Hypopharyngeal Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Hypopharyngeal Cancer

Epidemiology

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 people 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, current cases of hypopharyngeal cancer among women are more likely to be associated with excessive use of alcohol and tobacco, rather than with deficiency diseases.[2,9,10,11]

Anatomy

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.

Clinical Features

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 resulting from 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 high 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. 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 achieve larynx preservation without jeopardizing survival.[24]

Prognosis and Survival

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 when planning appropriate treatment.[1] The primary prognostic factors for hypopharyngeal SCC include:[1,25,26]

• Stage.
• Age.
• Performance status.

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

• Presentation at a late stage.
• Multisite involvement within the hypopharynx.
• Unrestricted soft-tissue tumor growth.
• An extensive regional lymphatic network conducive to 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]

Risk Factors

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.

Histopathology

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. Lippincott Williams & Wilkins, 2011, pp 729-80.
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.
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.
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.
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.
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.
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.
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.
9. Ahlbom HE: Simple achlorhydric anaemia, Plummer-Vinson syndrome, and carcinoma of the mouth, pharynx, and oesophagus in women: observations at Radiumhemmet, Stockholm. Br Med J 2 (3945): 331-3, 1936.
10. Larsson LG, Sandström 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.
11. Amos A: Women and smoking. Br Med Bull 52 (1): 74-89, 1996.
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.
13. Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003.
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.
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.
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.
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.
18. Horwitz SD, Caldarelli DD, Hendrickson FR: Treatment of carcinoma of the hypopharynx. Head Neck Surg 2 (2): 107-11, 1979 Nov-Dec.
19. Keane TJ: Carcinoma of the hypopharynx. J Otolaryngol 11 (4): 227-31, 1982.
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.
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.
22. Godballe C, Jørgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002.
23. Hinerman RW, Amdur RJ, Mendenhall WM, et al.: Hypopharyngeal carcinoma. Curr Treat Options Oncol 3 (1): 41-9, 2002.
24. Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012.
25. Jakobsen J, Hansen O, Jørgensen 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.
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.
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.
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.
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.
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.
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.
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.
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.

Cellular Classification of Hypopharyngeal Cancer

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:

• 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 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 histological 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. Mosby, 1996, pp 223-55.
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. Lippincott Williams & Wilkins, 2011, pp 729-80.
3. Ibrahim NB, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 54 (8): 1645-61, 1984.
4. Stanley RJ, Weiland LH, DeSanto LW, et al.: Lymphoepithelioma (undifferentiated carcinoma) of the laryngohypopharynx. Laryngoscope 95 (9 Pt 1): 1077-81, 1985.
5. McKay MJ, Bilous AM: Basaloid-squamous carcinoma of the hypopharynx. Cancer 63 (12): 2528-31, 1989.
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.
7. Olsen KD, Lewis JE, Suman VJ: Spindle cell carcinoma of the larynx and hypopharynx. Otolaryngol Head Neck Surg 116 (1): 47-52, 1997.
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.
9. Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003.
10. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug.

Stage Information for Hypopharyngeal Cancer

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 pathological 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.

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define hypopharyngeal cancer.[4]

Table 1. Definitions of Primary Tumor (T) for Hypopharyngeal Cancer^a

T Category	T Criteria
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
b Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.
TX	Primary tumor cannot be assessed.
Tis	Carcinomain situ.
T1	Tumor limited to one subsite of hypopharynx and/or ≤2 cm in greatest dimension.
T2	Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures >2 cm but ≤4 cm in greatest dimension without fixation of hemilarynx.
T3	Tumor >4 cm in greatest dimension or with fixation of hemilarynx or extension to esophageal mucosa.
T4	Moderately advanced and very advanced local disease.
‒T4a	Moderately advanced local disease. Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophageal muscle, or central compartment soft tissue.b
‒T4b	Very advanced local disease. Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures.

Table 2. Definitions of Regional Lymph Nodes (N) for Hypopharyngeal Cancer^a

N Category	Clinical N (cN) Criteria	Pathological N (pN) Criteria
ENE = extranodal extension.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(‒) or ENE(+).
NX	Regional lymph nodes cannot be assessed.	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.	No regional lymph node metastasis.
N1	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
N2	Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒);or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(‒);or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+);or>3 cm but ≤6 cm in greatest dimension and ENE(‒);or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(‒);or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
‒N2a	Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒).	Metastasis in single ipsilateral node ≤3 cm in greatest dimension and ENE(+);or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒).
‒N2b	Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(‒).	Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(‒).
‒N2c	Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).	Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
N3	Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒);or metastasis in any node(s) and clinically overt ENE(+).	Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒);or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+);or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+);or a single contralateral node of any size and ENE(+).
‒N3a	Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒).	Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒).
‒N3b	Metastasis in any node(s) and clinically overt ENE(+).	Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+);or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+);or a single contralateral node of any size and ENE(+).

Table 3. Definitions of Distant Metastasis (M)^a

M Category	M Criteria
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Definition of TNM Stage 0^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
0	Tis, N0, M0	Tis = Carcinomain situ.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 5. Definition of TNM Stage I^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
I	T1, N0, M0	T1 = Tumor limited to one subsite of hypopharynx and/or ≤2 cm in greatest dimension.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 6. Definition of TNM Stage II^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
II	T2, N0, M0	T2 = Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures >2 cm but ≤4 cm in greatest dimension without fixation of hemilarynx.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 7. Definitions of TNM Stage III^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis; ENE = extranodal extension.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
III	T3, N0, M0	T3 = Tumor >4 cm in greatest dimension or with fixation of hemilarynx or extension to esophageal mucosa.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.
III	T1, T2, T3, N1, M0	T1, T2, T3 = See Table1.
		N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
		M0 = No distant metastasis.

Table 8. Definitions of TNM Stage IV^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis; ENE = extranodal extension.
a Reprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
b Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.
IVA	T4a, N0, N1, M0	T4a = Moderately advanced local disease. Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophageal muscle, or central compartment soft tissue.b
		N0 = No regional lymph node metastasis.
		N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
		M0 = No distant metastasis.
IVA	T1, T2, T3, T4a, N2, M0	T1, T2, T3, T4a = See Table1.
		N2 = See Table2.
		M0 = No distant metastasis.
IVB	Any T, N3, M0	Any T = See Table1.
		N3 = See Table2.
		M0 = No distant metastasis.
IVB	T4b, Any N, M0	T4b = Very advanced local disease. Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures.
		Any N = See Table2.
		M0 = No distant metastasis.
IVC	Any T, Any N, M1	Any T = See Table1.
		Any N = See Table2.
		M1 = Distant metastasis.

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.
2. Becker M: Larynx and hypopharynx. Radiol Clin North Am 36 (5): 891-920, vi, 1998.
3. Keberle M, Kenn W, Hahn D: Current concepts in imaging of laryngeal and hypopharyngeal cancer. Eur Radiol 12 (7): 1672-83, 2002.
4. Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 123-35.

Treatment Option Overview for Hypopharyngeal Cancer

Hypopharyngeal cancer usually does not cause symptoms until late in the course of the disease. Coupled with 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 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 patient's general physical condition and emotional status, the experience of the treating team, and the available treatment facilities.[1,2]

Treatment Overview

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 therapy 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 with stage III or stage IV disease.[4,6,9,10] When used with surgery, radiation therapy is typically administered postoperatively. In selected advanced cases, alternative strategies using neoadjuvant chemotherapy and radiation therapy may increase the chance for local control as much as resection and PORT.[4]

A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[11,12]

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 when planning appropriate treatment.[6] Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not.[13] Consequently, patients should be counseled to stop smoking before beginning radiation therapy. 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 before therapy and as part of posttreatment follow-up.[14,15]

Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[16,17] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[16,17,18] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[19,20,21]DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[22] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[23]

References:

1. Thawley SE, Panje WR, Batsakis JG, et al., eds.: Comprehensive Management of Head and Neck Tumors. 2nd ed. WB Saunders, 1999.
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.
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.
4. Hinerman RW, Amdur RJ, Mendenhall WM, et al.: Hypopharyngeal carcinoma. Curr Treat Options Oncol 3 (1): 41-9, 2002.
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.
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. Lippincott Williams & Wilkins, 2011, pp 729-80.
7. Godballe C, Jørgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002.
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.
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.
10. Jones AS, Stell PM: Squamous carcinoma of the posterior pharyngeal wall. Clin Otolaryngol 16 (5): 462-5, 1991.
11. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992.
12. 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.
13. 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.
14. 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.
15. 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.
16. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021.
17. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016.
18. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021.
19. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018.
20. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018.
21. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022.
22. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022.
23. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023.

Treatment of Stage I Hypopharyngeal Cancer

Treatment Options for Stage I Hypopharyngeal Cancer

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.[1,2]

Treatment options for stage I hypopharyngeal cancer include:

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 lateral wall, a partial laryngopharyngectomy may be successfully used to preserve vocal function. All groups who use radiation therapy 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

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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.
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.

Treatment of Stage II Hypopharyngeal Cancer

Treatment Options for Stage II Hypopharyngeal Cancer

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.

Treatment options for stage II hypopharyngeal cancer include:

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 therapy 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 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 (GORTEC-TREMPLIN trial [NCT00169247]), the European Organisation for the Research and Treatment of Cancer compared surgery plus PORT with neoadjuvant chemotherapy (i.e., cisplatin plus fluorouracil) followed by radiation therapy 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 received 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 A1 and A3]

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

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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.
2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.
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.
4. Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012.
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.

Treatment of Stage III Hypopharyngeal Cancer

Treatment Options for Stage III Hypopharyngeal Cancer

The management of patients with stage III hypopharyngeal cancer 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 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.

Treatment options for stage III hypopharyngeal cancer include:

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 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 (GORTEC-TREMPLIN [NCT00169247]), the European Organisation for the Treatment and Research of Cancer compared surgery plus PORT with induction chemotherapy (i.e., cisplatin plus 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 survival (DFS) 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 received induction chemotherapy.[5][Level of evidence A1 and A3]

   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 A1 and A3] Although organ preservation was not discussed in this study, chemotherapy in combination with radiation therapy without surgery should not be considered standard treatment.

3. Patients with stage III hypopharyngeal cancer should consider 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 DFS (P < .02) were better in the group of patients receiving radiation therapy plus concurrent chemotherapy.[7][Level of evidence A1] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was administered concomitantly with radiation therapy.[8,9]

4. Chemotherapy combined with radiation therapy for patients with locally advanced disease (under clinical evaluation).[10,11,12]

   Concurrent chemotherapy is a standard treatment option for patients with locally advanced (stage III and stage IV) hypopharyngeal cancer. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients who received chemotherapy and radiation therapy.[13][Level of evidence B4] Patients who received concurrent chemotherapy had a greater survival benefit than those who received induction chemotherapy.

For more information about treatment options for stage III hypopharyngeal cancer, see the Treatment Options for Unresectable Stage IV Hypopharyngeal Cancer section.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51 (10): 1819-25, 1983.
2. 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.
3. Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991.
4. 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.
5. Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012.
6. Beauvillain C, Mahé M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107 (5): 648-53, 1997.
7. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 36 (5): 999-1004, 1996.
8. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.
9. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.
10. Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994.
11. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996.
12. 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.
13. Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009.

Treatment of Stage IV Hypopharyngeal Cancer

Treatment Options for Resectable Stage IV Hypopharyngeal Cancer

The management of patients with resectable hypopharyngeal cancer 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 within 3 to 4 weeks following resection.

Details of surgical procedures and 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.

Treatment options for resectable stage IV hypopharyngeal cancer include:

1. The combination of surgery and radiation, most often postoperative as seen in a follow-up study of preoperative versus postoperative radiation therapy (PORT) (RTOG-7303), has become the usual form of therapy for this group of patients in the United States.[1,2]
2. Neoadjuvant chemotherapy is commonly used to treat patients presenting 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 (GORTEC-TREMPLIN [NCT00169247]), the European Organisation for the Research and Treatment of Cancer compared surgery plus PORT with induction chemotherapy (i.e., cisplatin plus fluorouracil [5-FU]) followed by radiation in responding patients.[4] 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 survival (DFS) 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 received induction chemotherapy.[4][Level of evidence A1 and A3]

   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.[5][Level of evidence A1 and A3] Although organ preservation was not discussed, chemotherapy in combination with radiation therapy without surgery should not be considered standard treatment.

3. Patients with stage IV hypopharyngeal cancer should consider 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 DFS (P < .02) were better in the group of patients who received radiation therapy plus concurrent chemotherapy.[6][Level of evidence A1] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was given concomitantly with radiation therapy.[7,8]

Treatment Options for Unresectable Stage IV Hypopharyngeal Cancer

Treatment options for unresectable stage IV hypopharyngeal cancer include:

1. Radiation therapy.
2. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease.[9,10,11] In a randomized trial, the 3-year projected OS rate was 37% (P = .14) for patients with stage III or stage IV inoperable disease receiving single daily fractionated radiation with concurrent cisplatin.[11][Level of evidence A1]
3. Radiation therapy clinical trials evaluating hyperfractionation schedules may be considered with chemotherapy (under clinical evaluation).[12,13,14,15,16,17]

   Concurrent chemotherapy is a standard treatment option for patients with locally advanced (stage III and stage IV) hypopharyngeal cancer. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients who received chemotherapy and radiation therapy.[18][Level of evidence B4] Patients who received concurrent chemotherapy had a greater survival benefit than those who received induction chemotherapy.

Posttreatment follow-up for unresectable stage IV hypopharyngeal cancer

These patients should have a careful head and neck examination, looking for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months the third year, and every 6 months thereafter.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51 (10): 1819-25, 1983.
2. Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991.
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.
4. Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012.
5. Beauvillain C, Mahé M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107 (5): 648-53, 1997.
6. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 36 (5): 999-1004, 1996.
7. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.
8. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.
9. Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987.
10. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996.
11. Adelstein DJ, Li Y, Adams GL, et al.: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21 (1): 92-8, 2003.
12. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992.
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.
14. Staar S, Rudat V, Stuetzer H, et al.: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50 (5): 1161-71, 2001.
15. Wendt TG, Grabenbauer GG, Rödel CM, et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 16 (4): 1318-24, 1998.
16. 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.
17. Semrau R, Mueller RP, Stuetzer H, et al.: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 64 (5): 1308-16, 2006.
18. Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009.

Treatment of Metastatic and Recurrent Hypopharyngeal Cancer

Treatment Options for Metastatic and Recurrent Hypopharyngeal Cancer

Treatment options for metastatic and recurrent hypopharyngeal cancer include:

1. Surgical resection if radiation therapy fails and if technically feasible.[1]
2. Radiation therapy, if not previously used in curative doses that preclude further treatment, if surgery fails.
3. Surgical salvage, if technically feasible, when surgery fails.
4. Chemotherapy for metastatic disease.[2]
5. Immunotherapy.[3,4,5,6,7,8,9,10,11]
   • Pembrolizumab.
   • Nivolumab.
6. Clinical trials evaluating the use of chemotherapy should be considered.[12]

Immunotherapy

Pembrolizumab

Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death-1 (PD-1) pathway. Studies have evaluated pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (SCC).

Evidence (pembrolizumab as first-line therapy):

1. KEYNOTE-048 (NCT02358031) was a nonblinded, randomized, phase III study of participants with untreated locally incurable metastatic or recurrent head and neck SCC that was performed at 200 sites in 37 countries.[3] A total of 882 patients were randomly assigned in a 1:1:1 ratio to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (5-FU) (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and 5-FU (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the programmed death-ligand 1 (PD-L1) combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.

   The primary end points were overall survival (OS) and progression-free survival (PFS). Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.

   1. At the second interim analysis, pembrolizumab alone showed improved or noninferior OS compared with cetuximab with chemotherapy. The median OS results were reported as follows:[3][Level of evidence A1]
      • Among the population with a CPS of 20 or higher, the median OS was 14.9 months in patients who received pembrolizumab alone and 10.7 months in patients who received cetuximab with chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.45–0.83; P = .0007).
      • Among the population with a CPS of 1 or higher, the median OS was 12.3 months in patients who received pembrolizumab alone and 10.3 months in patients who received cetuximab with chemotherapy (HR, 0.78; 95% CI, 0.64–0.96; P = .0086).
      • Among the total population, patients who received pembrolizumab alone had noninferior OS (11.6 months) compared with patients who received cetuximab with chemotherapy (10.7 months) (HR, 0.85; 95% CI, 0.71–1.03; P = .0456).
   2. Pembrolizumab with chemotherapy showed improved OS versus cetuximab with chemotherapy. The OS results were reported as follows:
      • At the second interim analysis, among the total population, the median OS was 13.0 months in patients who received pembrolizumab with chemotherapy and 10.7 months in patients who received cetuximab with chemotherapy (HR, 0.77; 95% CI, 0.63–0.93; P = .0034).
      • At the final analysis, among the population with a CPS of 20 or higher, the median OS was 14.7 months in patients who received pembrolizumab with chemotherapy and 11.0 months in patients who received cetuximab with chemotherapy (HR, 0.60; 95% CI, 0.45–0.82; P = .0004).
      • At the final analysis, among the population with a CPS of 1 or higher, the median OS was 13.6 months in patients who received pembrolizumab with chemotherapy and 10.4 months in patients who received cetuximab with chemotherapy (HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
   3. At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
   4. At the final analysis, grade 3 or higher all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
   5. Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.

Pembrolizumab plus a platinum and 5-FU is an appropriate first-line treatment for patients with metastatic or recurrent head and neck SCC. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck SCC. These results were confirmed at a longer median follow-up of 45 months (interquartile range, 41.0–49.2).[9]

Evidence (pembrolizumab after progression on platinum-based treatment):

1. The phase III KEYNOTE-040 (NCT02252042) trial included patients with incurable metastatic or recurrent head and neck SCC who had received platinum-based treatment within 3 to 6 months.[4] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator's choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
   • The median OS was 8.4 months in the pembrolizumab arm and 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[4][Level of evidence A1]
   • Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
   • In patients who received pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified malignant progression. Two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
   • The PD-L1 CPS was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
   • Compared with patients treated with standard therapy, a reduced HR_death was noted for patients who received pembrolizumab and had PD-1 expression on their tumors or in the tumor microenvironment as noted by a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014).

Nivolumab

Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody.

Evidence (nivolumab combined with ipilimumab in patients who have not previously received systemic therapy):

1. The CheckMate 651 trial (NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab, cisplatin/carboplatin, and 5-FU for up to six cycles followed by cetuximab maintenance) in patients with recurrent or metastatic head and neck SCC.[5] The primary end points were OS in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher and PFS, objective response rate, and duration of response in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher.
   • Among all randomly assigned patients, there was no statistically significant difference in OS with nivolumab plus ipilimumab versus EXTREME (median OS, 13.9 vs. 13.5 months; HR, 0.95; 97.9% CI, 0.80–1.13; P = .4951). Among patients with a PD-L1 CPS of 20 or higher, there was also no statistically significant OS difference between the two treatments (median OS, 17.6 vs. 14.6 months; HR, 0.78; 97.51% CI, 0.59–1.03; P = .0469).[5][Level of evidence A1]
   • In patients with a CPS of 1 or higher, the median OS was 15.7 months for patients who received nivolumab plus ipilimumab versus 13.2 months for patients who received EXTREME (HR, 0.82; 95% CI, 0.69–0.97).
   • Among patients with a CPS of 20 or higher, the median PFS was 5.4 months for patients who received nivolumab plus ipilimumab and 7.0 months for patients who received EXTREME. The objective response rate was 34.1% for patients who received nivolumab plus ipilimumab and 36.0% for patients who received EXTREME.
   • Grade 3 or 4 treatment-related adverse events occurred in 28.2% of patients who received nivolumab plus ipilimumab and 70.7% of patients who received EXTREME.
   • CheckMate 651 did not meet its primary end points of OS in the randomly assigned or CPS of 20 or higher populations.

   The absence of a survival benefit for immune checkpoint inhibitors in this trial was an unexpected outcome, given the similarity of nivolumab to pembrolizumab in the studies of patients with cisplatin-refractory disease.[4,7] An editorial accompanying the CheckMate 651 trial analyzed some of the factors that may have contributed to a different result. The editorial suggested that survival in the control group, which was longer than that reported in prior studies, may have been impacted by the greater availability of second-line immunotherapy in the control group (46% in CheckMate 651 compared with 25% in the KEYNOTE-048 trial). The authors also suggested that the coadministration of ipilimumab detracted from the activity of nivolumab, as shown in the CheckMate 714 trial.[10]

2. CheckMate 714 (NCT02823574), a double-blind phase II trial, evaluated the clinical benefit of first-line nivolumab plus ipilimumab versus nivolumab alone in 425 patients with recurrent or metastatic head and neck SCC.[6] Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo. Treatment continued for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic disease. These were patients who had recurrent disease less than 6 months after completion of platinum-based chemotherapy (adjuvant or neoadjuvant, or as part of multimodal treatment [chemotherapy, surgery, and/or radiation therapy]). Among the 241 patients (56.7%) with platinum-refractory disease, 159 were assigned to receive nivolumab plus ipilimumab and 82 were assigned to receive nivolumab alone. Among the 184 patients (43.3%) with platinum-eligible disease, 123 were assigned to receive nivolumab plus ipilimumab and 61 were assigned to receive nivolumab alone.[6][Level of evidence B3]
   • At primary database lock, the objective response rate in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%–19.5%) with nivolumab plus ipilimumab and 18.3% (95% CI, 10.6%–28.4%) with nivolumab alone (odds ratio, 0.68; 95.5% CI, 0.33–1.43; P = .29).
   • The median duration of response was not reached (NR) in the nivolumab-plus-ipilimumab group (95% CI, 11.0 months–NR) and was 11.1 months (95% CI, 4.1–NR) in the nivolumab-alone group. In the population with platinum-eligible disease, the objective response rate was 20.3% (95% CI, 13.6%–28.5%) with nivolumab plus ipilimumab and 29.5% (95% CI, 18.5%–42.6%) with nivolumab alone.
   • Among the population with platinum-refractory disease, grade 3 or 4 treatment-related adverse events occurred in 25 of 158 patients (15.8%) who received nivolumab plus ipilimumab and in 12 of 82 patients (14.6%) who received nivolumab alone. Among the population with platinum-eligible disease, grade 3 or 4 treatment-related adverse events occurred in 30 of 122 patients (24.6%) who received nivolumab plus ipilimumab and in 8 of 61 patients (13.1%) who received nivolumab alone.
   • This trial did not meet its primary end point of objective response rate benefit with first-line nivolumab plus ipilimumab versus nivolumab alone in patients with platinum-refractory recurrent or metastatic head and neck SCC.

Evidence (nivolumab after progression on platinum-based treatment):

1. A phase III open-label trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was OS.[7]
   • The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was statistically significantly longer with nivolumab than with standard therapy (HR_death, 0.70; 97.73% CI, 0.51–0.96; P = .01). The estimated 1-year survival rate was approximately 19% higher in patients who received nivolumab (36.0%) than in those who received standard therapy (16.6%).[7][Level of evidence A1]
   • There was no statistically significant difference in median PFS between treatment groups. The 6-month PFS rate was 19.7% with nivolumab versus 9.9% with standard therapy.
   • The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
   • Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% of the patients in the standard therapy group.
   • Quality-of-life outcomes—including physical, role, and social functioning and pain, sensory, and social contact problems—were stable in the nivolumab group but worse in the standard therapy group. These outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35).
   • In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HR_death among patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83). In the subgroup of patients with a PD-L1 expression level lower than 1%, the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).
2. A randomized, phase III, superiority study in India evaluated the dose of immune checkpoint inhibitors in the setting of palliative care for patients with advanced head and neck cancer. Low-dose IV nivolumab (20 mg every 3 weeks) was added to a triple metronomic chemotherapy regimen of oral methotrexate (9 mg/m² once weekly), celecoxib (200 mg twice daily), and erlotinib (150 mg once daily). Notably, this nivolumab dose is less than 10% of the dose recommended by the U.S. Food and Drug Administration and the European Medicines Agency. A total of 151 patients were randomly assigned to receive either triple metronomic chemotherapy alone (n = 75) or triple metronomic chemotherapy with nivolumab (n = 76). The primary end point was 1-year OS.[8]
   • The addition of low-dose nivolumab to triple metronomic chemotherapy improved the 1-year OS rate from 16.3% (95% CI, 8.0%–27.4%) to 43.4% (95% CI, 30.8%–55.3%) (HR, 0.545; 95% CI, 0.362–0.820; P = .0036).[8][Level of evidence A1]
   • The median OS was 6.7 months (95% CI, 5.8–8.1) for patients who received triple metronomic chemotherapy alone and 10.1 months (95% CI, 7.4–12.6) for patients who received triple metronomic chemotherapy with nivolumab (P = .0052).
   • The rate of grade 3 or higher adverse events was 50% for patients who received triple metronomic chemotherapy alone and 46.1% for patients who received triple metronomic chemotherapy with nivolumab (P = .744).

   Although the control arm in this study cannot be considered standard care, lower doses of immunotherapy appeared to have some benefit in this setting.[11]

Posttreatment follow-up for metastatic and recurrent hypopharyngeal cancer

These patients should have a careful head and neck examination, looking for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months the third year, and every 6 months thereafter.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003.
2. Adelstein DJ, Tan EH, Lavertu P: Treatment of head and neck cancer: the role of chemotherapy. Crit Rev Oncol Hematol 24 (2): 97-116, 1996.
3. Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019.
4. Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019.
5. Haddad RI, Harrington K, Tahara M, et al.: Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol 41 (12): 2166-2180, 2023.
6. Harrington KJ, Ferris RL, Gillison M, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 9 (6): 779-789, 2023.
7. Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016.
8. Patil VM, Noronha V, Menon N, et al.: Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 41 (2): 222-232, 2023.
9. Harrington KJ, Burtness B, Greil R, et al.: Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol 41 (4): 790-802, 2023.
10. Burtness B: First-Line Nivolumab Plus Ipilimumab in Recurrent/Metastatic Head and Neck Cancer-What Happened? J Clin Oncol 41 (12): 2134-2137, 2023.
11. Mitchell AP, Goldstein DA: Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy. J Clin Oncol 41 (2): 170-172, 2023.
12. Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992.

Latest Updates to This Summary (11 / 22 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Metastatic and Recurrent Hypopharyngeal Cancer

Revised the list of treatment options for metastatic and recurrent hypopharyngeal cancer to include immunotherapy with pembrolizumab or nivolumab.

Added Immunotherapy as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult hypopharyngeal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Hypopharyngeal Cancer Treatment are:

• Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)
• Monaliben Patel, MD (University of Rochester Medical Center)
• Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Hypopharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/adult/hypopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389199]

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Last Revised: 2024-11-22