula development and swallowing difficulty occur in 18% of patients [39]. Jejunal harvesting is contraindicated in patients who have Crohn’s disease or ascites. The radial forearm fasciocutaneous flap is based on the radial artery. Because the radial artery in most patients is the dominant vessel to the deep palmar arch, it must be determined that there is a patent anastomosis across the palmar arch between the radial and ulnar arteries before harvest. The use of the radial forearm free flap, compared with the jejunal flap, is associated with a shorter hospitalization time and decreased time to oral alimentation; in addition, most patients are able to successfully achieve full oral alimentation without the need for supplemental enteral feedings [40,41]. This flap is associated with a somewhat higher incidence of stricture and fistula formation compared with the jejunal flap, however, presumably because the suture line is longer in a tubed flap. Donor site morbidity can be significant, but laparotomy and its attendant risks and longer recovery time are avoided. The lateral cutaneous thigh flap has gained in popularity as an alternative method of reconstruction and, unlike the radial forearm flap, the donor site defect is smaller and associated with less morbidity. Postcricoid lesions Postcricoid tumors are usually advanced at the time of presentation and require total laryngopharyngectomy and cervical esophagectomy. If disease extends below the lower border of the cricoid, total esophagectomy is required. The first-line reconstructive technique for the resulting pharyngoesophageal defect is gastric transposition, or the gastric pull-up. The primary advantage of the gastric pull-up is that it allows for reliable singlestage reconstruction with a single anastomosis. Stricture formation is

90

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

uncommon, because the only anastomosis is high in the neck where stricture rarely occurs. The entire esophagus is removed and the stomach is transposed through the superior mediastinum into the neck. The main disadvantage of the gastric pull-up is a significant morbidity and mortality from the procedure. The rate of major perioperative complications is 50%, and the operative mortality is approximately 10% [34]. Organ necrosis occurs in 3% of patients [38]. In addition, pulmonary complications can occur from thoracic dissection. The weight of the stomach and gravitational pull can cause anastomotic tension and suture line disruption. Gastric transposition entails a complete vagotomy and pyloroplasty, and swallowing after a gastric pull-up can be complicated by early satiety, reflux, and dumping syndrome. The most common long-term complication is reflux, which occurs in 20% of patients. Only 30% of patients develop good speech with available techniques of voice restoration [42]. Gastric pull-up is not warranted when disease is limited to the cervical esophagus. Colon transposition is a second-line method of pharyngoesophageal reconstruction when total esophagectomy is required. The right or left colon may be used, based on the superior mesenteric artery or middle colic artery, respectively. The distal anastomosis is made between the distal colon and stomach. Colon interposition has been associated with a high incidence of postoperative infection, and therefore the colon is usually placed in a subcutaneous pocket anterior to the sternum to avoid mediastinal complications if necrosis occurs. Colon interposition has fallen out of favor because of a 45% incidence of major medical complications; a 25% incidence of reconstructive complications, including necrosis, fistula and stricture; and an overall perioperative mortality rate of 20% [35,43]. Gastric transposition is considered the reconstructive technique of choice for total esophageal defects, with colon interposition reserved for patients with contraindications to gastric surgery or as a salvage technique. Neck dissection Because of the high incidence of nodal metastases, ipsilateral neck dissection is warranted in all patients who have hypopharyngeal cancer. Selective neck dissection of zones II through IV is recommended for all patients with clinically N0 neck disease. The scarcity of metastases to zones I and V supports sparing these zones in this scenario [12,44]. Ipsilateral paratracheal node dissection (zone VI) should be included as part of selective neck dissection for all patients who have postcricoid tumors and tumors that involve the pyriform fossa apex [14]. Patients with clinical evidence of neck disease (N+) require modified radical neck dissection or radical neck dissection of zones I through VI. Contralateral neck dissection is indicated in patients who have midline lesions of the posterior hypopharyngeal wall and postcricoid tumors because of the increased incidence of occult contralateral metastases. Patients who have laterally situated tumors are usually treated with

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

91

ipsilateral neck dissection alone, but T4 lesions may require bilateral neck dissection when involvement of the medial wall of the pyriform sinus or postcricoid mucosa is suspected. Tumors that involve the medial wall of the pyriform sinus have a higher incidence of regional failure in the contralateral neck compared with lateral wall lesions, and require bilateral neck dissection [6]. Bilateral zone VI dissections are rarely performed because of the risk of postoperative hypocalcemia [7].

Results Limited data exist regarding the results of surgical treatment alone, because the combination of surgery and postoperative radiation therapy has become the standard of care for all but very small primary lesions with negative margins and no histologic evidence of nodal metastases [7]. Postoperative radiation therapy is superior to preoperative radiation therapy, with better locoregional control and fewer surgical complications, and avoids the loss of important prognostic information obtained from a nonirradiated surgical specimen [45]. Most patients who have hypopharyngeal cancer have histologic indications for adjuvant postoperative radiation therapy, such as perineural invasion, lymphovascular invasion, more than two lymph nodes with metastatic disease, extracapsular spread, or close or positive margins. For most patients, surgery alone does not provide sufficient disease control. Retrospective reviews comparing surgical treatment alone with surgery plus postoperative radiation therapy have shown decreased locoregional recurrence rates (11%–14% versus 39%– 57%, respectively) and improved 5-year disease-specific survival rates (40%–48% versus 18%–25%, respectively) with the addition of postoperative radiation therapy [8,46]. Surgery with postoperative radiation therapy is associated with local recurrence rates of 4% to 18% and regional recurrence rates of 17% to 47% [3,6,7,11,46]. Locoregional recurrence has been reported to be higher in patients with postcricoid lesions compared with those who have lesions in other sites [2]. No significant difference has been shown in local or regional control rates between pyriform lesions and posterior wall lesions, with the exception that T4 lesions of the posterior wall seem to have a higher incidence of local recurrence when compared with lateral lesions, probably because of prevertebral muscle involvement [23]. Within subsites, medial wall pyriform sinus lesions have a higher incidence of failure in the contralateral neck when compared with lateral pyriform lesions but have equivalent local and regional recurrence rates [6]. Advanced-stage neck disease is significantly associated with increased locoregional recurrence rates and poorer 5-year disease-specific survival rates. N2 or N3 neck disease is associated with 5-year disease-specific survival rates of 0% to 20% compared with 28% to 57% in patients with N0 or N1 disease [3,7]. The presence of extracapsular spread is associated with

92

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

poorer survival rates among patients with nodal disease [8]. In patients with indications for elective treatment of the neck, the combination of surgery and radiation therapy seems to result in better regional control rates compared with reliance on postoperative radiation therapy alone to sterilize N0 neck disease [6,7]. In patients who have clinically staged N0 disease, the presence of occult metastatic disease results in poorer 5-year disease-specific survival rates compared with patients who have N0 disease without occult nodal disease (32% versus 50%, respectively) [7]. Surgical resection results in loss of the larynx in 56% to 79% of patients and pharyngoesophagectomy in 27% to 44% of patients [2,7,10,27,47]. These numbers have driven the search for effective organ-sparing methods of treatment. Primary radiation therapy The results of treatment with primary radiation therapy for curing patients who have hypopharyngeal cancer are not as favorable as they are for those who have tumors in other sites. Locoregional control has been reported to occur in 35% to 40% of patients in several nonrandomized single-institution trials [8,9,21–23,27,48]. Early-stage T1 or T2 lesions have the best prognosis for locoregional control with radiation therapy alone, with rates comparable to those obtained with combined surgery and radiation therapy [9,49]. Local control rates for early-stage disease have been reported to range from 77% to 89%, with 5-year disease-specific survival rates as high as 69% [2,3,7–10]. Advanced-stage primary disease (T3 and T4) and advanced-stage nodal disease (N2 or N3) are associated with dismal rates of laryngeal preservation and 5-year disease-specific survival rates of 0% to 12%. Surgical salvage after failure of radiation therapy is successful in less than 10% of patients, and larynx preservation is rarely possible [50,51]. Fewer than one third of patients are alive at 5 years with a functional larynx [48]. Because of the prevalence of nodal disease and the poor results of surgical salvage, primary radiation therapy is not considered a first-line treatment for most patients with advanced-stage hypopharyngeal cancer. Some of these studies, however, suffer from an inherent selection bias by including patients referred for radiation therapy because of inoperable disease or poor patient condition, thus contraindicating surgery or chemotherapy [21]. The addition of a neck dissection following radiation therapy for patients who have N2 or N3 disease improves regional control rates and may cure a subset of patients with residual microscopic regional disease [23,52–56]. More than 30% of patients who have N2 or N3 disease harbor residual occult microscopic disease in cervical lymph nodes after definitive radiation therapy. Neck dissection following radiation therapy may provide prognostic information, because residual disease may be more likely to recur locally [56]. Most surgeons believe postradiation neck dissection is

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

93

indicated for residual neck disease and for patients with N2 and N3 neck disease who seem to have had a complete response to treatment [57]. Several nonrandomized studies have reported that hyperfractionated radiation therapy provides a 15% to 25% improvement in local control rates for larger tumors [9,23,27]. It has been suggested that doses of 7680 to 7920 cGy administered by twice-daily fractionation are required to demonstrate benefit: the larynx must be shielded at doses greater than 7440 cGy to prevent laryngeal complications from treatment [23]. There is an increased incidence of treatment-related complications on this schedule when compared with conventional radiation therapy and these seem to be dose related [9,23]. Hyperfractionated radiation therapy seems to improve local control rates but incurs socioeconomic and time constraints and does not seem to result in improved survival when compared with conventional radiation therapy [9,23]. Prospective randomized studies are needed to separate out selection bias to determine the efficacy of radiation therapy alone in patients who have hypopharyngeal cancer compared with other modalities of therapy. Chemoradiation therapy Chemotherapy sometimes yields impressive initial tumor responses, but it is not a curative modality and does not improve survival rates in patients who have head and neck cancer. Multiple chemotherapeutic agents have been tried in combination with surgical therapy or radiation therapy. The response of SCC to cisplatin, particularly in combination with 5-fluorouracil (5-FU), has resulted in more widespread interest in chemotherapy as adjunctive treatment. Patients who respond to chemotherapy show a subsequent response to definitive radiation therapy, suggesting that tumors that are sensitive to chemotherapy are radiosensitive. Induction chemotherapy consists of the administration of two or three cycles of chemotherapy initially, to distinguish between responders who are likely to benefit from radiation therapy and nonresponders who are more likely to fail and require surgery. In 1990, the use of chemoradiation for organ preservation was established by the Department of Veterans Affairs Laryngeal Cancer Study Group in a landmark prospective randomized trial [58]. Induction chemotherapy with cisplatin and 5-FU, followed by definitive full-course radiation therapy in responders, resulted in larynx preservation in two thirds of patients who otherwise would have required total laryngectomy, without compromising survival. These findings resulted in the acceptance of organ preservation therapy in the treatment of laryngeal cancer and have led to interest in determining whether these findings hold true for other sites in the head and neck. The only randomized, prospective phase 3 trial to date investigating chemoradiation in patients who have hypopharyngeal cancer was conducted by the EORTC Head and Neck Cancer Cooperative Group [29]. Patients

94

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

with T2 to T4 lesions who required total laryngectomy as part of definitive surgical treatment were randomized to receive either induction chemotherapy with cisplatin and 5-FU followed by definitive radiation therapy, or to surgery with postoperative radiation therapy. This trial found no significant difference between the chemoradiation arm and the surgery arm in local (12% and 17%, respectively) or regional (19% and 23%) recurrence rates and 5-year disease-free survival rates. A decreased incidence of distant metastases was identified in the organ preservation group compared with the surgery group (25% versus 36%, respectively). The 5-year estimate of retaining a functional larynx for the chemoradiation group was 35% [29]. A similar incidence of laryngeal preservation with the use of platinum-based chemotherapy and radiation therapy has been reported by other institutions [27,28,59–61]. These data suggest that larynx preservation with chemoradiation is far less likely for hypopharyngeal cancer than for laryngeal cancer but can be attempted without compromising survival. More recently, concurrent chemoradiation, the simultaneous administration of chemotherapy with radiation therapy, has been used to take advantage of the effects of simultaneously administered chemotherapy as a radiation enhancer. The administration of chemotherapy and radiation therapy concurrently may result in a synergistic effect, which is suggested by impressive initial complete response rates [62]. Concurrent treatment with chemotherapy potentially treats distant disease and locoregional disease and may improve survival rates [63]. Prospective randomized trials to test this hypothesis are in progress. Acute side effects of treatment, particularly mucositis, seem to be more severe with concurrent regimes compared with induction chemotherapy and subsequent radiation therapy; however, there seems to be no difference in long-term side effects between either modality of chemotherapy delivery [30]. Although larynx preservation is possible with chemoradiation, the preserved organ is not always functional. Significant laryngeal and pharyngeal dysfunction has been reported following chemoradiation [64–68]. Dysphagia may have a slow onset during treatment and a prolonged recovery period: at 1 year after chemoradiation, 60% of patients treated with this modality have moderate to severe impairment in swallowing ability and a restricted diet caused by pharyngeal dysfunction [64–66]. Pretreatment vocal cord fixation seems to be the strongest predictor of a poor functional outcome, with more than 50% of patients requiring a feeding tube or tracheostomy 6 months after the completion of therapy compared with patients without vocal cord fixation [69]. Patients who present with a fixed vocal cord should be counseled accordingly as to expectations about treatment and results. When surgical salvage is required after treatment with organ-preserving techniques, the postoperative complication rate is significant. Neck dissection after chemoradiation is associated with a complication rate of 38% [70]. Primary resection without free-flap reconstruction is associated with a 77% incidence of postoperative complications, including wound breakdown and fistulas [71]. When free flaps are used for reconstruction, the

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

95

incidence of wound complications following chemoradiation has been reported to be 20%, and less severe with an average hospital stay of 8 days [72]. These data suggest that free-flap reconstruction should be performed when salvage surgery of the primary site is required.

Summary Despite advances in surgical and nonsurgical treatment, overall survival rates for patients who have hypopharyngeal carcinoma have not improved, and this disease still has a poor prognosis. The best results are obtained with multimodality therapy, but at best, two thirds of patients are palliated rather than cured of disease. Radical surgery with postoperative radiation therapy remains the standard of care. Organ preservation strategies have not been as successful in hypopharyngeal cancer as for cancers of other head and neck sites. Chemoradiation is an effective alternative method of aggressive treatment but may be associated with significant dysfunction of the end organ when preservation is possible. Because of poor long-term survival rates, local control remains the most important factor in planning treatment, to provide meaningful palliation and best possible quality of life.

References [1] Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base Report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:951–62. [2] Hoffman HT, Karnell LH, Shah JP, Ariyan S, Brown GS, Fee WE, et al. Hypopharyngeal patient care evaluation. Laryngoscope 1997;107:1005–17. [3] Ho CM, Lam KH, Wei WI, Yuen PW, Lam LK. Squamous cell carcinoma of the hypopharynx—analysis of treatment results. Head Neck 1993;15:405–12. [4] Shah JP, Shah AR, Spiro RH, Strong EW. Carcinoma of the hypopharynx. Am J Surg 1976;132:439–43. [5] Lefebvre JL, Castelain B, DeLaTorre JC, Delobelle-Deroide A, Vankemmel B. Lymph node invasion in hypopharynx and lateral epilarynx: a prognostic factor. Head Neck Surg 1987;10:14–8. [6] Johnson JT, Bacon GW, Myers EN, Wagner RL. Medial vs. lateral wall pyriform sinus carcinoma: implications for management of regional lymphatics. Head Neck 1994;16: 401–5. [7] Kraus DH, Zelefsky MJ, Brock HA, Huo J, Harrison LB, Shah JP. Combined surgery and radiation therapy for squamous cell carcinoma of the hypopharynx. Otolaryngol Head Neck Surg 1997;116:637–41. [8] El Badawi SA, Goepfert H, Fletcher GH, Herson J, Oswald MJ. Squamous cell carcinoma of the pyriform sinus. Laryngoscope 1982;92:357–64. [9] Garden AS, Morrison WH, Clayman GL, Ang KK, Peters LJ. Early squamous cell carcinoma of the hypopharynx: outcomes of treatment with radiation alone to the primary disease. Head Neck 1996;18:317–22. [10] Eckel HE, Staar S, Volling P, Sittel C, Damm M, Junghuelsing M. Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results. Otolaryngol Head Neck Surg 2001;124:561–9.

96

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

[11] Ho CM, Ng WF, Lam KH, Wei WI, Yuen AP. Submucosal tumor extension in hypopharyngeal cancer. Arch Otolaryngol Head Neck Surg 1997;123:959–65. [12] Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck 1990;12:197–203. [13] Mukherji SK, Armao D, Joshi VM. Cervical node metastases in squamous cell carcinoma of the head and neck: what to expect. Head Neck 2001;23:995–1005. [14] Buckley JG, MacLennan K. Cervical node metastases in laryngeal and hypopharyngeal cancer: a prospective analysis of prevalence and distribution. Head Neck 2000;22: 380–5. [15] Amatsu M, Mohri M, Kinishi M. Significance of retropharyngeal node dissection at radical surgery for carcinoma of the hypopharynx and cervical esophagus. Laryngoscope 2001;111: 1099–103. [16] McLaughlin MP, Mendenhall WM, Mancuso AA, Parsons JT, McCarty PJ, Cassisi NJ, et al. Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck. Head Neck 1995;17:190–8. [17] Morrissey DD, Talbot M, Cohen JI, Wax MK, Andersen PE. Accuracy of computed tomography in determining the presence or absence of metastatic retropharyngeal adenopathy. Arch Otolaryngol Head Neck Surg 2000;126:1478–81. [18] Wei WI. The dilemma of treating hypopharyngeal carcinoma: more or less. Arch Otolaryngol Head Neck Surg 2002;128:229–32. [19] Ellis ER, Mendenhall WM, Rao PV, Parsons JT, Spangler AE, Million RR. Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma? Int J Radiat Oncol Biol Phys 1989;17:293–7. [20] Spector G. Distant metastases from laryngeal and hypopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec 2001;63:224–8. [21] Vandenbrouck C, Eschwege F, De La Rochefordiere A, Sicot H, Mamelle G, Ridant AM, et al. Squamous cell carcinoma of the pyriform sinus: a retrospective study of 351 cases treated at the Institute Gustav-Roussy. Head Neck 1987;10:4–13. [22] Horwitz SD, Caldarelli DD, Hendrickson FR. Treatment of carcinoma of the hypopharynx. Head Neck Surg 1979;2:107–11. [23] Fein DA, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Pharyngeal wall carcinoma treated with radiotherapy: impact of treatment technique and fractionation. Int J Radiat Oncol Biol Phys 1993;26:751–7. [24] Ferlito A, Shah AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec 2001;63:202–7. [25] Alvi A, Johnson JT. Development of distant metastasis after treatment of advanced-stage head and neck cancer. Head Neck 1997;19:500–5. [26] Leibel SA, Scott CB, Mohiuddin M, Marcial VA, Coia LR, Davis LW, et al. The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: results of an analysis from the RTOG head and neck database. Int J Radiat Oncol Biol Phys 1991;21:549–56. [27] Zelefsky MJ, Kraus DH, Pfister DG, Raben A, Shah JP, Strong EW, et al. Combined chemotherapy and radiotherapy versus surgery and postoperative radiotherapy for advanced hypopharyngeal cancer. Head Neck 1996;18:405–11. [28] Adelstein DJ, Saxton JP, Lavertu P, Tuason L, Wood BG, Wanamaker JR, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 1997;19:567–75. [29] Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890–9. [30] Fu KK. Combined-modality therapy for head and neck cancer. Oncology 1997;11:1781–90.

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

97

[31] Zeitels SM, Koufman JA, Davis RK, Vaughan CW. Endoscopic treatment of supraglottic and hypopharynx cancer. Laryngoscope 1994;104:71–8. [32] Steiner W, Ambrosch P, Hess CF, Kron M. Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg 2001;124:58–67. [33] Ogura JH, Marks JE, Freeman RB. Results of conservation surgery for cancers of the supraglottis and piriform sinus. Laryngoscope 1980;90:591–600. [34] Stepnick DW, Hayden RE. Options for reconstruction of the pharyngoesophageal defect. Otolaryngol Clin N Am 1992;6:1151–8. [35] Surkin MI, Lawson W, Biller HF. Analysis of the methods of pharyngoesophageal reconstruction. Head Neck Surg 1984;6:953–70. [36] Stein DW, Schuller DE. Advantages of pectoralis musculocutaneous flap pharyngeal reconstruction. Laryngoscope 1989;99:691–6. [37] Schuller DE. Reconstructive options for pharyngeal and/or cervical esophageal defects. Arch Otolaryngol 1985;111:193–7. [38] Haller JR. Concepts in pharyngoesophageal reconstruction. Otolaryngol Clin N Am 1997; 30:655–61. [39] Shangold LM, Urken ML, Lawson W. Jejunal transplantation for pharyngoesophageal reconstruction. Otolaryngol Clin N Am 1991;24:1321–42. [40] Anthony JP, Singer MI, Deschler DG, Dougherty ET, Reed CG, Kaplan MJ. Long-term functional results after pharyngoesophageal reconstruction with the radial forearm free flap. Am J Surg 1994;168:441–5. [41] Harii K, Ebihara S, Ono I, Saito H, Terui S, Takato T. Pharyngoesophageal reconstruction using a fabricated forearm free flap. Plast Reconstr Surg 1985;75:463–76. [42] Davidge-Pitts KJ, Mannel A. Pharyngolaryngectomy with extrathoracic esophagectomy. Head Neck Surg 1983;6:571–4. [43] Carlson GW, Schusterman MA, Guillamondegui OM. Total reconstruction of the hypopharynx and cervical esophagus: a 20-year experience. Ann Plast Surg 1992;29:408–12. [44] Wenig BL, Applebaum EL. The submandibular triangle in squamous cell carcinoma of the larynx and hypopharynx. Laryngoscope 1991;101:516–8. [45] Wennerberg J. Pre versus post-operative radiotherapy of resectable squamous cell carcinoma of the head and neck. Acta Otolaryngol 1995;115:465–74. [46] Frank JL, Garb JL, Kay S, McClish DK, Bethke KP, Lind DS, et al. Postoperative radiotherapy improves survival in squamous cell carcinoma of the hypopharynx. Am J Surg 1994;168:476–80. [47] Barzan L, Talamini R, Politi D, Minatel E, Gobitti C, Franchin D. Squamous cell carcinoma of the hypopharynx treated with surgery and radiotherapy. J Laryngol Otol 2002;116:24–8. [48] Keane TJ, Hawkins NV, Beale FA, Cummings BJ, Harwood AR, Payne DG, et al. Carcinoma of the hypopharynx: results of primary radical radiation therapy. Int J Radiat Oncol Biol Phys 1983;9:659–64. [49] Dubois JB, Guerrier B, Di Ruggiero JM, Pourquier H. Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery. Radiology 1986;160:831–6. [50] Godballe C, Jorgensen K, Hansen O, Bastholt L. Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 2002;112:834–8. [51] Stoeckli SJ, Pawlick AB, Lipp M, Huber A, Schmid S. Salvage surgery after failure of nonsurgical therapy for carcinoma of the larynx and hypopharynx. Arch Otolaryngol Head Neck Surg 2000;126:1473–7. [52] Mendenhall WM, Million RR, Cassisi NJ. Squamous cell carcinoma of the head and neck treated with radiation therapy: the role of neck dissection for clinically positive neck nodes. Int J Radiat Oncol Biol Phys 1986;2:733–40. [53] Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ, Million RR. Twice-a-day radiotherapy for squamous cell carcinoma of the head and neck: the University of Florida experience. Head Neck 1993;5:87–96.

98

C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

[54] Parsons JT, Mendenhall WM, Cassisi NJ, Stringer SP, Million RR. Neck dissection after twice-a-day radiotherapy: morbidity and recurrence rates. Head Neck 1989;11:400–4. [55] Narayan K, Crane CH, Kleid S, Hughes PG, Peters LJ. Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all? Head Neck 1999;21:606–13. [56] Newkirk KA, Cullen KJ, Harter KW, Picken CA, Sessions RB, Davidson BJ. Planned neck dissection for advanced primary head and neck malignancy treated with organ preservation therapy: disease control and survival outcomes. Head Neck 2001;23:73–9. [57] Robbins KT, Arkinson JL, Byers RM, Cohen JI, Lavertu P, Pellitteri P. The use and misuse of neck dissection for head and neck cancer. J Am Coll Surg 2001;193:91–102. [58] Department of Veterans Affairs Laryngeal Cancer Cooperative Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685–90. [59] Pfister DG, Strong E, Harrison L, Haines IE, Pfister DA, Sessions R, et al. Larynx preservation with combined chemotherapy and radiation therapy in advanced but resectable head and neck cancer. J Clin Oncol 1991;9:850–9. [60] Kraus DH, Pfister DG, Harrison LB, Shah JP, Spiro RH, Armstrong JG, et al. Larynx preservation with combined chemotherapy and radiation therapy in advanced hypopharynx cancer. Otolaryngol Head Neck Surg 1994;111:31–7. [61] Demard F, Chauvel P, Santini J, Vallicioni J, Thyss A, Schneider M. Response to chemotherapy as a justification for modification of the therapeutic strategy for pharyngolaryngeal carcinomas. Head Neck 1990;12:225–31. [62] Pfister DG, Shaha AR, Harrison LB. The role of chemotherapy in the curative treatment of head and neck cancer. Surg Oncol Clin N Am 1997;6:749–68. [63] Gillison ML, Forastiere AA. Larynx preservation in head and neck cancers. A discussion of the National Comprehensive Cancer Network practice guidelines. Hematol Oncol Clin N Am 1999;13:699–718. [64] Koch WM, Lee DJ, Eisele DW, Miller D, Poole M, Cummings CW, et al. Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 1995;121:974–80. [65] Vokes EE, Kies MS, Haraf DJ, Stenson K, List M, Humerickhouse R, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000;18:1652–61. [66] Eisbruch A, Lyden T, Bradford CR, Dawson LA, Haxer MJ, Miller AE, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53:23–8. [67] Smith RV, Kotz T, Beitler JJ, Wadler S. Long-term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea. Arch Otolaryngol Head Neck Surg 2000;126:384–9. [68] Kotz T, Abraham S, Beitler JJ, Wadler S, Smith RV. Pharyngeal transport dysfunction consequent to an organ-sparing protocol. Arch Otolaryngol Head Neck Surg 1999;125: 410–3. [69] Staton J, Robbins KT, Newman L, Samant S, Sebelik M, Viera F. Factors predictive of poor functional outcome after chemoradiation for advanced laryngeal cancer. Otolaryngol Head Neck Surg 2002;127:43–7. [70] Davidson BJ, Newkirk KA, Harter KW, Picken CA, Cullen KJ, Sessions RB. Complications from planned, posttreatment neck dissections. Arch Otolaryngol Head Neck Surg 1999;125:401–5. [71] Sassler AM, Esclamado RM, Wolf GT. Surgery after organ preservation therapy. Analysis of wound complications. Arch Otolaryngol Head Neck Surg 1995;121:162–5. [72] Teknos TN, Myers LL, Bradford CR, Chepeha DB. Free tissue reconstruction of the hypopharynx after organ preservation therapy: analysis of wound complications. Laryngoscope 2001;111:1192–6.