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NCI/PDQ^® Health professionals: Hypopharyngeal Cancer Treatment (PDQ®)

National Cancer Institute
Last Modified: July 16, 2012

TABLE OF CONTENTS

• General Information About Hypopharyngeal Cancer

• Cellular Classification of Hypopharyngeal Cancer

• Stage Information for Hypopharyngeal Cancer
  • Definitions of TNM

• Treatment Option Overview

• Stage I Hypopharyngeal Cancer
  • Current Clinical Trials

• Stage II Hypopharyngeal Cancer
  • Current Clinical Trials

• Stage III Hypopharyngeal Cancer
  • Current Clinical Trials

• Stage IV Hypopharyngeal Cancer
  • Resectable Hypopharyngeal Cancer
  • Unresectable Hypopharyngeal Cancer
  • Current Clinical Trials

• Recurrent Hypopharyngeal Cancer
  • Current Clinical Trials

• Changes to This Summary (07/16/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Hypopharyngeal Cancer

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Cancer of the hypopharynx is uncommon; approximately 2,500 new cases are diagnosed in the United States each year. 1 The peak incidence of this cancer occurs in males and females aged 50 to 60 years. 2 Excessive alcohol and tobacco use are the primary risk factors for hypopharyngeal cancer. 3 4 In the United States, hypopharyngeal cancers are more common in men than in women. 5 In Europe and Asia, high incidences of pharyngeal cancers, namely, oropharyngeal and hypopharyngeal, have been found among men in France, in the counties of Bas-Rhin and Herault; Switzerland, in the section of Vaud; Spain, in the Basque Country region; Slovakia, Slovenia, and India, in the cities of Bombay and Madras. 6 This cancer is extremely rare in children. 7

Upper hypopharyngeal cancers appear to be associated more with heavy drinking and smoking, whereas the lower hypopharyngeal, or postcricoid, cancers are more often associated with nutritional deficiencies. 1 8 Although earlier reports from northern Europe, particularly from Sweden, indicated a link between Plummer-Vinson syndrome, which consisted of sideropenic anemia and epithelial changes of the aerodigestive tract, and other nutritional deficiencies in women, cases of hypopharyngeal cancer among women are currently more likely to be associated with excessive use of alcohol and tobacco, rather than with deficiency diseases. 2 9 10 11

Anatomically, the hypopharynx extends from the plane of the hyoid bone above to the plane of the inferior border of the cricoid cartilage below. The hypopharynx is composed of the following three parts and does not include the larynx:

• The pyriform sinus.
• The postcricoid area.
• The posterior pharyngeal wall.

The lymphatic drainage from the pharynx is into the jugulodigastric, jugulo-omohyoid, upper and middle deep cervical, and retropharyngeal nodes. In the United States and Canada, 65% to 85% of hypopharyngeal carcinomas involve the pyriform sinuses, 10% to 20% involve the posterior pharyngeal wall, and 5% to 15% involve the postcricoid area. 12 Pyriform sinus and postcricoid carcinomas are typically flat plaques with raised edges and superficial ulceration. In contrast, posterior hypopharyngeal wall tumors tend to be exophytic and are often large (i.e., 80% >5 cm) at presentation. 13 Hypopharyngeal carcinomas tend to spread within the mucosa, beneath intact epithelium, and are prone to skip metastasis and to resurface at various locations remote from the primary site. 1 13 Because of this fact and the abundant lymphatic network of the region, a localized hypopharyngeal tumor is the exception. 1

Almost all hypopharyngeal cancers are mucosal squamous cell carcinomas (SCCs). 1 Multiple primary tumors are not uncommon. Approximately 25% of patients in a retrospective study of 150 cases were found to have second primary tumors. 14 Field cancerization may be responsible, in part, for the multiple, synchronous, primary malignant neoplasms that occur in patients with hypopharyngeal cancer. 1 14 15 16 The concept of field cancerization, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue that has been chronically exposed to carcinogens. 17

Clinically, cancers of the hypopharynx tend to be aggressive and demonstrate a natural history that is characterized by diffuse local spread, early metastasis, and a relatively high rate of distant spread. More than 50% of patients with hypopharyngeal cancer have clinically positive cervical nodes at the time of presentation. In 50% of these individuals, a neck mass is the presenting symptom. 2 18 19 In a retrospective study of 78 cases of hypopharyngeal cancer, other symptoms in addition to a neck mass (25.6%) included dysphagia (46.1%), odynophagia (44.8%), voice change (16.3%), and otalgia (14.2%). 2 A voice change due to pyriform sinus or postcricoid lesions is a late symptom that usually indicates invasion into the larynx or the recurrent laryngeal nerve. 1

In a large, retrospective study of patients with SCC of the larynx and hypopharynx, 87% of patients with pyriform sinus SCC were found to have stage III or stage IV disease; 82% of patients with SCC of the posterior pharyngeal wall were found to have stage III or stage IV disease. 20 As many as 17% of hypopharyngeal SCCs may be associated with distant metastases when clinically diagnosed. 20 This is quite different from the rate of distant metastasis detected at autopsy, which has been reported to be as much as 60%. 21 A relatively high incidence of delayed regional (i.e., 2 or more years after completion of primary therapy) and distant metastatic disease in hypopharyngeal SCC is related to the advanced stage of the disease at diagnosis. Almost 33% of pyriform sinus tumors may be associated with delayed regional metastases. 20

The treatment of hypopharyngeal cancer is controversial, in part because of its low incidence and the inherent difficulty in conducting adequately powered, prospective, randomized clinical studies. 22 Therefore, it is difficult to define the ideal therapy for a specific site or stage of hypopharyngeal cancer. In general, both surgery and radiation therapy are the mainstays of most curative efforts aimed at this cancer. In recent years, chemotherapy has been added to the treatment strategies for selected advanced presentations of hypopharyngeal cancer. 23 In pyriform sinus cancer, neoadjuvant chemotherapy followed by radiation therapy may afford larynx preservation without jeopardizing survival. 24

Chronic pulmonary and hepatic diseases related to the excessive use of tobacco and alcohol are found in patients with hypopharyngeal cancer. Recognition of these comorbidities is essential in the formulation of an appropriate treatment plan. 1 The primary prognostic factors for hypopharyngeal SCC are the following: 1 25 26

• Stage.
• Age.
• Performance status.

Factors that contribute to an overall poor prognosis with hypopharyngeal SCC include the following:

• Presentation at a late stage.
• Multisite involvement within the hypopharynx.
• Unrestricted soft-tissue tumor growth.
• An extensive regional lymphatic network allowing development of metastases.
• Restricted surgical options for complete resection.

In many patients, a poor prognosis is related to poor overall health. 13 The most common cause of failure of treatment of the primary tumor is local and/or regional recurrence. Most treatment failures occur within the first 2 years following definitive therapy. The burden of lymph node metastases may yield information of prognostic value. In a retrospective study, a total volume of metastatic disease of more than 100 cm³ indicated a particularly poor prognosis. 25

In addition to the risk of delayed regional metastases, the risk of developing a second primary tumor in patients with tumors of the upper aerodigestive tract has been estimated to be 4% to 7% per year. 20 26 27 28 Because of these risks, surveillance of patients with hypopharyngeal cancer should be lifelong.

To date, SCC of the hypopharynx has not been associated with any specific chromosomal or genetic abnormalities; 13 however, loss of chromosome 18 was observed in 57% of hypopharyngeal tumors in one study. 29 Several other studies have emphasized the importance of chromosome 11q13 amplification, which may be related to the presence of nodal metastases, greater local aggressiveness, and a higher incidence of tumor recurrence. 30 31 32 33

References:

1. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80. [PUBMED Abstract]
2. Uzcudun AE, Bravo Fernández P, Sánchez JJ, et al.: Clinical features of pharyngeal cancer: a retrospective study of 258 consecutive patients. J Laryngol Otol 115 (2): 112-8, 2001. [PUBMED Abstract]
3. Blot WJ, McLaughlin JK, Winn DM, et al.: Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48 (11): 3282-7, 1988. [PUBMED Abstract]
4. Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994. [PUBMED Abstract]
5. Canto MT, Devesa SS: Oral cavity and pharynx cancer incidence rates in the United States, 1975-1998. Oral Oncol 38 (6): 610-7, 2002. [PUBMED Abstract]
6. Franceschi S, Bidoli E, Herrero R, et al.: Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol 36 (1): 106-15, 2000. [PUBMED Abstract]
7. Siddiqui F, Sarin R, Agarwal JP, et al.: Squamous carcinoma of the larynx and hypopharynx in children: a distinct clinical entity? Med Pediatr Oncol 40 (5): 322-4, 2003. [PUBMED Abstract]
8. WYNDER EL, HULTBERG S, JACOBSSON F, et al.: Environmental factors in cancer of the upper alimentary tract; a Swedish study with special reference to Plummer-Vinson (Paterson-Kelly) syndrome. Cancer 10 (3): 470-87, 1957 May-Jun. [PUBMED Abstract]
9. Ahlbom HE: Simple achlorhydric anaemia, Plummer-Vinson syndrome, and carcinoma of the mouth, pharynx, and oesophagus in women. Br Med J 2 (3945): 331-3, 1936. [PUBMED Abstract]
10. Larsson LG, Sandstrím A, Westling P: Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden. Cancer Res 35 (11 Pt. 2): 3308-16, 1975. [PUBMED Abstract]
11. Amos A: Women and smoking. Br Med Bull 52 (1): 74-89, 1996. [PUBMED Abstract]
12. Barnes L, Johnson JT: Pathologic and clinical considerations in the evaluation of major head and neck specimens resected for cancer. Part I. Pathol Annu 21 Pt 1: 173-250, 1986. [PUBMED Abstract]
13. Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003. [PUBMED Abstract]
14. Raghavan U, Quraishi S, Bradley PJ: Multiple primary tumors in patients diagnosed with hypopharyngeal cancer. Otolaryngol Head Neck Surg 128 (3): 419-25, 2003. [PUBMED Abstract]
15. Tabor MP, Brakenhoff RH, van Houten VM, et al.: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7 (6): 1523-32, 2001. [PUBMED Abstract]
16. Braakhuis BJ, Tabor MP, Kummer JA, et al.: A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 63 (8): 1727-30, 2003. [PUBMED Abstract]
17. Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6 (5): 963-8, 1953. [PUBMED Abstract]
18. Horwitz SD, Caldarelli DD, Hendrickson FR: Treatment of carcinoma of the hypopharynx. Head Neck Surg 2 (2): 107-11, 1979 Nov-Dec. [PUBMED Abstract]
19. Keane TJ: Carcinoma of the hypopharynx. J Otolaryngol 11 (4): 227-31, 1982. [PUBMED Abstract]
20. Spector JG, Sessions DG, Haughey BH, et al.: Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope 111 (6): 1079-87, 2001. [PUBMED Abstract]
21. Kotwall C, Sako K, Razack MS, et al.: Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 154 (4): 439-42, 1987. [PUBMED Abstract]
22. Godballe C, Jírgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002. [PUBMED Abstract]
23. Hinerman RW, Amdur RJ, Mendenhall WM, et al.: Hypopharyngeal carcinoma. Curr Treat Options Oncol 3 (1): 41-9, 2002. [PUBMED Abstract]
24. Lefebvre JL, Chevalier D, Luboinski B, et al.: 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 88 (13): 890-9, 1996. [PUBMED Abstract]
25. Jakobsen J, Hansen O, Jírgensen KE, et al.: Lymph node metastases from laryngeal and pharyngeal carcinomas--calculation of burden of metastasis and its impact on prognosis. Acta Oncol 37 (5): 489-93, 1998. [PUBMED Abstract]
26. Khuri FR, Lippman SM, Spitz MR, et al.: Molecular epidemiology and retinoid chemoprevention of head and neck cancer. J Natl Cancer Inst 89 (3): 199-211, 1997. [PUBMED Abstract]
27. Pfister DG, Shaha AR, Harrison LB: The role of chemotherapy in the curative treatment of head and neck cancer. Surg Oncol Clin N Am 6 (4): 749-68, 1997. [PUBMED Abstract]
28. León X, Quer M, Diez S, et al.: Second neoplasm in patients with head and neck cancer. Head Neck 21 (3): 204-10, 1999. [PUBMED Abstract]
29. Poetsch M, Kleist B, Lorenz G, et al.: Different numerical chromosomal aberrations detected by FISH in oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma. Histopathology 34 (3): 234-40, 1999. [PUBMED Abstract]
30. Meredith SD, Levine PA, Burns JA, et al.: Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Association with poor prognosis. Arch Otolaryngol Head Neck Surg 121 (7): 790-4, 1995. [PUBMED Abstract]
31. Muller D, Millon R, Velten M, et al.: Amplification of 11q13 DNA markers in head and neck squamous cell carcinomas: correlation with clinical outcome. Eur J Cancer 33 (13): 2203-10, 1997. [PUBMED Abstract]
32. Rodrigo JP, García LA, Ramos S, et al.: EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res 6 (8): 3177-82, 2000. [PUBMED Abstract]
33. Rodrigo JP, González MV, Lazo PS, et al.: Genetic alterations in squamous cell carcinomas of the hypopharynx with correlations to clinicopathological features. Oral Oncol 38 (4): 357-63, 2002. [PUBMED Abstract]

Cellular Classification of Hypopharyngeal Cancer

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Almost all hypopharyngeal cancers are epithelial in origin, predominantly squamous cell (i.e., epidermoid) carcinomas (SCCs), and may be preceded by various precancerous lesions. 1 2 Rare types of hypopharyngeal carcinomas include the following:

• Basaloid squamoid carcinomas.
• Spindle-cell (i.e., sarcomatoid) carcinomas.
• Small-cell carcinomas.
• Nasopharyngeal-type undifferentiated carcinomas (i.e., lymphoepitheliomas).
• Carcinomas of the minor salivary glands.

Nonepithelial tumors, including lymphomas, sarcomas, and melanomas, require separate consideration and are not included in the staging and treatment options discussed in this summary. 1 3 4 5 6 7 8

Invasive SCCs are usually moderately differentiated or poorly differentiated and invariably stain positively for keratin. 1 In situ carcinoma is often seen adjacent to invasive SCC. 1 9

The term, leukoplakia, should be used only as a clinically descriptive term meaning that the observer sees a white patch that does not rub off, the significance of which depends on the histologic findings. 10 Based on this description, leukoplakia can range from hyperkeratosis to an actual early invasive carcinoma or may represent only a fungal infection, lichen planus, or other benign oral disease.

References:

1. Oral cavity and oropharynx. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 223-55. [PUBMED Abstract]
2. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80. [PUBMED Abstract]
3. Ibrahim NB, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 54 (8): 1645-61, 1984. [PUBMED Abstract]
4. Stanley RJ, Weiland LH, DeSanto LW, et al.: Lymphoepithelioma (undifferentiated carcinoma) of the laryngohypopharynx. Laryngoscope 95 (9 Pt 1): 1077-81, 1985. [PUBMED Abstract]
5. McKay MJ, Bilous AM: Basaloid-squamous carcinoma of the hypopharynx. Cancer 63 (12): 2528-31, 1989. [PUBMED Abstract]
6. Frank DK, Cheron F, Cho H, et al.: Nonnasopharyngeal lymphoepitheliomas (undifferentiated carcinomas) of the upper aerodigestive tract. Ann Otol Rhinol Laryngol 104 (4 Pt 1): 305-10, 1995. [PUBMED Abstract]
7. Olsen KD, Lewis JE, Suman VJ: Spindle cell carcinoma of the larynx and hypopharynx. Otolaryngol Head Neck Surg 116 (1): 47-52, 1997. [PUBMED Abstract]
8. Lengyel E, Gilde K, Remenár E, et al.: Malignant mucosal melanoma of the head and neck. Pathol Oncol Res 9 (1): 7-12, 2003. [PUBMED Abstract]
9. Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003. [PUBMED Abstract]
10. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]

Stage Information for Hypopharyngeal Cancer

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The staging systems are all clinical staging and are based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation, when possible, and by both indirect mirror examination and direct endoscopy. The tumor must be confirmed histologically, and any other pathologic data obtained from a biopsy may be included. Additional radiographic studies may be included. As an adjunct to clinical examination, computed tomography and/or magnetic resonance imaging are needed for an accurate staging of laryngeal and hypopharyngeal carcinomas because both cross-sectional imaging modalities are known to reliably evaluate deep tumor infiltration. 1 2 3 The appropriate nodal drainage areas are examined by careful palpation. If a patient relapses, complete restaging must be done to select the appropriate additional therapy.

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define hypopharyngeal cancer. 4

Table 1. Primary Tumor (T)^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.^bCentral compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.

TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinoma in situ.
Hypopharynx
T1	Tumor limited to 1 subsite of hypopharynx and/or 2 cm in greatest dimension.
T2	Tumor invades >1 subsite of hypopharynx or an adjacent site, or measures >2 cm but not >4 cm in greatest dimension without fixation of hemilarynx.
T3	Tumor >4 cm in greatest dimension or with fixation of hemilarynx or extension to esophagus.
T4a	Moderately advanced local disease.
	Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue.b
T4b	Very advanced local disease.
	Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures.

Table 2. Regional Lymph Nodes (N)^a,b

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.^bMetastases at level VII are considered regional lymph node metastases.

Oropharynx and Hypopharynx
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1	Metastasis in a single ipsilateral lymph node, 3 cm in greatest dimension.
N2	Metastases in a single ipsilateral lymph node, >3 cm but 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension.
N2a	Metastasis in a single ipsilateral lymph node >3 cm but 6 cm in greatest dimension.
N2b	Metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension.
N2c	Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension.
N3	Metastasis in a lymph node >6 cm in greatest dimension.

Table 3. Distant Metastasis (M)^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.

M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groups^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.

Stage	T	N	M
Oropharynx, Hypopharynx
0	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
III	T3	N0	M0
	T1	N1	M0
	T2	N1	M0
	T3	N1	M0
IVA	T4a	N0	M0
	T4a	N1	M0
	T1	N2	M0
	T2	N2	M0
	T3	N2	M0
	T4a	N2	M0
IVB	T4b	Any N	M0
	Any T	N3	M0
IVC	Any T	Any N	M1

References:

1. Thabet HM, Sessions DG, Gado MH, et al.: Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope 106 (5 Pt 1): 589-94, 1996. [PUBMED Abstract]
2. Becker M: Larynx and hypopharynx. Radiol Clin North Am 36 (5): 891-920, vi, 1998. [PUBMED Abstract]
3. Keberle M, Kenn W, Hahn D: Current concepts in imaging of laryngeal and hypopharyngeal cancer. Eur Radiol 12 (7): 1672-83, 2002. [PUBMED Abstract]
4. Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56. [PUBMED Abstract]

Treatment Option Overview

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Hypopharyngeal cancer usually does not give rise to symptoms until late in the course of the disease. Because of this and the high incidence of early metastasis, survival rates for carcinoma of the hypopharynx are perhaps the lowest of all cancer sites in the head and neck.

No single therapeutic regimen offers a clear-cut superior survival advantage over other regimens. Although the literature highlights various therapeutic options, few reports present any valid comparative studies. The ultimate therapeutic choice will depend on a careful review of each individual case, paying attention to the staging of the neoplasm, the general physical condition of the patient, the emotional status of the patient, the experience of the treating team, and the available treatment facilities. 1 2

Except for very early stage (T1) cancers of this region, treatment has primarily been surgery, usually followed with postoperative radiation therapy (PORT). Some early stage (T1 and T2), low-volume, exophytic pyriform sinus carcinomas have been successfully treated with radiation alone. 3 4 5 Single-modality therapy of advanced-stage hypopharyngeal cancer, with either surgery or radiation therapy, has resulted in consistently poor survival. 6 7 8 Combined-modality treatment should be considered for patients who present with stage III or stage IV disease. 4 6 9 10 When used in conjunction with surgery, radiation therapy is typically administered postoperatively. Alternative strategies using neoadjuvant chemotherapy and radiation therapy may increase the chance for local control in selected advanced presentations to a level approaching that of resection and PORT. 4 In addition, combined chemotherapy and radiation therapy may offer better tumor control with organ preservation than does radiation therapy alone. 11 12 13 Patients with stage III and advanced resectable stage IV cancer should be considered for a larynx preservation approach including neoadjuvant chemotherapy and radiation therapy. 14 15 16

A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible. 17 18 Chronic pulmonary and hepatic diseases related to excessive tobacco and alcohol use are common in patients with head and neck cancer; recognition of these comorbidities is essential to the formulation of an appropriate treatment plan. 6 Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not; 19 consequently, patients should be counseled to stop smoking before beginning radiation therapy. Accumulating evidence has demonstrated a high incidence (i.e., >30%40%) of hypothyroidism in patients who have received external-beam radiation therapy to the entire thyroid gland or to the pituitary gland. Thyroid function testing of patients should be considered prior to therapy and as part of posttreatment follow-up. 20 21

References:

1. Thawley SE, Panje WR, Batsakis JG, et al., eds.: Comprehensive Management of Head and Neck Tumors. 2nd ed. Philadelphia, Pa: WB Saunders, 1999. [PUBMED Abstract]
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-24. [PUBMED Abstract]
3. Pameijer FA, Mancuso AA, Mendenhall WM, et al.: Evaluation of pretreatment computed tomography as a predictor of local control in T1/T2 pyriform sinus carcinoma treated with definitive radiotherapy. Head Neck 20 (2): 159-68, 1998. [PUBMED Abstract]
4. Hinerman RW, Amdur RJ, Mendenhall WM, et al.: Hypopharyngeal carcinoma. Curr Treat Options Oncol 3 (1): 41-9, 2002. [PUBMED Abstract]
5. Mendenhall WM, Parsons JT, Stringer SP, et al.: Radiotherapy alone or combined with neck dissection for T1-T2 carcinoma of the pyriform sinus: an alternative to conservation surgery. Int J Radiat Oncol Biol Phys 27 (5): 1017-27, 1993. [PUBMED Abstract]
6. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80. [PUBMED Abstract]
7. Godballe C, Jírgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002. [PUBMED Abstract]
8. Johansen LV, Grau C, Overgaard J: Hypopharyngeal squamous cell carcinoma--treatment results in 138 consecutively admitted patients. Acta Oncol 39 (4): 529-36, 2000. [PUBMED Abstract]
9. Spector JG, Sessions DG, Emami B, et al.: Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope 105 (4 Pt 1): 397-406, 1995. [PUBMED Abstract]
10. Jones AS, Stell PM: Squamous carcinoma of the posterior pharyngeal wall. Clin Otolaryngol 16 (5): 462-5, 1991. [PUBMED Abstract]
11. Brizel DM, Albers ME, Fisher SR, et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338 (25): 1798-804, 1998. [PUBMED Abstract]
12. Samant S, Kumar P, Wan J, et al.: Concomitant radiation therapy and targeted cisplatin chemotherapy for the treatment of advanced pyriform sinus carcinoma: disease control and preservation of organ function. Head Neck 21 (7): 595-601, 1999. [PUBMED Abstract]
13. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
14. Lefebvre JL, Chevalier D, Luboinski B, et al.: 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 88 (13): 890-9, 1996. [PUBMED Abstract]
15. Kim S, Wu HG, Heo DS, et al.: Advanced hypopharyngeal carcinoma treatment results according to treatment modalities. Head Neck 23 (9): 713-7, 2001. [PUBMED Abstract]
16. Okamoto M, Takahashi H, Yao K, et al.: Clinical impact of using chemoradiotherapy as a primary treatment for hypopharyngeal cancer. Acta Otolaryngol Suppl (547): 11-4, 2002. [PUBMED Abstract]
17. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
18. Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 43 (1): 47-51, 1997. [PUBMED Abstract]
19. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
20. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
21. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]

Stage I Hypopharyngeal Cancer

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Except for the very early T1 cancers of this region, treatment has been primarily surgery, usually followed with postoperative radiation therapy. Because these tumors are clinically silent until they reach advanced stages, it is very unusual to diagnose them at the T1 N0 stage. In most available retrospective reviews, T1 N0 cases represent only 1% to 2% of all patients seen. In the case of exophytic T1 N0 lesions, radiation therapy alone may be considered for treatment. 1 2

Standard treatment options:

• Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers. In very selected cases of pyriform sinus cancers, that is, those arising in the upper lateral wall, a partial laryngopharyngectomy may be successfully used to preserve vocal function. All groups who use radiation advocate high-dose treatment to the primary site and to both sides of the neck to include the retropharyngeal and lateral cervical nodes. 1

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I hypopharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-24. [PUBMED Abstract]

Stage II Hypopharyngeal Cancer

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Treatment has been primarily surgery, which is usually followed with postoperative radiation therapy (PORT). Because these tumors are clinically silent until they reach advanced stages, it is very unusual to diagnose these tumors at the T2 N0 stage.

Standard treatment options:

1. Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers. In very selected cases of pyriform sinus cancers, that is, those arising in the upper medial wall, a partial laryngopharyngectomy may be successfully used to preserve vocal function. In T2 cases, PORT has been given in combination with surgery in an effort to improve the local control rates of surgery alone. There are advocates of preoperative radiation therapy, but all groups giving radiation advocate high-dose treatment to the primary site and to both sides of the neck to include the retropharyngeal and lateral cervical nodes. 1 2
2. Neoadjuvant chemotherapy, as given in clinical trials, has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. The chemotherapy is given prior to the other modalities, hence the designation, neoadjuvant, to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy. Neoadjuvant chemotherapy is commonly used to treat patients who present with advanced disease to improve locoregional control or survival, despite the lack of data from randomized, prospective trials. 3 The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial, referred to as the GORTEC-TREMPLIN trial (NCT00169247), the European Organization for the Research and Treatment of Cancer compared surgery plus PORT to neoadjuvant chemotherapy (i.e., cisplatin plus 5-fluorouracil) followed by radiation in responding patients. Local and regional failures were similar in both groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (P = .006), 5-year disease-free and overall survival were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who were receiving induction chemotherapy. These data have not been confirmed by other phase III trials but suggest that larynx preservation may be feasible without jeopardizing survival. 4[Level of evidence: 1iiA,1iiC]

   Most neoadjuvant chemotherapy clinical trials have included stage II hypopharyngeal carcinoma patients for the trials because of the low survival rates for this group of patients. 5

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II hypopharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-24. [PUBMED Abstract]
3. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15 (5): 2050-5, 1997. [PUBMED Abstract]
4. Lefebvre JL, Chevalier D, Luboinski B, et al.: 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 88 (13): 890-9, 1996. [PUBMED Abstract]
5. Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, et al.: Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. Int J Radiat Oncol Biol Phys 4 (7-8): 579-85, 1978 Jul-Aug. [PUBMED Abstract]

Stage III Hypopharyngeal Cancer

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The management of this group of patients is complex and requires multidisciplinary input to establish the optimal treatment regimen. New surgical techniques and reconstructions using the gastric pull-up operation or free jejunal transfers have greatly reduced the morbidity associated with resection of these tumors and have almost eliminated the need for multistage reconstructions. This has greatly aided the combined treatment regimens because these patients have a high likelihood of beginning postoperative radiation therapy (PORT) within 3 to 4 weeks following resection.

Details of surgical procedures and their modifications of radiation fields or dosage schedules are not specifically designated here because of legitimate variations in techniques that, according to various retrospective data, give similar survival results in different treatment centers. This group of patients should be managed by surgeons and radiation oncologists who are skilled in the multiple procedures and techniques available and who are actively and frequently involved in the care of these patients.

Standard treatment options:

1. The combination of surgery and radiation, most often postoperative as seen in a follow-up study of preoperative versus PORT (RTOG-7303), has become the usual form of therapy for this group of patients in the United States. 1 2 3
2. Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. Chemotherapy is given prior to the other modalities, hence the designation, neoadjuvant, to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy. Neoadjuvant chemotherapy is commonly used to treat patients who present with advanced disease to improve locoregional control or survival, despite the lack of data from randomized, prospective trials. 4 The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial, referred to as the GORTEC-TREMPLIN trial (NCT00169247), the European Organization for the Treatment and Research of Cancer compared surgery plus PORT to induction chemotherapy (i.e., cisplatin plus 5-fluorouracil [5-FU]) followed by radiation in responding patients. 5 Local and regional failures were similar in both groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (P = .006), 5-year disease-free and overall survival (OS) were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who were receiving induction chemotherapy. 5[Level of evidence: 1iiA,1iiC] In contrast to this, another randomized, prospective trial has demonstrated a statistically significant survival advantage for patients undergoing chemotherapy (i.e., cisplatin plus 5-FU) followed by laryngopharyngectomy and PORT when compared with chemotherapy and radiation therapy. 6[Level of evidence: 1iiA,1iiC] Although organ preservation was not discussed in this study, chemotherapy in combination with radiation therapy without surgery should not be considered standard.
3. Patients with stage III hypopharyngeal cancer should be considered for treatment with combined postoperative, adjuvant radiation therapy and chemotherapy. In a prospective, randomized trial, postoperative, adjuvant radiation therapy alone was compared with postoperative, adjuvant radiation therapy plus concurrent chemotherapy. Both the OS (P < .01) and the disease-free survival (P < .02) were better in the group of patients receiving radiation therapy plus concurrent chemotherapy. 7[Level of evidence:1iiA] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was administered concomitantly with radiation therapy. 8 9

To review treatment options for stage III unresectable hypopharyngeal cancer, see Stage IV Hypopharyngeal Cancer, Unresectable.

Treatment options under clinical evaluation: